REFERENCIAS BIBLIOGRÁFICAS / BIBLIOGRAPHICAL REFERENCES

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1.) A 21-kDa surface protein of Mycobacterium leprae binds peripheral nerve laminin-2 and mediates Schwann cell invasion.

2.) Localization of Mycobacterium leprae to endothelial cells of epineurial and perineurial blood vessels and lymphatics.

3.) Delayed-type hypersensitivity to Mycobacterium leprae soluble antigens as a test for infection with the leprosy bacillus.

4.) Detection of M. leprae by gene amplification; combined ethidium-bromide staining and probe hybridization.

5.) In vitro and in vivo activity of K-130, a dihydrofolate reductase inhibitor, against Mycobacterium leprae.

6.) Secreted proteins of Mycobacterium leprae.

7.) In vitro studies on extracellular matrix production by M.leprae infected murine neurofibroblasts.

8.) Opposite effects of M. leprae or M. bovis BCG delipidation on cellular accumulation into mouse pleural cavity. Distinct accomplishment of mycobacterial lipids in vivo.

9.) Role of alpha-dystroglycan as a Schwann cell receptor for Mycobacterium leprae [see comments]

10.) Human T cell recognition of the Mycobacterium leprae LSR antigen: epitopes and HLA restriction.

11.) A Mycobacterium leprae-specific human T cell epitope cross-reactive with an HLA-DR2 peptide.

12.) Association of HLA antigens with differential responsiveness to Mycobacterium w vaccine in multibacillary leprosy patients.

13.) HLA antigens and neural reversal reactions in Ethiopian borderline tuberculoid leprosy patients.

14.) Evidence for an HLA-DR4-associated immune-response gene for Mycobacterium tuberculosis. A clue to the pathogenesis of rheumatoid arthritis?

15.) Species-specific identification of Mycobacterium leprae by PCR-restriction fragment length polymorphism analysis of the hsp65 gene.

16.) Use of a whole blood assay to evaluate in vitro T cell responses to new leprosy skin test antigens in leprosy patients and healthy subjects.

17.) Relapse of leprosy after multidrug therapy.

18.) Leprosy resistant to multi-drug-therapy (MDT) successfully treated with ampicillin-sulbactam combination--(a case report).

19.) Specificity and function of immunogenic peptides from the 35-kilodalton protein of

Mycobacterium leprae.

20.) [Morphological features to be considered as the growth of Mycobacterium leprae Thai-53 strain on a silicon coated slide in a cell-free liquid medium]

21.) Leprosy patients with lepromatous disease recognize cross-reactive T cell epitopes in the Mycobacterium leprae 10-kD antigen.

22.) Diaminodiphenylsulfone resistance of Mycobacterium leprae due to mutations in the dihydropteroate synthase gene.

23.) In vitro activity of epiroprim, a dihydrofolate reductase inhibitor, singly and in combination with brodimoprim and dapsone, against Mycobacterium leprae.

24.) Lymphoproliferative responses of leprosy patients and healthy controls to nitrocellulose-bound M. leprae antigens.

25.) Dominant recognition of a cross-reactive B-cell epitope in Mycobacterium leprae 10 K antigen by immunoglobulin G1 antibodies across the disease spectrum in

leprosy.

26.) Immune responses to recombinant proteins of Mycobacterium leprae.

27.) Causative organism and host response. International Leprosy Congress,

28.) Immunohistological analysis of in situ expression of mycobacterial antigensin skin lesions of leprosy patients across the histopathological spectrum.Association of Mycobacterial lipoarabinomannan (LAM) and Mycobacterium leprae phenolic glycolipid-I (PGL-I) with leprosy reactions.

29.) IL-18 promotes type 1 cytokine production from NK cells and T cells in human intracellular infection.

30.) Identification of M.leprae in conjunctiva of leprosy patients using the superior tarsal conjunctiva scrape technique.

31.) [Present situation of leprosy in highly endemic area of tropical Asia--a seroepidemiological study of Mycobacterium leprae infection in general inhabitants]

32.) Anti M. leprae IgM antibody determination by ultramicroimmunoenzymatic (UMELISA HANSEN) for the diagnosis and monitoring leprosy.

33.) Opposite cellular accumulation and nitric oxide production in vivo after pleural immunization with M. leprae or M. bovis BCG.

34.) Use of a whole blood assay to monitor the immune response to mycobacterial antigens in leprosy patients: a predictor for type 1 reaction onset?

35.) A clinical and bacteriological examination of Mycobacterium leprae in the epidermis and cutaneous appendages of patients with multibacillary leprosy.

36.) Quality control tests for vaccines in leprosy vaccine trial, Avadi.

37.) Comparative leprosy vaccine trial in south India.

38.) Evolutionary bottlenecks in the agents of tuberculosis, leprosy, and paratuberculosis.

39.) Role of S-100 staining in differentiating leprosy from other granulomatous diseases of the skin.

40.) Assessment of anti-PGL-I as a prognostic marker of leprosy reaction.

41.) Conjunctival biopsy in patients with leprosy.

42.) Experimental leprosy in rhesus monkeys: transmission, susceptibility, clinical and immunological findings.

43.) Lepromatous uveitis diagnosed by iris biopsy.

44.) Preservation of Mycobacterium leprae in vitro for four years by lyophilization.

45.) Minocycline in lepromatous leprosy.

46.) Efficacy of minocycline in single dose and at 100 mg twice daily for lepromatous leprosy.

47.) Field trial on efficacy of supervised monthly dose of 600 mg rifampin, 400 mg ofloxacin and 100 mg minocycline for the treatment of leprosy; first results.

48.) Bactericidal activity of a single-dose combination of ofloxacin plus minocycline, with or without rifampin, against Mycobacterium leprae in mice and in lepromatous patients.

49.) Efficacy of single dose multidrug therapy for the treatment of single-lesion paucibacillary leprosy. Single-lesion Multicentre Trial Group.

50.) Bactericidal activity of single dose of clarithromycin plus inocycline, with or without ofloxacin, against Mycobacterium leprae in patients.

51.) WHO Expert Committee on Leprosy.

52.) Experimental evaluation of possible new short-term drug regimens for treatment of multibacillary leprosy.

53.) Powerful bactericidal activities of clarithromycin and minocycline against Mycobacterium leprae in lepromatous leprosy.

54.) Differential protective effect of bacillus calmette-guerin vaccine against multibacillary and paucibacillary leprosy in nagpur, india.

55.) An immunotherapeutic vaccine for multibacillary leprosy.

56.) Protective effect of Bacillus Calmette Guerin (BCG) against leprosy: a population-based case-control study in Nagpur, India.

57.) The antigen 85 complex vaccine against experimental Mycobacterium leprae infection in mice.

58.) Induction of lepromin positivity following immuno-chemotherapy with Mycobacterium w vaccine and multidrug therapy and its impact on  bacteriological clearance in multibacillary leprosy: report on a hospital-based clinical trial with the candidate antileprosy vaccine.

59.) Disabilities in multibacillary leprosy following multidrug therapy with and without immunotherapy with Mycobacterium w antileprosy vaccine.

60.) SIMLEP: a simulation model for leprosy transmission and control.

61.) Antigenic definition of plasma membrane proteins of BacillusCalmette-Guerin: predominant activation of human T cells by low-molecular-mass integral proteins.

62.) A lost talisman: catastrophic decline in yields of leprosy bacilli from armadillos used for vaccine production.

63.) HLA-DRB1 leprogenic motifs in nigerian population groups.

64.) Testing candidate genes that may affect susceptibility to leprosy.

65.) [Leprosy, an "exemplary" humanitarian disease]?

66.) Prediction of elimination of leprosy in leprosy endemic areas of China.

67.)[Global leprosy, current status and a future outlook].

68.) Lot quality assurance sampling (LQAS) for monitoring a leprosy elimination program.

69.) Patient contact is the major determinant in incident leprosy: implications for future control.

70.) A continuing focus of Hansen's disease in Texas.

71.) An epidemiological study on Mycobacterium leprae infection and prevalence of leprosy in endemic villages by molecular biological technique.

72.) Antimycobacterial activities of riminophenazines.

73.) Nasal mucosa and skin of smear-positive leprosy patients after 24 months of fixed duration MDT: histopathological and microbiological study.

74.) Resolution of lepromatous leprosy after a short course of amoxicillin/clavulanic acid, followed by ofloxacin and clofazimine.

75.) Effect of zafirlukast on leprosy reactions.

76.) Immunochemotherapy with interferon-gamma and multidrug therapy for multibacillary leprosy.

77.) Thalidomide's effectiveness in erythema nodosum leprosum is associated with a decrease in CD4+ cells in the peripheral blood.

78.) La lepra, Evolucion Historia, epidemiologica y medidas de control.

79.) Leprosy in infants.

80.) Leprosy in a child of less than two months of age.

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1.) A 21-kDa surface protein of Mycobacterium leprae binds peripheral nerve

laminin-2 and mediates Schwann cell invasion.

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Author

Shimoji Y; Ng V; Matsumura K; Fischetti VA; Rambukkana A Address

Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, NY 10021, USA.

Source

Proc Natl Acad Sci U S A, 96(17):9857-62 1999 Aug 17

Abstract Nerve damage is the hallmark of Mycobacterium leprae infection, which results from M. leprae invasion of the Schwann cell of the peripheral nervous system. We have recently shown that the laminin-2 isoform, specially the G domain of laminin alpha2 chain, on the Schwann cell-axon unit serves as an initial neural target for M. leprae. However, M. leprae surface molecules that mediate bacterial invasion of peripheral nerves are entirely unknown. By using human alpha2 laminins as a probe, a major 28-kDa protein in the M. leprae cell wall fraction that binds alpha2 laminins was identified. After N-terminal amino acid sequence analysis, PCR-based strategy was used to clone the gene that encodes this protein.

Deduced amino acid sequence of this M. leprae laminin-binding protein predicts a 21-kDa molecule (ML-LBP21), which is smaller than the observed molecular size in SDS/PAGE. Immunofluorescence and immunoelectron microscopy on intact M. leprae with mAbs against recombinant (r) ML-LBP21 revealed that the protein is surface exposed. rML-LBP21 avidly bound to alpha2 laminins, the rG domain of the laminin-alpha2 chain, and the native peripheral nerve laminin-2. The role of ML-LBP21 in Schwann cell adhesion and invasion was investigated by using fluorescent polystyrene beads coated with rML-LBP21. Although beads coated with rML-LBP21 alone specifically adhered to and were ingested by primary Schwann cells, these functions were significantly enhanced when beads were preincubated with exogenous alpha2 laminins. Taken together, the present data suggest that ML-LBP21 may function as a critical surface adhesin that facilitates the entry of M. leprae into Schwann cells.

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2.) Localization of Mycobacterium leprae to endothelial cells of epineurial and perineurial blood vessels and lymphatics.

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Author

Scollard DM; McCormick G; Allen JL

Address

Department of Research Pathology, G. W. L. Hansen's Disease Center at Louisiana State University, Baton Rouge, LA, USA. dscoll1@lsu.edu

Source

Am J Pathol, 154(5):1611-20 1999 May

Abstract

Infection of peripheral nerve by Mycobacterium leprae, the histopathological hallmark of leprosy, is a major factor in this disease, but the route and mechanisms by which bacilli localize to peripheral nerve are unknown. Experimentally infected armadillos have recently been recognized as a model of lepromatous neuritis; the major site of early accumulation of M. leprae is epineurial. To determine the epineurial cells involved, 1-cm segments of 44 nerves from armadillos were screened for acid-fast bacilli and thin sections were examined ultrastructurally. Of 596 blocks containing nerve, 36% contained acid-fast bacilli. Overall, M. leprae were found in endothelial cells in 40% of epineurial blood vessels and 75% of lymphatics, and in 25% of vessels intraneurally. Comparison of epineurial and endoneurial findings suggested that colonization of epineurial vessels preceded endoneurial infection. Such colonization of epineurial nutrient vessels may greatly increase the risk of endoneurial M. leprae bacteremia, and also enhance the risk of ischemia following even mild increases in inflammation or mechanical stress. These findings also raise the possibility that early, specific mechanisms in the localization of M. leprae to peripheral nerve may involve adhesion events between M. leprae (or M. leprae-parasitized macrophages) and the endothelial cells of the vasa nervorum.

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3.) Delayed-type hypersensitivity to Mycobacterium leprae soluble antigens as a test for infection with the leprosy bacillus.

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Author

Sterne JA; Fine PE; P¨onnighaus JM; Rees RJ; Chavula D

Address

Department of Public Health Medicine, United Medical and Dental Schools of Guy's and St Thomas's Hospitals, London, UK.

Source

Int J Epidemiol, 27(4):713-21 1998 Aug

Abstract

BACKGROUND: Mycobacterium leprae (M. leprae) soluble antigen (MLSA) reagents have been developed with the aim of finding a reagent, comparable to tuberculin, which could identify individuals infected with the leprosy bacillus. They have yet to be evaluated fully in human populations.

METHODS: More than 15000 individuals living in a leprosy endemic area of northern Malawi were skin tested with one of five batches of MLSA prepared using two different protocols. The main difference in preparation was the introduction of a high G centrifugation step in the preparation of the last three ('second-generation') batches. RESULTS: The prevalence of skin-test positivity (delayed-type hypersensitivity (DTH)) and association with the presence of a BCG scar were greater for first (batches A6, A22) than second (batches AB53, CD5, CD19) generation reagents.

The association of positivity with M. leprae infection was investigated by comparing results among known (household) contacts of leprosy cases, and among newly diagnosed leprosy patients with those in the general population. While positivity to 'first-generation' antigens appeared to be associated with M. leprae infection, positivity to later antigens was unrelated either to exposure to leprosy cases or presence of leprosy disease. There were geographical differences in the prevalence of DTH to the various batches, probably reflecting exposure to various mycobacteria in the environment.

CONCLUSIONS: Our results suggest that the 'second-generation' batches have lost antigens that can detect M. leprae infections, but that they retain one or more antigens which are shared between M. leprae and environmental mycobacteria. Natural exposure to these both sensitizes individuals and provides natural protection against M. leprae infection or disease. Identification of antigens present in these groups of skin test reagents may assist in production of improved skin test reagents.

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4.) Detection of M. leprae by gene amplification; combined ethidium-bromide staining and probe hybridization.

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Sharma RK; Katoch K; Shivannavar CT; Sharma VD; Natrajan M; Bhatia AS; Saxena N; Katoch VM

Central JALMA Institute for Leprosy (ICMR), Taj Ganj, Agra, India.

Int J Lepr Other Mycobact Dis (UNITED STATES) Dec 1996 64 (4) p409-16

ISSN: 0148-916X Language: ENGLISH

Document Type: JOURNAL ARTICLE

Journal Announcement: 9705

Subfile: INDEX MEDICUS Biopsy and skin-scraping specimens from 130 leprosy cases across the disease spectrum (56 TT/BT/I, 73 BB/BL/LL, and 1 neuritic case) and 50 healthy contacts were studied to assess the application of gene amplification. The nucleic acids from these clinical specimens were extracted by an integrated freeze-thawing-optimized lysozyme-/proteinase-k treatment-purification and fractionation procedure. The nucleic acids from cultured organisms were isolated by the stepwise procedure earlier standardized at this laboratory. Gene amplification for a 360-bp fragment of the 18-kDa protein gene was carried out using primer and the procedure described by its developers, and a 360-bp fragment on Southern blot was taken as the yardstick of positivity. The polymerase chain reaction product was analyzed by electrophoresis, ethidium-bromide (EB) staining, and blot (B) hybridization. Overall sensitivity ranged from 71% in specimens with undetectable acid-fast organisms to 100% in specimens with demonstrable acid-fast bacilli. A positivity of 73% in TT/BT/I specimens and 93% in BB/BL/LL specimens was observed. Four combinations were discerned: EB+, B+ (71%); EB-suspicious, B+ (14%); EB-, B+ (3%) and EB-, B- (12%). By combining the blot hybridization with EB staining, the sensitivity could be significantly improved as compared to EB staining alone. The test was found to be absolutely specific by the absence of any false positivity in control specimens as well as with purified DNAs from mycobacterial as well as non-mycobacterial organisms, grown from these specimens. It is recommended that for optimum sensitivity and specificity both EB staining and blot hybridization should be done.

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5.) In vitro and in vivo activity of K-130, a dihydrofolate reductase

inhibitor, against Mycobacterium leprae.

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Author

Dhople AM

Address Florida Institute of Technology, Department of Biological Sciences, Melbourne, USA.

Source Arzneimittelforschung, 49(3):267-71 1999 Mar

Abstract

The antimicrobial effects of a new dihydrofolate reductase inhibitor, K-130

(2,4-diaminodiphenyl sulfone substituted 2,4-diamino-5-benzylpyrimidine), alone and in combination with dapsone (CAS 80-08-0) against both dapsone-sensitive and dapsone-resistant strains of Mycobacterium leprae were evaluated in vitro, in cell-free culture system, and in vivo, in mouse foot pads. The minimal inhibitory concentration of K-130 against dapsone-sensitive as well as dapsone resistant strains of M, leprae was 0.03 microgram/ml, and the activity was bactericidal in both cases. However, when combined with dapsone, K-130 exhibited synergism in case of dapsone-sensitive M. leprae, while in case of dapsone-resistant M. leprae, the effect was merely additive. Similar synergistic effects were also observed in the mouse foot pad system for both types of M. leprae strains.

============================================================ 6.) Secreted proteins of Mycobacterium leprae.

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Author

Harboe M; Wiker HG

Address Institute of Immunology and Rheumatology, University of Oslo, Norway.

Source Scand J Immunol, 48(6):577-84 1998 Dec

Abstract In mycobacteria, secreted proteins represent a distinct group, probably of particular importance for development of immune responses following infection. Quantification of individual proteins in culture fluid and corresponding disrupted bacilli permits determination of a localization index for identification of secreted proteins. This procedure cannot be applied to Mycobacterium leprae because secreted proteins are lost during isolation of bacilli from tissues. The DNA sequences of secreted proteins of Mycobacterium tuberculosis were compared with sequences of M. leprae. Genes for homologues of the 85a, 85b, 85c, mpt32 (apa), mpt51, erp, mtc28, Rv2376c, Rv3354 and Rv0526 genes were identified. All of these contain signal sequences typical for secretion in M. leprae. In several instances the local distance between marker genes and occurrence on the same or the complementary DNA strand was similar in these two species. The genomic organisation of genes for secreted proteins is thus very similar in M. leprae and M. tuberculosis, the homology being higher for the mature polypeptide chains than for the corresponding signal peptides.

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7.) In vitro studies on extracellular matrix production by M.leprae infected murine neurofibroblasts.

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Author Singh N; Birdi TJ; Chandrashekar S; Antia NH

Address Foundation for Medical Research, R.G. Thadani Marg, Bombay, India.

Source Lepr Rev, 69(3):246-56 1998 Sep

Abstract

Fibroblasts and a host of macrophage secretory products have been implicated in a number of diseases where excess extracellular matrix (ECM) deposition is the main pathological feature. Fibrosis characterized by excessive deposition of collagen also contributes to the irreversible nerve damage observed in leprosy. Since M. leprae are seen within neurofibroblasts (Nf) in the advanced stages of the disease and macrophages form a common infiltrating cellular constituent of leprous nerves at all stages, secretion of ECM proteins by Nf was studied, in vitro following infection with M. leprae and in the presence of macrophage secretory products. These studies were compared in cells derived from two strains of mice, Swiss White (SW) and C57BL/6, as they differ in their response to M. leprae infection and parallel those observed in lepromatous and tuberculoid patients, respectively. On infection with M. leprae, Nfs showed a decrease in secretion of collagen type IV in SW and type I in C57Bl/6 strain. Macrophages caused a further decrease in the secretion of collagen types affected by M. leprae infection per se, while the other collagen types, viz. I and III in SW strain and III and IV in C57Bl/s strain, were unaffected. This study indicates that neural collagenization in nerves in advanced leprosy may be of Nf origin. However, unlike other diseases with excess collagen deposition, ECM proteins produced by Nfs in response to nerve damage may not be of prime importance in the progression of leprous neuropathy and occur as a general response to loss of cellular content in leprous nerves.

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8.) Opposite effects of M. leprae or M. bovis BCG delipidation on cellular accumulation into mouse pleural cavity. Distinct accomplishment of mycobacterial lipids in vivo.

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Author Moura AC; Leonardo PS; Henriques MG; Cordeiro RS

Address Departmento de Biologia Celular e Gen´etica, Instituto de Biologia,

Universidade do Rio de Janeiro, Brazil. cmoura@uerj.br

Source Inflamm Res, 48(6):308-13 1999 Jun

Abstract OBJECTIVES AND DESIGN: The effect of mycobacterial lipids on the onset of the early acute inflammatory response in BALB/c mice pleurisy was investigated.

MATERIALS AND METHODS: Intact Mycobacterium leprae and Mycobacterium bovis BCG (BCG), their lipids, and delipidated mycobacteria were used to evaluate total leukocytes and cell types migrated to the pleural cavity (8 animals/experimental group). RESULTS: BCG Moreau (x10(-6)/cavity), delipidated BCG and its lipids gradually recruited cells leading to arrival, respectively, of neutrophils (7.8+/-1.9, 4.7+/-0.9, 1.8+/-0.25) followed by mononuclear cells (4.8+/-0.8, 3.7+/-0.7, 2.45+/-0.22) and eosinophils (0.39+/-0.08, 0.32+/-0.11, 0.41+/-0.65). BCG delipidation decreased the number of migrated total leukocytes (ANOVA, and Newman-Keuls-Student-test), whereas M. leprae delipidation accumulated neutrophils (0.85+/-0.01) and eosinophils (1.65+/-0.18).

CONCLUSIONS: Intact M. leprae and its lipids did not incite any cell recruitment. Apolar external cell wall lipids from M. leprae and BCG induce different cellular responses. They seem to have a crucial importance at the first contact of mycobacteria with the host cell, modulating the influx of neutrophils/macrophages in the early (4/24 h) onset of the inflammatory reaction.

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9.) Role of alpha-dystroglycan as a Schwann cell receptor for Mycobacterium leprae [see comments]

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Author Rambukkana A; Yamada H; Zanazzi G; Mathus T; Salzer JL; Yurchenco PD; Campbell KP; Fischetti VA

Address Laboratory of Bacterial Pathogenesis and Immunology, Rockefeller

University, New York, NY 10021, USA. rambuka@rockvax.rockefeller.edu

Source Science, 282(5396):2076-9 1998 Dec 11

Abstract

alpha-Dystroglycan (alpha-DG) is a component of the dystroglycan complex, which is involved in early development and morphogenesis and in the pathogenesis of muscular dystrophies. Here, alpha-DG was shown to serve as a Schwann cell receptor for Mycobacterium leprae, the causative organism of leprosy. Mycobacterium leprae specifically bound to alpha-DG only in the presence of the G domain of the alpha2 chain of laminin-2. Native alpha-DG competitively inhibited the laminin-2-mediated M. leprae binding to primary Schwann cells. Thus, M. leprae may use inkage between the extracellular matrix and cytoskeleton through laminin-2 and alpha-DG for its interaction with Schwann cells.

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10.) Human T cell recognition of the Mycobacterium leprae LSR antigen:

epitopes and HLA restriction.

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Author

Oftung F; Lundin KE; Meloen R; Mustafa AS

Address

Department of Vaccinology, National Institute of Public Health, Oslo,

Norway. frederik.oftung@folkehelsa.no

Source

FEMS Immunol Med Microbiol, 24(2):151-9 1999 Jun

Abstract

We have in this work mapped epitopes and HLA molecules used in human T cell recognition of the Mycobacterium leprae LSR protein antigen. HLA typed healthy subjects immunized with heat killed M. leprae were used as donors to establish antigen reactive CD4+ T cell lines which were screened for proliferative responses against overlapping synthetic peptides covering the C-terminal part of the antigen sequence. By using this approach we were able to identify two epitope regions represented by peptide 2 (aa 29-40) and peptide 6 (aa 49-60), of which the former was mapped in detail by defining the N- and C-terminal amino acid positions necessary for T cell recognition of the core epitope. MHC restriction analysis showed that peptide 2 was presented to T cells by allogeneic cells coexpressing HLA-DR4 and DRw53 or DR7 and DRw53. In contrast, peptide 6 was presented to T cells only in the context of HLA-DR5 molecules. In conclusion, the M. leprae LSR protein antigen can be recognized by human T cells in the context of multiple HLA-DR molecules, of which none are reported to be associated with the susceptibility to develop leprosy. The results obtained are in support of using the LSR antigen in subunit vaccine design.

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11.) A Mycobacterium leprae-specific human T cell epitope cross-reactive with an HLA-DR2 peptide.

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ARTICLE SOURCE: Science (United States), Oct 14 1988, 242(4876) p259-61

AUTHOR(S): Anderson DC; van Schooten WC; Barry ME; Janson AA; Buchanan

TM;

de Vries RR

PUBLICATION TYPE: JOURNAL ARTICLE

ABSTRACT: Mycobacterium leprae induces T cell reactivity and protective immunity in the majority of exposed individuals, but the minority that develop leprosy exhibit various types of immunopathology. Thus, the definition of epitopes on M. leprae antigens that are recognized by T cells from different individuals might result in the development of an effective vaccine against leprosy. A sequence from the 65-kD protein of this organism was recognized by two HLA-DR2-restricted, M. leprae-specific helper T cell clones that were derived from a tuberculoid leprosy patient. Synthetic peptides were used to define this epitope as Leu-Gln-Ala-Ala-Pro-Ala-Leu-Asp-Lys-Leu. A similar peptide that was derived from the third hypervariable region of the HLA-DR2 chain, Glu-Gln-Ala-Arg-Ala-Ala-Val-Asp-Thr-Tyr, also activated the same clones. The unexpected cross-reactivity of this M. leprae-specific DR2-restricted T cell epitope with a DR2 peptide may have to be considered in the design of subunit

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12.) Association of HLA antigens with differential responsiveness to Mycobacterium w vaccine in multibacillary leprosy patients.

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ARTICLE SOURCE: J Clin Immunol (United States), Jan 1992, 12(1) p50-5

AUTHOR(S): Rani R; Zaheer SA; Suresh NR; Walia R; Parida SK; Mukherjee A; Mukherjee R; Talwar GP

PUBLICATION TYPE: JOURNAL ARTICLE

ABSTRACT: Leprosy patients undergoing phase II trials in two hospitals of New Delhi, India, were HLA typed to see the association of HLA with differential responsiveness to Mycobacterium w vaccine. The vaccine comprises an atypical, nonpathogenic mycobacterium, Mycobacterium w, which has cross-reactive antigens with M. leprae. Multibacillary patients who are lepromin negative are vaccinated at an interval of 3 months. Considerable improvement is evident in the patients in terms of a decline in bacterial indices and histopathological and immunological upgrading. But all the patients do not respond to the vaccine in the same manner; some are slow responders, while others are good responders. HLA-A28 and DQw3 (DQw8 + 9) were found to be associated with slow responsiveness, while DQw1 and DQw7 were found to be associated with a more rapid responsiveness to the M. w vaccine. However, these associations were not significant after P correction for the number of antigens tested for each locus except for HLA-DQw3 (DQw8 and DQw9) and DQw7. DQw7, a new defined split of HLA-DQw3, seems to be associated with the responsiveness to M. w vaccine.

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13.) HLA antigens and neural reversal reactions in Ethiopian borderline tuberculoid leprosy patients.

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ARTICLE SOURCE: Int J Lepr Other Mycobact Dis (United States), Jun 1987,

55(2) p261-6

AUTHOR(S): Ottenhoff TH; Converse PJ; Bjune G; de Vries RR

PUBLICATION TYPE: JOURNAL ARTICLE

ABSTRACT: Reversal reactions (RR) or acute neuritis episodes are frequently observed in borderline tuberculoid (BT) leprosy patients during the first year of treatment, and are associated with a rapid increase in cell-mediated immunity. Because HLA-linked genes have been shown to be an important factor in determining the type of leprosy that develops in susceptible individuals and because HLA molecules regulate cellular interactions in the immune system, we have investigated whether RR are associated with HLA antigens in Ethiopian patients. The data reported here indicate that this is not the case: no significant differences in the distribution of HLA class I and class II antigens were observed among three groups: 28 BT patients with a history of RR, 27 BT patients with no history of RR, and 33 healthy individuals. In contrast to these negative results, we observed that HLA-DR3 was associated with high skin-test responsiveness against Mycobacterium leprae antigens among RR patients. Since DR3 was not associated with RR per se, the observed DR3-associated high responsiveness to M. leprae may not be primarily

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14.) Evidence for an HLA-DR4-associated immune-response gene for Mycobacterium tuberculosis. A clue to the pathogenesis of rheumatoid arthritis?

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ARTICLE SOURCE: Lancet (England), Aug 9 1986, 2(8502) p310-3

AUTHOR(S): Ottenhoff TH; Torres P; de las Aguas JT; Fernandez R; van Eden W; de Vries RR; Stanford JL

PUBLICATION TYPE: JOURNAL ARTICLE

ABSTRACT: Antigens of Mycobacterium tuberculosis, M leprae, M scrofulaceum, and M vaccae were injected intradermally in 86 caucasoid leprosy patients, and skin responses (measured in mm of induration at 72 h) were analysed in relation to HLA class II phenotypes. HLA-DR4 was associated with high responsiveness to antigens specific to M tuberculosis but not to antigens shared with other mycobacteria (p = 0.0005). Because DR4 is associated with rheumatoid arthritis (RA) and because a role for M tuberculosis antigens has been suggested both in experimentally induced autoimmune arthritis in rats and in RA, the DR4 associated regulation of the immune response to M tuberculosis may be relevant to the pathogenesis of RA.

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15.) Species-specific identification of Mycobacterium leprae by PCR-restriction fragment length polymorphism analysis of the hsp65 gene.

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Author Rastogi N; Goh KS; Berchel M

Address Unit´e de la Tuberculose et des Mycobact´eries, Institut Pasteur, 97165 Pointe `a Pitre Cedex, Guadeloupe. rastogi@ipagua.gp

Source J Clin Microbiol, 37(6):2016-9 1999 Jun

Abstract

PCR-restriction fragment length polymorphism analysis (PRA) of the hsp65 gene present in all mycobacteria was used in the present investigation to characterize Mycobacterium leprae. Bacilli were extracted and purified from different organs from experimentally infected armadillos and nude mice (Swiss mice of nu/nu origin). A total of 15 samples were assayed in duplicate, and the results were compared with those obtained for a total of 147 cultivable mycobacteria representing 34 species. Irrespective of its origin or viability, M. leprae strains from all the samples were uniformly characterized by two fragments of 315 and 135 bp upon BstEII digestion and two fragments of 265 and 130 bp upon HaeIII digestion. PRA is a relatively simple method and permits the conclusive identification of M. leprae to the species level.

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16.) Use of a whole blood assay to evaluate in vitro T cell responses to new leprosy skin test antigens in leprosy patients and healthy subjects.

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Author Weir RE; Brennan PJ; Butlin CR; Dockrell HM

Address Department of Infectious and Tropical Diseases, London School of Hygiene &

Tropical Medicine, London, UK. r.weir@lshtm.ac.uk

Source Clin Exp Immunol, 116(2):263-9 1999 May

Abstract

Development of an immunological tool to detect infection with Mycobacterium leprae would greatly benefit leprosy control programmes, as demonstrated by the contribution of the tuberculin test to tuberculosis control. In a new approach to develop a 'tuberculin-like' reagent for use in leprosy, two new fractions of M. leprae depleted of cross-reactive and immunomodulatory lipids- MLSA-LAM (cytosol-derived) and MLCwA (cell wall-derived)-have been produced in a form suitable for use as skin test reagents. T cell responses (interferon-gamma (IFN-gamma) and lymphoproliferation) to these two new fractions were evaluated in a leprosy-endemic area of Nepal using a simple in vitro whole blood test. The two fractions were shown to be highly potent T cell antigens in subjects exposed to M. leprae-paucibacillary leprosy patients and household contacts. Responses to the fractions decreased towards the lepromatous pole of leprosy. Endemic control subjects also showed high responses to the fractions, indicating high exposure to M. leprae, or cross-reactive mycobacterial antigens, in this Nepali population. The new fractions, depleted of lipids and lipoarabinomannan (LAM) gave enhanced responses compared with a standard M. leprae sonicate. The cell wall fraction appeared a more potent antigen than the cytosol fraction, which may be due to the predominance of the 65-kD GroEL antigen in the cell wall. The whole blood assay proved a robust field tool and a useful way of evaluating such reagents prior to clinical trials.

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17.) Relapse of leprosy after multidrug therapy.

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Dasananjali K

Department of Communicable Disease Control, Ministry of Public Health, Nonthaburi, Thailand.

J Med Assoc Thai (THAILAND) Oct 1996 79 (10) p635-9 ISSN: 0125-2208

Language: ENGLISH

Document Type: JOURNAL ARTICLE

Journal Announcement: 9704 Subfile:

INDEX MEDICUS Relapse of leprosy after multidrug therapy among leprosy patients treated at Mahasarakarm, Kalasin and Roi-et from 1984 to 1994 were analyzed. Twenty PB relapses (45.45%) and twenty four MB relapses (54.55%) were found among 5,298 originally classified PB patients and 5 MB relapses occurred in 2,624 originally classified MB patients. Mean relapse interval was between 3-4 years. The relapse rate within 10 years after stopping MDT was 0.83 per cent in PB and 0.19 per cent in MB. The estimated relapse rate per 1,000 patient-years was 1.55 for PB and 0.41 for MB respectively.

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18.) Leprosy resistant to multi-drug-therapy (MDT) successfully treated with ampicillin-sulbactam combination--(a case report).

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Mehta VR L.T.M.M. College, Bombay.

Indian J Med Sci (INDIA) Nov 1996 50 (11) p305-7 ISSN: 0019-5359

Language: ENGLISH

Document Type: JOURNAL ARTICLE

Journal Announcement: 9707

Subfile: INDEX MEDICUS

A 50 year male developed a discoid lesion of leprosy on the face. Inspite of Dapsone 100 mg/day and Rifampicin 600 mgm per day the disease spread to both sides of the face and forehead. It became worse with Prednisolone and Clofazimine. It cleared completely when Sultamicillin was added to the latter. This seems to be the first patient of leprosy to be treated with this combination and reported.

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19.) Specificity and function of immunogenic peptides from the 35-kilodalton protein of Mycobacterium leprae.

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Author Wilkinson RJ; Wilkinson KA; Jurcevic S; Hills A; Sinha S; Sengupta U; Lockwood DN; Katoch K; Altman D; Ivanyi J

Address MRC Clinical Sciences Center, Imperial College School of Medicine,

Hammersmith Hospital, London W12 0NN, United Kingdom.

Source Infect Immun, 67(3):1501-4 1999 Mar

Abstract

We identified a T-cell determinant of the 35-kDa antigen of Mycobacterium leprae which is discriminatory against cross-sensitization by its closely related homologue in Mycobacterium avium. From synthetic peptides covering the entire sequence, those with the highest affinity and permissive binding to purified HLA-DR molecules were evaluated for the stimulation of proliferation of peripheral blood mononuclear cells (PBMCs) from leprosy patients and healthy sensitized controls. Responses to the peptide pair 206-224, differing by four residues between M. leprae and M. avium, involved both species-specific and cross-reactive T cells. Lymph node cell proliferation in HLA-DRB1*01 transgenic mice was reciprocally species specific, but only the response to the M. leprae peptide in the context of DR1 was immunodominant. Of the cytokines in human PBMC cultures, gamma interferon production was negligible, while interleukin 10 (IL-10) responses in both patients and controls were more pronounced. IL-10 was most frequently induced by the shared 241-255 peptide, indicating that environmental cross-sensitization may skew the response toward a potentially pathogenic cytokine phenotype.

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20.) [Morphological features to be considered as the growth of Mycobacterium leprae Thai-53 strain on a silicon coated slide in a cell-free liquid medium]

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Author Nakamura M; Matsuoka M

Address Koga Hospital Medical Research Institute, Kurume, Japan.

Source Nihon Hansenbyo Gakkai Zasshi, 67(2):287-91 1998 Jul

Abstract

Morphological findings of the cells of Mycobacterium leprae Thai-53 strain smeared on a silicon-coated slide cultured in Kirchner liquid medium pH 7.0, enriched with adenosine, egg yolk, folinic acid, vitamin K3, lecithin, and N-acetylglucosamine at 30 degrees C were demonstrated. On the basis of the results with exquisite morphological growth patterns and the increase in the amount of tempelate DNA prepared from the cultured cells, it is evident that the cells of M.leprae are capable of multiplication under cell-free in vitro conditions. The reason why the ATP content did not increase in parallel with morphological features and the increase in the DNA is presumably that the multiplication of M.leprae in this culture system was supported only by consuming the energy derived from the infected host cells.

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21.) Leprosy patients with lepromatous disease recognize cross-reactive T cell epitopes in the Mycobacterium leprae 10-kD antigen.

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Author

Hussain R; Dockrell HM; Shahid F; Zafar S; Chiang TJ

Address

Department of Microbiology, The Aga Khan University, Karachi, Pakistan.

Source

Clin Exp Immunol, 114(2):204-9 1998 Nov

Abstract

T cell responses play a critical role in determining protective responses to leprosy. Patients with self-limiting tuberculoid leprosy show high T cell reactivity, while patients with disseminated lepromatous form of the disease show absent to low levels of T cell reactivity. Since the T cell reactivity of lepromatous patients to purified protein derivative (PPD), a highly cross-reactive antigen, is similar to that of tuberculoid patients, we queried if lepromatous patients could recognize cross-reactive epitopes in Mycobacterium leprae antigens as well. T cell responses were analysed to a recombinant antigen 10-kD (a heat shock cognate protein) which is available from both M. tuberculosis (MT) and M. leprae (ML) and displays 90% identity in its amino acid sequence. Lymphoproliferative responses were assessed to ML and MT 10 kD in newly diagnosed leprosy patients (lepromatous, n = 23; tuberculoid, n = 65). Lepromatous patients showed similar, but low, lymphoproliferative responses to ML and MT 10 kD, while tuberculoid patients showed much higher responses to ML 10 kD. This suggests that the tuberculoid patients may be recognizing both species-specific and cross-reactive epitopes in ML 10 kD, while lepromatous patients may be recognizing only cross-reactive epitopes. This was further supported by linear regression analysis. Lepromatous patients showed a high concordance in T cell responses between ML and MT 10 kD (r=0.658; P<0.0006) not observed in tuberculoid patients (r=0.203; P>0.1). Identification of cross-reactive T cell epitopes in M. leprae which could induce protective responses should prove valuable in designing second generation peptide-based vaccines.

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22.) Diaminodiphenylsulfone resistance of Mycobacterium leprae due to mutations in the dihydropteroate synthase gene.

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Author Kai M; Matsuoka M; Nakata N; Maeda S; Gidoh M; Maeda Y; Hashimoto K; Kobayashi K; Kashiwabara Y

Address Leprosy Research Center, National Institute of Infectious Diseases, Tokyo,

Japan. mkai@nih.go.jp

Source FEMS Microbiol Lett, 177(2):231-5 1999 Aug 15

Abstract

The nucleotide sequence analysis of the dihydropteroate synthase (DHPS) gene of six diaminodiphenylsulfone-resistant Mycobacterium leprae strains revealed that the mutation was limited at highly conserved amino acid residues 53 or 55. Though the mutation at amino acid residue 55 or its homologous site has been reported in other bacteria, the mutation at residue 53 is the first case in bacteria. This is the first paper which links the mutations in DHPS and sulfonamide resistance in M. leprae. This finding is medically and socially relevant, since leprosy is still a big problem in certain regions.

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23.) In vitro activity of epiroprim, a dihydrofolate reductase inhibitor, singly and in combination with brodimoprim and dapsone, against Mycobacterium leprae.

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Author Dhople AM

Address Department of Biological Sciences, Florida Institute of Technology,

Melbourne 32901, USA. adhople@fit.edu

Source Int J Antimicrob Agents, 12(4):319-23 1999 Aug

Abstract

The antimicrobial effects of a new dihydrofolate reductase inhibitor, epiroprim, alone and in combination with dapsone and brodimoprim against Mycobacterium leprae were evaluated in vitro in cell-free culture system. Two biochemical parameters were used to measure metabolic activity (and growth) of the organism. The minimal inhibitory activity of epiroprim against M. leprae was 10 mg/l and the action was bactericidal. When combined with dapsone, epiroprim exhibited a strong synergism; on the other hand, combination of epiroprim and brodimoprim provided only additive effects. The results suggest that epiroprim can be a component in multidrug therapy regimen in leprosy.

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24.) Lymphoproliferative responses of leprosy patients and healthy controls to nitrocellulose-bound M. leprae antigens.

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Author Sachdeva G; Kaur G; Bhutani LK; Bamezai RN

Address Human Genetics Laboratory, School of Life Sciences, Jawaharlal Nehru

University, New Delhi, India.

Source Int J Lepr Other Mycobact Dis, 67(2):133-42 1999 Jun

Abstract

The lymphoproliferative responses of 51 leprosy patients and 11 healthy contacts were analyzed using the nitrocellulose-bound specific antigen fractions from the cell-free extract of Mycobacterium leprae. The main proliferation-inducing fraction for peripheral blood mononuclear cells of the healthy contacts was found to be the Fraction II, bearing antigens in the range of 66-45 kDa. However, this fraction failed to induce lymphoproliferation in the leprosy patients, unlike healthy contacts (p < 0.032). The number of responders as well as the strength of the responses to 66-45 kDa proteins were found to be low in the leprosy patients compared to the healthy contacts. Further, preliminary analysis with the subfractions of Fraction II produced a similar pattern, suggesting that the immune response to the antigens in the range of 66-45 kDa M. leprae proteins remains suppressed in subjects with clinical signs and symptoms of the disease.

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25.) Dominant recognition of a cross-reactive B-cell epitope in Mycobacterium leprae 10 K antigen by immunoglobulin G1 antibodies across the disease spectrum in leprosy.

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Author Hussain R; Dockrell HM; Chiang TJ

Address Department of Microbiology, The Aga Khan University. PO Box 3500, Karachi, Pakistan.

Source Immunology, 96(4):620-7 1999 Apr

Abstract

Mycobacterium leprae-specific immunoglobulin G1 (IgG1) antibodies in patients with leprosy show a direct correlation with bacterial load (rho=0.748; P<0002) suggesting that IgG1 B-cell responses may be surrogate markers of disease progression. To investigate if this upregulation was a general feature of IgG1 responses to all M. leprae (ML) antigens, we analysed responses to several recombinant purified ML heat-shock proteins (HSP). Three recombinant HSPs (ML10 K, ML 18 K and ML 65 K) were tested for their ability to induce various IgG subclasses in patients with either the lepromatous (LL/BL, n=26) or tuberculoid form (BT/TT, n=39) of the disease as well as in healthy households (HC, n=14) and endemic controls (EC=19). Our major findings were: (1) selective augmentation of IgG1 antibody responses to ML10 K; (2) recognition of a restricted number of epitopes across the disease spectrum and healthy controls by IgG1 antibodies; (3) dominant recognition of cross-reactive epitopes which were common to both ML and MT 10 K. This response was not related to contamination with endotoxin. Epitope mapping using 15-mer overlapping peptides spanning the ML 10 000 MW revealed an immunodominant IgG1 binding peptide (aa41-55) in patients as well as healthy controls. This peptide is a shared epitope with M. tuberculosis 10 K suggesting that postswitched IgG1 B cells recognizing this epitope rather than naive B cells are being expanded.

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26.) Immune responses to recombinant proteins of Mycobacterium leprae.

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Author Wilkinson KA; Katoch K; Sengupta U; Singh M; Sarin KK; Ivanyi J; Wilkinson RJ

Address Medical Research Council Clinical Sciences Center, Imperial College of Science, Technology, and Medicine, Hammersmith Hospital, London, W12 ONN, United Kingdom. kaw10@po.cwru.edu

Source J Infect Dis, 179(4):1034-7 1999 Apr

Abstract

Identification of antigenic determinants of the polar immune response in leprosy may illuminate both protection and pathogenesis. Thirty subjects were studied (22 with polar disease and 8 healthy controls who were heavily exposed but disease-free) by assaying the proliferative, interferon (IFN)-gamma, and antibody responses to recombinant antigens of Mycobacterium leprae (10, 28, 36, and 65 kDa). The 10-kDa antigen elicited IFN-gamma production from all tuberculoid (TT) and borderline tuberculoid (BT) patients but little from controls, lepromatous (LL), or borderline lepromatous (BL) patients (P<.05). Production of 65-kDa-specific IFN-gamma was higher in TT/BT than in controls or LL/BL patients (P<.006). All subjects produced 65-kDa-specific antibody, but it was higher in LL/BL patients than in healthy controls, whose responses were higher than in TT/BT subjects (P=.035). The 36-kDa antibody responses were selectively increased in LL/BL subjects (P<.02). The intermediate phenotype of the controls suggests that M. leprae-specific production of IFN-gamma may contribute to pathology and to protection in leprosy.

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27.) Causative organism and host response. International Leprosy Congress,

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Beijing, 7-12 September 1998. Workshop report.

Author Krahenbuhl JL

Source Lepr Rev, 70(1):95-102 1999 Mar

Abstract

Whether or not the leprosy elimination target is met in all endemic countries by the year 2000, the MDT programme will have greatly reduced worldwide prevalence. However, our workshop chairmen were asked to ignore the prevalence-based leprosy 'elimination' programme and focus on recommendations for a long term, incidence-based eradication target where transmission is blocked. They were asked to be concerned with basic leprosy research goals in the post 2000 era. The members of our workshops are actively productive workers, committed to their special interests. They are fully cognizant of the obstacles faced daily in working with leprosy and M. leprae, the requirement for clever experimental design even with the availability of the powerful tools of molecular biology which can now be brought to bear on some of the research obstacles. They are also aware of our lack of understanding about leprosy and M. leprae. How do you block transmission if you don't know how infection is transmitted? Can infection be detected, diagnosis made earlier? Is there a non-human reservoir host, a carrier state, an environmental source? What is the basis of M. leprae's predilection for nerves, the mechanisms underlying reactions? What needs to be targeted to treat reactions? Can a vaccine play a role?

There is nothing startling in the workshops' recommendations. Other individuals and groups of experts have made the same suggestions, with slightly varying priorities. What one can read between the lines of these reports, is a sense of urgency to get as much done as soon as possible. Worldwide interest in leprosy will soon be diminished, not by design but as a consequence of the laudable success of the MDT programme. The experiment is still underway, but chemotherapy alone, killing bacilli in the detectable human host, does not appear to be the answer to blocking transmission. A number of goals must be addressed while there are still intact national and international leprosy programmes, while there are still leprosy treatment and research centres that can co-ordinate and facilitate the necessary trials for early diagnosis, early detection of reactions, evaluation of immunosuppressive regimens for reactions.

A key recommendation is concerned with the means of measuring progress. A clear and explicit means of reporting incidence, prevalence and 'case detection' should be implemented to avoid a distorted picture of worldwide leprosy. These recommendations are non-controversial. What should be done is clear. The uncertainty is in determining who will do the work. Who will fund the laboratories engaged in this work? Look around you. There are fewer scientists attending this Congress but browsing the abstracts and attending our sessions and posters clearly revealed to me that fewer of us are doing far better work than in the past. Alternative sources of funding will help. Tuberculosis research is enticing researchers away from leprosy in the developed countries but is visibly sustaining leprosy research in many centres in developing countries. Formation of alliances was a key goal of this Congress.

I asked my colleagues from Carville to identify in their own discipline, dedicated people, committed laboratories that will sustain their leprosy research efforts over the next 5, 10 or more years. These are the people with whom we wish to collaborate, form alliances, share resources and expertise, address the future of worldwide leprosy.

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28.) Immunohistological analysis of in situ expression of mycobacterial antigensin skin lesions of leprosy patients across the histopathological spectrum. Association of Mycobacterial lipoarabinomannan (LAM) and Mycobacterium leprae phenolic glycolipid-I (PGL-I) with leprosy reactions.

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Author

Verhagen C; Faber W; Klatser P; Buffing A; Naafs B; Das P

Address

Departments of Dermatology, Academic Medical Center, University of Amsterdam, The Netherlands.

Source

Am J Pathol, 154(6):1793-804 1999 Jun

Abstract

The presence of mycobacterial antigens in leprosy skin lesions was studied by immunohistological methods using monoclonal antibodies (MAbs) to Mycobacterium leprae-specific phenolic glycolipid I (PGL-I) and to cross-reactive mycobacterial antigens of 36 kd, 65 kd, and lipoarabinomannan (LAM). The staining patterns with MAb to 36 kd and 65 kd were heterogeneous and were also seen in the lesions of other skin diseases. The in situ staining of PGL-I and LAM was seen only in leprosy. Both antigens were abundantly present in infiltrating macrophages in the lesions of untreated multibacillary (MB) patients, whereas only PGL-I was occasionally seen in scattered macrophages in untreated paucibacillary lesions. During treatment, clearance of PGL-I from granulomas in MB lesions occurred before that of LAM, although the former persisted in scattered macrophages in some treated patients. This persistence of PGL-I in the lesions paralleled high serum anti-PGL-I antibody titers but was not indicative for the presence of viable bacilli in the lesions. Interestingly, we also observed a differential expression pattern of PGL-I and LAM in the lesions of MB patients with reactions during the course of the disease as compared with those without reactions. In conclusion, the in situ expression pattern of PGL-I and LAM in MB patients may assist in early diagnosis of reactions versus relapse.

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29.) IL-18 promotes type 1 cytokine production from NK cells and T cells in human intracellular infection.

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Author

Garc´ia VE; Uyemura K; Sieling PA; Ochoa MT; Morita CT; Okamura H; Kurimoto M; Rea TH; Modlin RL

Address

Division of Dermatology and Department of Microbiology and Immunology, University of California, Los Angeles, CA 90095, USA.

Source

J Immunol, 162(10):6114-21 1999 May 15

Abstract

We investigated the role of IL-18 in leprosy, a disease characterized by polar cytokine responses that correlate with clinical disease. In vivo, IL-18 mRNA expression was higher in lesions from resistant tuberculoid as compared with susceptible lepromatous patients, and, in vitro, monocytes produced IL-18 in response to Mycobacterium leprae. rIL-18 augmented M. leprae-induced IFN-gamma in tuberculoid patients, but not lepromatous patients, while IL-4 production was not induced by IL-18. Anti-IL-12 partially inhibited M. leprae-induced release of IFN-gamma in the presence of IL-18, suggesting a combined effect of IL-12 and IL-18 in promoting M. leprae-specific type 1 responses. IL-18 enhanced M. leprae-induced IFN-gamma production rapidly (24 h) by NK cells and in a more sustained manner (5 days) by T cells. Finally, IL-18 directly induced IFN-gamma production from mycobacteria-reactive T cell clones. These results suggest that IL-18 induces type 1 cytokine responses in the host defense against intracellular infection.

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30.) Identification of M.leprae in conjunctiva of leprosy patients using the superior tarsal conjunctiva scrape technique.

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Author

Campos WR; Rodrigues CA; Or´efice F; Monteiro LG

Address

S~ao Geraldo Hospital, Medical School, Federal University of Minas Gerais, Belo Horizonte, Brazil.

Source

Indian J Lepr, 70(4):397-403 1998 Oct-Dec

Abstract

The technique of superior tarsal conjunctiva scrape was used for identifying M.leprae in the conjunctiva in 56 leprosy patients (all of them multibacillary, some untreated and others treated with multidrug therapy). The technique of tarsal conjunctiva scrape was shown to be more suitable than conjunctival biopsy for identifying lepra bacilli. This technique is also easier to perform and has shown a statistical relation between bacilloscopical index of skin (BIsk) and bacilloscopical index of tarsal conjunctiva (BIconj) values. Thus, if the bacilli can be identified at tarsal conjunctiva we can assume greater systemic bacillary load in the patients.

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31.) [Present situation of leprosy in highly endemic area of tropical Asia--a seroepidemiological study of Mycobacterium leprae infection in general inhabitants]

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Author

Izumi S; Budiawan T; Matsuoka M; Saeki K; Kawatsu K

Address

National Leprosarium Oshima Seisho-En, Kagawa, Japan.

Source

Nihon Hansenbyo Gakkai Zasshi, 67(3):401-8 1998 Nov

Abstract

One of the most important unsolved problems in epidemiology of leprosy is the heterogeneous geographic distribution of the disease. There are highly endemic area called "Pocket" in the endemic countries. Little is known why leprosy is so endemic in the area. We conducted, therefore, an epidemiological study on M. leprae infection and distribution of leprosy bacilli in the environment by using serological and molecular biological techniques. It was found that considerable number of general inhabitants in the pocket are infected with leprosy bacilli and more than 20% of the villagers are carrying M. leprae on the surface of the nasal cavity; suggesting that leprosy bacilli in the residential environment play an important role in high prevalence of leprosy in the endemic area. New preventive measures such as chemoprophylaxis, in addition to MDT, will be needed for global elimination of the disease.

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32.) Anti M. leprae IgM antibody determination by ultramicroimmunoenzymatic (UMELISA HANSEN) for the diagnosis and monitoring leprosy.

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Author

Torrella A; Solis RL; Perez E; Medina Y; Kerguelen C; Olaya P

Address

Immunoassay Center, C. Habana, Cuba.

Source

Rev Inst Med Trop Sao Paulo, 40(3):177-81 1998 May-Jun

Abstract

The relationship between the IgM antibody response, antigenic load as well as the clinical improvement after chemotherapy was studied in order to obtain useful data for the early diagnosis and monitoring leprosy. A level of 82% (94/115) agreement was obtained between IgM UMELISA HANSEN and slit-skin smear examination. Discrepant results were observed in 16 patients who showed positive IgM response despite negative by the skin smear examination. In these patients, the IgM response was seen to be associated to the early signal for bacilli recurrence in the skin. In one of these patients the presence of bacilli was demonstrated in the skin, two months after IgM antibodies being detected by UMELISA HANSEN. Also in one of the treated patients positive by both diagnostic techniques, a remarkable decrease in the IgM antibody levels was seen, correlating with a significant clinical improvement. Moreover it was found a direct relationship between the IgM antibody response and bacterial antigenic load, regardless the time elapsed in the disease's evolution.

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33.) Opposite cellular accumulation and nitric oxide production in vivo after pleural immunization with M. leprae or M. bovis BCG.

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Author

Moura AC; Werneck-Barroso E; Rosas EC; Henriques MG; Cordeiro RS

Address

Department of Cell Biology and Genetics, Universidade do Rio de Janeiro

(UERJ), Rio de Janeiro, Brazil.

Source

Int J Mol Med, 3(1):69-74 1999 Jan

Abstract

Mycobacteria as intracellular pathogens have evolved mechanisms to survive within macrophages. Our previous data showed that M. leprae (ML), unlike M. bovis BCG, did not induce an inflammatory response in the mice subcutaneous tissue. Further, ML inhibited BCG-induced foot pad oedema and seemed to transform macrophages in epithelioid cells. Since these mycobacteria share common antigens, here we seeked to compare the acute and chronic cellular response evoked by ML and BCG in pleurisy of a mycobacteria-susceptible mice (BALB/c). The total leukocytes, the cell type that migrated to the pleural cavity and macrophage activation assayed by nitric oxide release were determined. Live or dead BCG Moreau recruited the same extent of cells, essentially monocytes and neutrophils, dose-dependently, in both acute and chronic pleurisy. BCG-induced eosinophilia was observed only in the acute response (after 24 h of injection). A significant nitric oxide release by pleural macrophages was triggered by BCG Moreau without previous activation. Nevertheless, ML failed to recruit leukocytes to the pleural space or to lead to nitric oxide production despite the number of bacilli used and the time studied (1, 7 or 14 days after injection). Although these mycobacteria have common antigens that cross-react, these data show a distinct ability of ML or BCG to recruit cells to the pleural space and to activate pleural macrophage for nitric oxide production in vivo.

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34.) Use of a whole blood assay to monitor the immune response to mycobacterial antigens in leprosy patients: a predictor for type 1 reaction onset?

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Author Weir RE; Butlin CR; Neupane KD; Failbus SS; Dockrell HM

Address Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, UK.

Source Lepr Rev, 69(3):279-93 1998 Sep

Abstract

Longitudinal studies are more appropriate than cross-sectional studies for investigating changes in the immune response to Mycobacterium leprae during leprosy, such as occur in type 1 (reversal) reactions. A test for predicting the onset of reactions in leprosy would greatly reduce disability associated with leprosy. Whole blood assays are appropriate for longitudinal studies of the in vitro T-cell response, as they are robust and reproducible, and require only a small volume of blood. Whole blood assays were used to assess the natural variation in the 'normal' T-cell response to mycobacterial antigens in healthy UK donors, and healthy Nepali donors, tested over 6 months.

This was compared with variation in T-cell responses measured over 6 months in 22 leprosy patients in Nepal, including eight who developed type 1 reactions during this time. The in vitro T-cell response to M. leprae sonicate, M. tuberculosis PPD, the mitogen PHA, and (in the UK study) recombinant mycobacterial antigens (70 kD and 30/31 kD proteins) was measured by lymphoproliferation and interferon-gamma (IFN gamma) responses, and variation in responses over time in each subject calculated as a coefficient of variation (CV).

The baseline high, low or non-responder status of the healthy UK donors remained stable. The magnitude of IFN gamma responses varied by mean CV ranging from 26% (to PPD) to 63% (to Mtb 70 kD); proliferation responses showed less variation, ranging from mean CV of 18% (to PHA) to 47% (to Mtb 70 kD).

Response variation was independent of lymphocyte number in culture. Similar variation in lymphoproliferation responses to MLS, PPD and PHA was observed in the group of healthy Nepali subjects, and in Nepali leprosy patients who did not experience reactions during the study. Of the eight leprosy patients who developed type 1 reactions, four (two BT, one BB, one BL) showed significantly increased proliferation to MLS at the time of reaction (74-300% above baseline); four (one BB, two BL, one LL) remained low or non-responders to MLS throughout. An alternative marker of immune response--anti-phenolic glycolipid-1 (PGL-1) antibody titre--was not predictive of reaction onset in these patients.

This study demonstrated that whole blood assays provide reproducible in vitro measurements that can be used to monitor changes in T-cell responses to M. leprae antigens; their practical use as a diagnostic marker of type 1 reaction onset is discussed.

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35.) A clinical and bacteriological examination of Mycobacterium leprae in the epidermis and cutaneous appendages of patients with multibacillary leprosy.

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Author Hosokawa A

Address Department of Dermatology, Ryukyu University School of Medicine, Okinawa, Japan.

Source J Dermatol, 26(8):479-88 1999 Aug

Abstract

In the specimens examined at Ryukyu University Hospital, acid-fast bacilli (AFB) were observed in the epidermis, cutaneous appendages and endothelial cells of capillaries. These specimens were taken from non-ulcerating skin lesions of patients with multibacillary leprosies such as LL and borderline lepromatous leprosy (BL). Of the 211 specimens examined, 23 (10.9%) were AFB-positive [AFB (+)] in the above mentioned skin regions. These AFB (+) samples were taken from nine leprosy patients; six cases (17 samples) of LL, two cases (5 samples) of BL, and one case (one sample) of BB. The AFB positive rate [AFB (+)-rate] in the above mentioned skin regions was high in the unmedicated LL sample (50.0%, 7/14) and low in the medicated mid-borderline leprosy (BB) samples (0.0%, 0/10). Particularly in the intraepidermal eccrine sweat duct (acrosyringium), a relatively high number of AFB were observed. The AFB (+)-rate appears likely to be higher in non-ulcering skin lesions with minor inflammation or in lesions with leprosy reaction than typical skin lesions such as papules, nodules, and infiltrated punched out skin lesions. Although the possibility that viable bacilli could be excreted from non-ulcerating skin lesions appeared to be small, these lesions were suspected of being a possible source of infection.

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36.) Quality control tests for vaccines in leprosy vaccine trial, Avadi.

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Author Sreevatsa; Hari M; Gupte MD

Address BCG Vaccine Laboratory, Guindy, Chennai.

Source Indian J Lepr, 70(4):389-95 1998 Oct-Dec

Abstract

All the vaccines supplied for the large scale comparative leprosy vaccine trial of ICRC bacilli, M.w, BCG plus killed M. leprae (candidate vaccines), BCG and normal saline (control arms) at CJIL Field Unit, Chennai were tested for quality control by the suppliers following the procedures laid down in the WHO protocol for killed M. leprae. Quality control for BCG was carried out at BCG vaccine laboratory as per protocol. Toxicity and sterility tests were done on all the vaccine batches/lots received. As part of the quality control, bacterial count, and protein estimation were also done. Studies showed that the bacterial content and protein concentration were comparable with the original preparations. Vaccines were free from micro-organisms, toxic materials and safe for human use. Thus the quality of all vaccine preparations was satisfactory.

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37.) Comparative leprosy vaccine trial in south India.

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Author Gupte MD; Vallishayee RS; Anantharaman DS; Nagaraju B; Sreevatsa; Balasubramanyam S; de Britto RL; Elango N; Uthayakumaran N; Mahalingam VN;

Lourdusamy G; Ramalingam A; Kannan S; Arokiasamy J

Source Indian J Lepr, 70(4):369-88 1998 Oct-Dec

Abstract

This report provides results from a controlled, double blind, randomized, prophylactic leprosy vaccine trial conducted in South India. Four vaccines, viz BCG, BCG+ killed M. leprae, M.w and ICRC were studied in this trial in comparison with normal saline placebo. From about 3,00,000 people, 2,16,000 were found eligible for vaccination and among them, 1,71,400 volunteered to participate in the study. Intake for the study was completed in two and a half years from January 1991. There was no instance of serious toxicity or side effects subsequent to vaccination for which premature decoding was required. All the vaccine candidates were safe for human use. Decoding was done after the completion of the second resurvey in December 1998.

Results for vaccine efficacy are based on examination of more than 70% of the original "vaccinated" cohort population, in both the first and the second resurveys. It was possible to assess the overall protective efficacy of the candidate vaccines against leprosy as such. Observed incidence rates were not sufficiently high to ascertain the protective efficacy of the candidate vaccines against progressive and serious forms of leprosy. BCG+ killed M. leprae provided 64% protection (CI 50.4-73.9), ICRC provided 65.5% protection (CI 48.0-77.0), M.w gave 25.7% protection (CI 1.9-43.8) and BCG gave 34.1% protection (CI 13.5-49.8).

Protection observed with the ICRC vaccine and the combination vaccine (BCG+ killed M. leprae) meets the requirement of public health utility and these vaccines deserve further consideration for their ultimate applicability in leprosy prevention.

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38.) Evolutionary bottlenecks in the agents of tuberculosis, leprosy, and paratuberculosis.

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Author Frothingham R

Address Infectious Disease Section, Durham Veterans Affairs Medical Center, Durham, North Carolina 27705, USA. rfr@galactose.mc.duke.edu

Source Med Hypotheses, 52(2):95-9 1999 Feb

Abstract

Parasitic mycobacteria cause important human and animal diseases including tuberculosis, leprosy, and paratuberculosis. Several methods demonstrate a high degree of sequence conservation in three parasitic mycobacterial species (Mycobacterium tuberculosis, M. leprae, and M. avium subspecies paratuberculosis). Each of these species has completely conserved deoxyribonucleic acid (DNA) sequence in an internal transcribed spacer. In contrast, several species of environmental mycobacteria (M. intracellulare, M. kansasii, M. gordonae, and M. scrofulaceum) have substantial strain-to-strain variation in this region. These data suggest that each of the parasitic species has gone through a recent evolutionary bottleneck. Comparisons of tandem-repeat DNA from ancient and modern mycobacterial strains may allow this hypothesis to be tested directly.

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39.) Role of S-100 staining in differentiating leprosy from other granulomatous diseases of the skin.

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Author Thomas MM; Jacob M; Chandi SM; George S; Pulimood S; Jeyaseelan L; Job CK

Address Department of Dermatology, Christian Medical College and Hospital, Vellore, Tamil Nadu, India.

Source Int J Lepr Other Mycobact Dis, 67(1):1-5 1999 Mar

Abstract

Since Mycobacterium leprae are rarely demonstrable in the tuberculoid spectrum of leprosy, a confirmatory diagnosis of leprosy can be made on the basis of finding active destruction of cutaneous nerves by granulomatous inflammation in a skin biopsy. Immunoperoxidase staining for S-100 protein, which is a marker for Schwann cells, was used to delineate nerves in lesional skin biopsies of 25 patients with tuberculoid and borderline tuberculoid leprosy as well as 15 controls with nonleprous granulomatous inflammation. Four different patterns of nerve damage were observed: infiltrated, fragmented, absent, and intact. All of the nonleprous granulomatous dermatoses showed only intact nerves, either inside or outside the granuloma, and so S-100 staining can be used to rule out leprosy.

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40.) Assessment of anti-PGL-I as a prognostic marker of leprosy reaction.

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Author Stefani MM; Martelli CM; Morais-Neto OL; Martelli P; Costa MB; de Andrade AL

Address Department of Immunology, University Hospital, Federal University of Goias, Goiania, Brazil. stefani@internetional.com.br

Source Int J Lepr Other Mycobact Dis, 66(3):356-64 1998 Sep

Abstract

The anti-phenolic glycolipid-I (PGL-I) assay as currently applied for leprosy is conceived as an early marker of asymptomatic infection, early disease diagnosis and cure monitoring. Its use as a prognostic marker of reaction is still a matter of controversy. We conducted a case-control study to investigate whether IgM and IgG anti-PGL-I antibodies could discriminate patients at increased risk of developing reactions. Eligible cases were untreated leprosy patients at the onset of type 1 and type 2 reactions recruited from among 600 concurrent, newly detected, untreated leprosy patients attending an outpatient clinic in central Brazil.

For the patients with reaction, approximately the same number of leprosy cases without reaction matched as to bacterial index (BI), age and gender were randomly selected. Individuals without clinical leprosy were evaluated as healthy controls. Sera from type 1 reaction (N = 43) and type 2 reaction (N = 26) patients were tested by an ELISA using PGL-I synthetic disaccharide-BSA antigen and 1:300 sera dilution (cut-off point > or = 0.2 OD). Antibody profiles were evaluated by exploratory data analysis and reverse cumulative distribution curves. The IgG anti-PGL-I response did not have a defined pattern, being detected only at low levels. Our results indicate that leprosy patients, independently of their reactional status, produce high levels of IgM anti-PGL-I, demonstrating a strong correlation between the magnitude of antibody response and the BI. Patients with a higher BI were at least 3.4 times more prone to produce an antibody response compared to healthy controls.

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41.) Conjunctival biopsy in patients with leprosy.

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Author Campos WB; Or´efice F; Sucena MA; Rodrigues CA

Address S~ao Geraldo Hospital, Medical School of the Federal University of Minas Gerais, Brazil.

Source Indian J Lepr, 70(3):291-4 1998 Jul-Sep

Abstract

The authors examined the eyes of 120 leprosy patients comprising of 30 cases each of tuberculoid, indeterminate, borderline and lepromatous leprosy. The investigation included biopsy of the bulbar conjunctiva on the upper temporal quadrant of the right eye. The study patients included both who were untreated, those that were being treated and those who were in observation after the end of treatment. The aim of the study was to identify the presence of M. leprae in the conjunctiva. Four such cases were found: one borderline patient with no treatment and three lepromatous patients who were being treated with MDT.

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42.) Experimental leprosy in rhesus monkeys: transmission, susceptibility, clinical and immunological findings.

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Author Gormus BJ; Xu K; Baskin GB; Martin LN; Bohm RP Jr; Blanchard JL; Mack PA; Ratterree MS; Meyers WM; Walsh GP

Address Department of Microbiology, Pathology, Tulane Regional Primate Research Center, Covington, LA 70433, USA.

Source Lepr Rev, 69(3):235-45 1998 Sep

Abstract

A total of 46 Rhesus monkeys (RM) was inoculated with Mycobacterium leprae (ML) and followed clinically and immunologically for extended periods. Twenty-one (45.7%) of the RM developed leprosy spanning the known leprosy spectrum, with six of 21 (28.6%) having disease in the borderline lepromatous to lepromatous area of the spectrum. RM with paucibacillary forms of leprosy produced predominantly IgG anti-phenolic glycolipid (PGL-I) antibodies and positive lepromin skin test and/or in vitro blastogenesis responses; IgM anti-PGL-I predominated in animals with BB-LL leprosy and correlated with negative immune responses to lepromin. IgG anti-PGL-I antibodies persisted in a number of RM for several years without histopathological evidence of leprosy, suggesting possible persisting subclinical infection. The data show that RM are a valuable model for the study of leprosy. Eleven of the 46 RM were inoculated with ML from sources infected with simian immunodeficiency virus (SIV), the monkey counterpart to the human immunodeficiency virus (HIV). The possible effect of SIV on the clinical outcome of ML infection could not be determined due to insufficient numbers of animals to yield statistically significant results.

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43.) Lepromatous uveitis diagnosed by iris biopsy.

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Author Messmer EM; Raizman MB; Foster CS

Address University Eye Hospital, Munich, Germany.

Source Graefes Arch Clin Exp Ophthalmol, 236(9):717-9 1998 Sep

Abstract

Ocular leprosy is rarely seen in developed countries. We report the long-term follow-up of a patient with bilateral uveitis, glaucoma, and keratitis. Skin, iris and aqueous humor biopsies disclosed abundant Wade-Fite-positive organisms consistent with Mycobacterium leprae. Leprosy must be considered in the differential diagnosis of keratitis and uveitis.

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44.) Preservation of Mycobacterium leprae in vitro for four years by lyophilization.

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ARTICLE SOURCE: Int J Lepr Other Mycobact Dis (United States), Sep 1993, 61(3) p415-20

AUTHOR(S): Kohsaka K; Matsuoka M; Hirata T; Nakamura M

PUBLICATION TYPE: JOURNAL ARTICLE

ABSTRACT:

Although the viability of Mycobacterium leprae suspended in distilled water with or without 10% fetal calf serum was reduced approximately 10(-2) to 10(-4) from that of the starting material during the process of lyophilization, bacilli capable of multiplication in nude mouse foot pads were found in the lyophilized samples stored for 4 years at 4 degrees C. The multiplication rate of the lyophilized bacilli which were suspended in 10% serum-water was much higher than that of the bacilli suspended in water only. On the other hand, no reduction of the viability of M. leprae suspended in 10% skim milk-water was demonstrated during the process of lyophilization as well as storage for 2 years at 4 degrees C. From the results obtained here, it could be suggested that M. leprae might be preserved in vitro by means of lyophilized M. leprae was extremely stable during cryopreservation when the bacilli were suspended in 10% skim milk-water. Therefore, the composition of the solution for suspending the bacilli is definitely critical for the maintenance of M. leprae viability by means of lyophilization.

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45.) Minocycline in lepromatous leprosy.

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Author Fajardo TT Jr; Villahermosa LG; dela Cruz EC; Abalos RM; Franzblau SG; Walsh GP

Address Clinical Research Branch, Leonard Wood Memorial Center, Cebu City, The Philippines.

Source Int J Lepr Other Mycobact Dis, 63(1):8-17 1995 Mar

Abstract

Twelve patients were treated with three dose levels of minocycline for 30 days, primarily to detect the dose-related effects on Mycobacterium leprae viability, followed by another 5 months of daily minocycline for overall efficacy and persistence of clinical and antibacterial effects. Subsequently, the patients were given standard WHO/MDT chemotherapy for multibacillary leprosy. Clinical improvement was recognizable during the first month, occurring much earlier among those on minocycline 200 mg daily than those who received minocycline 100 mg daily. A similar change also was observed in one patient 11 days after three daily doses of 100 mg of minocycline. At the end of 6 months, all patients were clinically improved with a slight reduction in the average bacterial index (BI) and logarithmic index of bacilli in biopsy (LIB). T

he effects of minocycline on viability by mouse foot pad inoculation and palmitic acid oxidation assays were noted beginning at 10 to 14 days of daily dosing and becoming more definite after 30 days of treatment. Both tests correlated fairly well. Doses of 200 mg daily did not appear to be more efficient than minocycline 100 daily. Phenolic glycolipid-I (PGL-I) antigen determinations done on some patients during the first month remained positive and did not correlate with changes in viability results. At the end of 6 months, after 5 months of 100 mg of minocycline monotherapy, no viable organisms could be demonstrated by mouse foot pad inoculation and palmitic acid oxidation assays; assays for PGL-I antigen were all negative.(ABSTRACT TRUNCATED AT 250 WORDS)

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46.) Efficacy of minocycline in single dose and at 100 mg twice daily for lepromatous leprosy.

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Int J Lepr Other Mycobact Dis (United States), Dec 1994, 62(4) p568-73

AUTHOR(S): Gelber RH; Murray LP; Siu P; Tsang M; Rea TH

AUTHOR'S ADDRESS: San Francisco Regional Hansen's Disease Program, CA 94115.

PUBLICATION TYPE: CLINICAL TRIAL; JOURNAL ARTICLE

 ABSTRACT: A clinical trial of minocycline in a total of 10 patients with previously untreated lepromatous leprosy was conducted in order to evaluate the efficacy of a single, initial, 200-mg dose and 100 mg twice daily of minocycline for a total duration of up to 3 months. Patients improved remarkably quickly. Although single-dose therapy did not result in a significant killing of Mycobacterium leprae, viable M. leprae were cleared from the dermis regularly by 3 months of twice-daily therapy, a rate similar to that achieved by minocycline 100 mg once daily. Because more side effects were noted herein than previously with 100 mg daily, we recommend that minocycline, when applied, be administered at 100 mg daily to leprosy patients.

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47.) Field trial on efficacy of supervised monthly dose of 600 mg rifampin, 400 mg ofloxacin and 100 mg minocycline for the treatment of leprosy; first results.

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Author Mane I; Cartel JL; Grosset JH

Address Institut de Leprologie Appliquee, Dakar CD Annexe, Senegal.

Source Int J Lepr Other Mycobact Dis, 65(2):224-9 1997 Jun

Abstract

In 1995, a field trial was implemented in Senegal in order to evaluate the efficacy of a regimen based on the monthly supervised intake of rifampin 600 mg, ofloxacin 400 mg and minocycline 100 mg to treat leprosy. During the first year of the trial, 220 patients with active leprosy (newly detected or relapsing after dapsone monotherapy) were recruited: 102 paucibacillary (PB) (60 males and 42 females) and 118 multibacillary (MB) (71 males and 47 females). All of them accepted the new treatment (none requested to be preferably put under standard WHO/MDT), no clinical sign which could be considered as a toxic effect of the drug was noted, and none of the patients refused to continue treatment because of any clinical trouble.

The compliance was excellent: the 113 patients (PB and MB) detected during the first 6 months of the trial have taken six monthly doses in 6 months, as planned.

The rate of clearance and the progressive decrease of cutaneous lesions was satisfactory. Although it is too soon to give comprehensive results, it should be noted that no treatment failure was observed in the 56 PB patients who have completed treatment and have been followed up for 6 months. The long-term efficacy of the new regimen is to be evaluated on the rate of relapse during the years following the cessation of treatment. If that relapse rate is acceptable (similar to that observed in patients after treatment with current standard WHO/ MDT), the new regimen could be a solution to treat, for instance, patients very irregular and/or living in remote or inaccessible areas since no selection of rifampin-resistant Mycobacterium leprae should be possible (a monthly dose of ofloxacin and minocycline being as effective as a dose of dapsone and clofazimine taken daily for 1 month).

Nevertheless, until longer term results of this and other trials become available, there is no justification for any change in the treatment strategy, and all leprosy patients should be put under standard WHO/MDT.

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48.) Bactericidal activity of a single-dose combination of ofloxacin plus minocycline, with or without rifampin, against Mycobacterium leprae in mice and in lepromatous patients.

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Author Ji B; Sow S; Perani E; Lienhardt C; Diderot V; Grosset J

Address Facult´e de M´edecine Piti´e-Salp^etri`ere, Paris, France. bacterio@biomath.jussieu.fr

Source Antimicrob Agents Chemother, 42(5):1115-20 1998 May

Abstract

To develop a fully supervisable, monthly administered regimen for treatment of leprosy, the bactericidal effect of a single-dose combination of ofloxacin (OFLO) and minocycline (MINO), with or without rifampin (RMP), against Mycobacterium leprae was studied in the mouse footpad system and in previously untreated lepromatous leprosy patients. Bactericidal activity was measured by the proportional bactericidal method. In mouse experiments, the activity of a single dose of the combination OFLO-MINO was dosage related; the higher dosage of the combination displayed bactericidal activity which was significantly inferior to that of a single dose of RMP, whereas the lower dosage did not exhibit a bactericidal effect. In the clinical trial, 20 patients with previously untreated lepromatous leprosy were treated with a single dose consisting of either 600 mg of RMP plus 400 mg of OFLO and 100 mg of MINO or 400 mg of OFLO plus 100 mg of MINO.

The OFLO-MINO combination exhibited definite bactericidal activity in 7 of 10 patients but was less bactericidal than the RMP-OFLO-MINO combination. Both combinations were well tolerated. Because of these promising results, a test of the efficacy of multiple doses of ROM in a larger clinical trial appears justified.

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49.) Efficacy of single dose multidrug therapy for the treatment of single-lesion paucibacillary leprosy. Single-lesion Multicentre Trial Group.

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Source Indian J Lepr, 69(2):121-9 1997 Apr-Jun

Abstract

A multicentre double-blind controlled clinical trial was carried out to compare the efficacy of a combination of rifampicin 600 mg plus ofloxacin 400 mg plus minocycline 100 mg (ROM) administered as single dose with that of the standard six-month WHO/MDT/PB regimen. The subjects included 1483 cases with one skin lesion who were previously untreated, were smear-negative, and had no evidence of peripheral nerve trunk involvement, and they were randomly divided into study and control groups. The total duration of the study from the day of intake was 18 months, and 1381 patients completed study. Only 12 patients were categorized as treatment failure and no difference was observed between the two regimens. Occurrence of mild side-effects and leprosy reactions were minimal (less than 1%) in both groups. This study showed that ROM is almost as effective as the standard WHO/MDT/PB in the treatment of single lesion PB leprosy. =========================================================================

50.) Bactericidal activity of single dose of clarithromycin plus minocycline, with or without ofloxacin, against Mycobacterium leprae in patients.

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Author Ji B; Jamet P; Perani EG; Sow S; Lienhardt C; Petinon C; Grosset JH

Address Facult´e de M´edecine Piti´e-Salp^etri`ere, Paris, France.

Source Antimicrob Agents Chemother, 40(9):2137-41 1996 Sep

Abstract

Fifty patients with newly diagnosed lepromatous leprosy were allocated randomly to one of five groups and treated with either a month-long standard regimen of multidrug therapy (MDT) for multibacillary leprosy, a single dose of 600 mg of rifampin, a month-long regimen with the dapsone (DDS) and clofazimine (CLO) components of the standard MDT, or a single dose of 2,000 mg of clarithromycin (CLARI) plus 200 mg of minocycline (MINO), with or without the addition of 800 mg of ofloxacin (OFLO).

At the end of 1 month, clinical improvement accompanied by significant decreases of morphological indexes in skin smears was observed in about half of the patients of each group. A significant bactericidal effect was demonstrated in the great majority of patients in all five groups by inoculating the footpads of mice with organisms recovered from biopsy samples obtained before and after treatment.

Rifampin proved to be a bactericidal drug against Mycobacterium leprae more potent than any combination of the other drugs. A single dose of CLARI-MINO, with or without OFLO, displayed a degree of bactericidal activity similar to that of a regimen daily of doses of DDS-CLO for 1 month, suggesting that it may be possible to replace the DDS and CLO components of the MDT with a monthly dose of CLARI-MINO, with or without OFLO.

However, gastrointestinal adverse events were quite frequent among patients treated with CLARI-MINO, with or without OFLO, and may be attributed to the higher dosage of CLARI or MINO or to the combination of CLARI-MINO plus OFLO. In future trials, therefore, we propose to reduce the dosages of the drugs to 1,000 mg of CLARI, 100 mg of MINO, and 400 mg of OFLO.

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51.) WHO Expert Committee on Leprosy.

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Source: World Health Organ Tech Rep Ser, 874():1-43 1998

Abstract

Considerable progress has been made in the fight against leprosy during the past 10-15 years, following the introduction of multidrug therapy (MDT) regimens and the establishment of the goal of eliminating leprosy as a public health problem by the year 2000. Current estimates indicate that there are about 1.15 million cases of leprosy in the world, compared with 10-12 million cases in the mid-1980s. This report presents the conclusions of a WHO Expert Committee convened to review the global leprosy situation and the technology available for eliminating the disease, to identify the remaining obstacles to reaching the goal of eliminating leprosy as a public health problem, and to make appropriate recommendations for the future on technical and operational matters.

 The current status of leprosy elimination is discussed, and the various antileprosy drugs are reviewed, including the most recently available drugs. On the basis of field trials and clinical studies, the Committee concludes that a single dose of a combination of rifampicin, ofloxacin and minocycline is an acceptable and cost-effective alternative regimen for the treatment of single-lesion paucibacillary leprosy, and that the duration of the current MDT regimen for multibacillary leprosy could possibly be shortened to 12 months.

The Committee points out the need for improved management of reactions and neuritis and prevention of leprosy-related disabilities and impairments, and recommends that antileprosy activities should become an integral part of general health services and should involve communities to the fullest extent possible.

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52.) Experimental evaluation of possible new short-term drug regimens for treatment of multibacillary leprosy.

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Author Banerjee DK; McDermott-Lancaster RD; McKenzie S

Address Department of Medical Microbiology, St George's Hospital Medical School,

London, United Kingdom. banerjee@sghms.ac.uk.

Source Antimicrob Agents Chemother, 41(2):326-30 1997 Feb

Abstract

Groups of nude mice, with both hind footpads infected with 10(8) Mycobacterium leprae organisms, were treated with 4-week courses of different drug combinations. The effect treatment on each group was evaluated by subinoculating footpad homogenates from the treated mice into groups of normal and nude mice for subsequent regrowth, assessed 1 year later. A combination of rifampin (RMP) with clarithromycin (CLARI), minocycline (MINO), and ofloxacin (OFLO) resulted in the complete killing of M. leprae after 3 weeks of treatment.

A combination of sparfloxacin (SPAR) and RMP also resulted in a similar bactericidal effect after 3 weeks of treatment. Other drug combinations showed variable effects. Very little or no effect was observed with any regimen if the treatment was given for less than 2 weeks. World Health Organization (WHO) multidrug therapy (MDT) given for 8 weeks was as effective as the two combinations described above.

The results suggest that multidrug combinations consisting of RMP-OFLO (or SPAR)-CLARI (and/or MINO) are as effective as the WHO MDT for the treatment of experimental leprosy. Moreover, they imply that these combinations, which were found to be active in a 4-week experimental treatment protocol, could be administered as treatment to patients for a period of time shorter than the present 2-year regimen without a loss of effectiveness.

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53.) Powerful bactericidal activities of clarithromycin and minocycline against Mycobacterium leprae in lepromatous leprosy.

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ARTICLE SOURCE: J Infect Dis (United States), Jul 1993, 168(1) p188-90

AUTHOR(S): Ji B; Jamet P; Perani EG; Bobin P; Grosset JH

AUTHOR'S ADDRESS: Faculte de Medecine Pitie-Salpetriere, Paris, France.

PUBLICATION TYPE: CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL

ABSTRACT: Thirty-six patients with newly diagnosed lepromatous leprosy were allocated randomly to three groups and treated for 56 days with minocycline (100 mg daily), clarithromycin (500 mg daily), or clarithromycin (500 mg) plus minocycline (100 mg daily). All groups had rapid and remarkable clinical improvement and significant decline of the bacterial and morphologic indices in skin smears during treatment. More than 99% and 99.9% of the viable Mycobacterium leprae had been killed by 28 and 56 days of treatment, respectively, as measured by inoculation of organisms recovered from skin samples, taken before and during treatment, into the footpads of immunocompetent and nude mice.

Clinical improvement and bactericidal activity did not differ significantly among the three groups. Adverse reactions were rare and mild, and no laboratory abnormality was detected during the trial. Both clarithromycin and minocycline displayed powerful bactericidal activities against M. leprae in leprosy patients and may be considered important components of new multidrug regimens for the treatment of multibacillary leprosy.

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54.) Differential protective effect of bacillus calmette-guerin vaccine against multibacillary and paucibacillary leprosy in nagpur, india.

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Public Health 1999 Nov;113(6):311-3

Kulkarni HR, Zodpey SP

Department of Preventive and Social Medicine and Clinical Epidemiology Unit, Government Medical College, Nagpur, India.

For this paper we conducted a secondary data analysis to test the hypothesis that a linear trend exists in the protective effect of bacillus Calmette-Guerin (BCG) vaccine against types of leprosy. We used data from two previous case-control studies to perform an unmatched test for linear trend. We observed that both the studies revealed a significant linear trend (P<0.00001). One study that estimated an insignificant protective effect of BCG against paucibacillary leprosy showed a significant departure from linearity. We conclude that, the protective effect of BCG vaccination is differential across severity of leprosy as it brings about a shift in the immune response to a higher level of cell mediated immunity. We recommend that future studies dealing with the protective effect of BCG against leprosy should also conduct an analysis for trend.

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55.) An immunotherapeutic vaccine for multibacillary leprosy.

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Int Rev Immunol 1999;18(3):229-49

Talwar GP

International Centre for Genetic Engineering & Biotechnology, New Delhi, India.

On January 30, 1998, a vaccine for leprosy based on Mycobacterium w (the code word under which this species hitherto unspecified was investigated) was launched for public use for therapeutic purposes. The vaccine has completed phase III immunotherapeutic trials as an adjunct to chemotherapy in urban and rural leprosy control centres and has received the authorization from the Drugs Controller of India for industrial manufacture.

It will be made available by M/s Cadila Pharmaceuticals, Ahmedabad. As an adjunct to chemotherapy, the vaccine expediates bacterial clearance and accelerates clinical regression of lesions. It shortens significantly the period for release from treatment (RFT) of patients. It is effective in inducing a fall of bacterial index (BI) in multibacillary patients who are either nonresponders or slow responders to the standard multidrug therapy and who have persistent BI over long periods.

An additional benefit of immunization with this vaccine is the conversion of >60% of LL, 71% of BL and 100% of BB patients from lepromin negativity to lepromin positivity status. A significant number of vaccinated patients showed histopathological upgrading and eventually attainment of a state of nonspecific infiltration without dermal granulomas.

The vaccine was well tolerated and the incidence of Type 2 reactions and their severity was less in combined immuno cum chemotherapy group than in the group receiving only chemotherapy. This review describes the nature of the vaccine and the way it was developed.

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56.) Protective effect of Bacillus Calmette Guerin (BCG) against leprosy: a population-based case-control study in Nagpur, India.

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Lepr Rev 1999 Sep;70(3):287-94

Zodpey SP, Bansod BS, Shrikhande SN, Maldhure BR, Kulkarni SW

Clinical Epidemiology Unit, Govt Medical College, Nagpur, MS, India.

A population-based pair-matched case-control study was carried out in an urban community, Nagpur, India, to estimate the effectiveness of BCG vaccination in the prevention of leprosy. The study included 212 cases of leprosy (diagnosed by WHO criteria), below the age of 35 years, detected during a leprosy survey conducted by the Government of Maharashtra over a population of 20,03,325. Each case was pair-matched with one neighbourhood control for age, sex and socioeconomic status. A significant protective association between BCG and leprosy was observed (OR = 0.40, 95% CI = 0.23-0.68).

The overall vaccine effectiveness (VE) was estimated to be 60% (95% CI = 32-77). The BCG effectiveness against multi-bacillary and paucibacillary leprosy was 72% (95% CI = 35-88) and 45% (95% CI = 3-73), respectively. Vaccine was more effective during the first decade of life, among females and in lower socioeconomic strata. The overall prevented fraction was 39% (95% CI = 16-58). In conclusion, this first ever population-based case control study performed in Central India, identified a beneficial role of BCG vaccination in prevention of leprosy in study population.

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57.) The antigen 85 complex vaccine against experimental Mycobacterium leprae infection in mice.

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Vaccine 1999 Dec 10;18(9-10):795-8

Naito M, Matsuoka M, Ohara N, Nomaguchi H, Yamada T

Department of Oral Bacteriology, Nagasaki University School of Dentistry, Sakamoto 1-7-1, Nagasaki, Japan.

The proteins in culture filtrate derived from Bacillus Calmette-Guerin (BCG) were examined for protection against infection by Mycobacterium leprae. Immunization with the major secreted proteins, antigen 85 complex (Ag 85) A, B and C, induced effective protective immunity against multiplication of M. leprae in the foot pads of mice. The most effective protection was observed when mice were immunized with Ag 85A. A single immunization with Ag 85 could induce antigen-specific interferon gamma (IFNgamma) synthesis and more effective protection than live BCG vaccine. This study demonstrates that Ag 85 is an important immunoprotective molecule against leprosy infection.

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58.) Induction of lepromin positivity following immuno-chemotherapy with Mycobacterium w vaccine and multidrug therapy and its impact on bacteriological clearance in multibacillary leprosy: report on a hospital-based clinical trial with the candidate antileprosy vaccine.

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Int J Lepr Other Mycobact Dis 1999 Sep;67(3):259-69

Sharma P, Kar HK, Misra RS, Mukherjee A, Kaur H, Mukherjee R, Rani R

National Institute of Immunology, New Delhi, India.

A vaccine based on autoclaved Mycobacterium w was administered, in addition to standard multidrug therapy (MDT), to 157 bacteriologically positive, lepromin-negative, multibacillary (LL, BL and BB) leprosy patients. The vaccinees were supported by a well-matched control group of 147 patients with similar type of disease who received a placebo injection in addition to MDT. The MDT was given for a minimum period of 2 years and continued until skin-smear negativity, while the vaccine was given at 3-month intervals up to a maximum of 8 doses.

 The lepromin response evaluated in terms of percentage of subjects converting to positivity status, measurement in millimeters, and duration of lepromin positivity sustained, reflected a statistically significant better outcome in the vaccine group patients (especially LL and BL leprosy) in comparison to those in the placebo group.

The data indicate that lepromin-positivity status seems to have an impact on accelerating the bacteriological clearance, as is evident by the statistically significant accelerated decline in the BI of those patients who converted to lepromin positivity as compared to those remaining lepromin negative throughout therapy and post-therapy follow up. To conclude, the addition of the Mycobacterium w vaccine to standard MDT induces a lepromin response of a statistically significant higher magnitude than that observed with MDT alone.

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59.) Disabilities in multibacillary leprosy following multidrug therapy with and without immunotherapy with Mycobacterium w antileprosy vaccine.

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Int J Lepr Other Mycobact Dis 1999 Sep;67(3):250-8

Sharma P, Kar HK, Misra RS, Mukherjee A, Kaur H, Mukherjee R, Rani R

National Institute of Immunology, New Delhi, India. rajni@nii.res.in

A vaccine based on autoclaved Mycobacterium w was administered, in addition to standard multidrug therapy (MDT), to 157 bacteriologically positive, lepromin-negative, multibacillary leprosy patients supported by a well-matched control group of 147 patients with similar type of disease who received a placebo injection in addition to MDT. The MDT was given for a minimum period of 2 years and continued until skin-smear negativity, while the vaccine/placebo was given at 3-month intervals up to a maximum of 8 doses in the initial 2 years.

The overall incidence of type 1 and type 2 reactions and neuritis during treatment and follow up was nearly equal in the patients in the vaccine and placebo groups; the differences were not statistically significant. The occurrence of disabilities, such as anesthesia, trophic ulcers, claw hand and grade 3 deformities, were not different statistically in the vaccine and placebo groups, an observation valid both for deformities present at induction and for those which developed during the course of therapy and surveillance.

A statistically significant difference was observed in the recovery of newly developed trophic ulcers; recovery was quicker in the vaccine group. The recovery rate for motor deformities was marginally higher in the vaccine group, although not significant (p = 0.068) statistically. There was a statistically significant reduction in the incidence of grade 3 deformities following MDT with and without immunotherapy.

To conclude, the addition of vaccine to MDT did not precipitate neuritis or deformities over and above that encountered with MDT alone, although it did accelerate bacteriological clearance, histopathological upgrading, conversion to lepromin positivity, and clinical improvement.

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60.) SIMLEP: a simulation model for leprosy transmission and control.

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Int J Lepr Other Mycobact Dis 1999 Sep;67(3):215-36

Meima A, Gupte MD, van Oortmarssen GJ, Habbema JD

Department of Public Health, Faculty of Medicine, Erasmus University Rotterdam, The Netherlands. Meima@mgz.fgg.eur.nl

SIMLEP is a computer program for modeling the transmission and control of leprosy which can be used to project epidemiologic trends over time, producing output on indicators such as prevalence, incidence and case-detection rates of leprosy. In SIMLEP, health states have been defined that represent immunologic conditions and stages of leprosy infection and disease. Three types of interventions are incorporated: vaccination, case detection and chemotherapy treatment. Uncertainties about leprosy have led to a flexible design in which the user chooses which of many aspects should be included in the model. These aspects include natural immunity, asymptomatic infection, type distribution of new cases, delay between onset of disease and start of chemotherapy, and mechanisms for leprosy transmission. An example run illustrates input and output of the program.

The output produced by SIMLEP can be readily compared with observed data, which allows for validation studies. The support that SIMLEP can give to health policy research and actual decision making will depend upon the extent of validation that has been achieved. SIMLEP can be used to improve the understanding of observed leprosy trends, for example, in relation to early detection campaigns and the use of multidrug therapy, by exploring which combinations of assumptions can explain these trends. In addition, SIMLEP allows for scenario analysis in which the effects of control strategies combining different interventions can be simulated and evaluated.

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61.) Antigenic definition of plasma membrane proteins of Bacillus Calmette-Guerin: predominant activation of human T cells by low-molecular-mass integral proteins.

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Scand J Immunol 1999 Oct;50(4):411-9

Mehrotra J, Mittal A, Rastogi AK, Jaiswal AK, Bhandari NK, Sinha S Division of Membrane Biology, Central Drug Research Institute, Lucknow, India.

Mycobacterial plasma membrane proteins, in particular the detergent-soluble or 'integral' ones, comprise a class of mostly unexplored antigens capable of inducing potent activation of human T cells. Plasma membrane isolated from culture-grown Bacillus Calmette-Guerin (BCG; Indian vaccine; Danish strain) was subjected to a Triton X-114-based biphasic extraction procedure for isolation of peripheral (water-soluble) and integral proteins (PMP and IMP). A distinction between the two protein pools was evident from results of SDS-PAGE and immunoblotting using antisera raised in rabbits.

 An enzyme-linked immunosorbant assay with a panel of WHO-IMMYC monoclonal antibodies against various mycobacterial antigens revealed that three well-known antigens, 19 kDa, 33/36 kDa (proline rich) and 38 kDa (PstS homologue), were part of the IMP pool; and another such antigen, 14/16 kDa alpha-crystallin homologue, partly constituted the PMP pool.

Apparently, antigenically distinct species of the immunomodulatory moiety lipoarabinomannan partitioned in aqueous and detergent phases. Human T-cell proliferation assays in donors comprising tuberculoid leprosy and pulmonary tuberculosis patients and healthy BCG vaccinees showed significantly greater potency of IMP over PMP and this immunodominance appeared to be directed towards CD4+ cells. IMP of < 56 kDa were resolved by 'continuous elution SDS-PAGE' into 15 fractions which, after extraction of SDS, were used in T-cell proliferation assays for the identification of immunodominant constituents.

Proteins falling within three low-molecular-mass zones (all < 35 kDa) performed better than the rest, particularly a approximately 22 kDa fraction, which strongly stimulated T cells from all five donors. Partial overlap between IMP and secreted proteins, as noticed in this study, could provide clues to immunodominance of the latter. The apparent uniqueness and a high T-cell activating potency make mycobacterial IMP attractive candidates for designing future vaccines or immunotherapeutic agents.

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62.) A lost talisman: catastrophic decline in yields of leprosy bacilli from armadillos used for vaccine production.

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Int J Lepr Other Mycobact Dis 1999 Mar;67(1):67-70 Storrs EE

Publication Types:

Letter

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63.) HLA-DRB1 leprogenic motifs in nigerian population groups.

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Clin Exp Immunol 1999 Oct;118(1):56-62

Uko GP, Lu LY, Asuquo MA, Fici D, Mahan S, Awdeh Z, Udim ER, Ding W, Umana U, Adewole T, Fraser PA

The Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria.

Amino acid residues involved in the peptide binding groove of HLA-DRB1 alleles were examined in three Nigerian ethnic groups with leprosy (n = 287) and 170 controls to determine the role of DRB1 alleles in disease outcome with Mycobacterium leprae. Nine positively charged motifs and two others with neutral charge to the binding groove were detected. These motifs occurred more frequently in leprosy (leprogenic) than was expected by chance (P < 0.0001). In contrast, five motifs with net negative or 'modified' neutral charges to the pocket were negatively associated with leprosy.

We conclude that clinical outcome of infection with M. leprae is largely determined by a shared epitope in DRB1 alleles marked by several motifs. These motifs occur in otherwise normal DRB1 alleles, characterized by net positive or neutral charges in the binding groove. We hypothesize that these polarities cause poor binding of DRB1 to M. leprae. On presentation, the signal via the T cell receptor results in muted cell-mediated immunity. The resulting response translates to various forms of leprosy depending on degree of charge consonance between M. leprae and host DRB1 allele. Other factors within or without the HLA complex, such as the T cell receptor repertoire, may also influence the resulting disease.

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64.) Testing candidate genes that may affect susceptibility to leprosy.

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Tissue Antigens 1998 Aug;52(2):147-52

Cervino AC, Curnow RN

Department of Applied Statistics, University of Reading, U.K.

Several statistical methods have been used to search familial data sets for marker alleles associated with the occurrence of a disease. In the present paper, a recently developed method is used to re-analyze published data on leprosy and candidate genes at the HLA loci. This new method of analysis, the randomization transmission disequilibrium test (TDT), confirmed previous conclusions that there was no significant evidence against random transmission at the HLA-A locus but significant positive association with the HLA-DR2 allele. The randomization TDT detected significant protective associations, that had not previously been found, with alleles HLA-B8 in Egyptian families and HLA-B21 (current nomenclature B x 4901, 5001-5002) in South Indian families, highlighting a major advantage of permutation tests in analyzing candidate gene loci with rare alleles.

These findings provide evidence that HLA class I restricted T lymphocytes may be of protective importance in leprosy.

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65.) [Leprosy, an "exemplary" humanitarian disease]?

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Ann Chir Plast Esthet 1999 Feb;44(1):46-55

Mole B

Leprosy still remains a dreaded disease despite the possibilities of permanent cure, the efficacy of surgical corrections, and its forthcoming disappearance. The authors conducted several surgical missions in Benin-Africa--over 4 years and report an interesting rate of control in the survey of patients as the results of their procedures were reviewed in 84% of them. Leprosy represents the perfect example of the difficulties of any humanitarian involvement with apparent contradictions between the aims of the medical wishes and the presence of a dreaded symbol that--fortunately or not--allow the existence of the many associations involved in the fight against leprosy.

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66.) Prediction of elimination of leprosy in leprosy endemic areas of China.

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Indian J Lepr 1999 Apr-Jun;71(2):189-201

Chen XS, Li WZ, Jiang C, Ye GY

Institute of Dermatology, CAMS&PUMC National Centre for STD and Leprosy Control, Nanjing, China.

A study was carried out based upon the data from the National System for Leprosy Surveillance and using appropriate mathematical models.

The results showed that of 337 counties where the national goal of basic eradication of leprosy had not been reached and in 40 counties where the WHO goal of leprosy elimination had not been achieved in 1996, the detection rates in calendar years followed exponential models with significant goodness-of-fit. In the 67 counties with downward trends of detection rates, the national goal can be met in terms of detection rate in 6% of counties before the year 2000 or 34.4% before the year 2010, or, in terms of prevalence rate in 31.3% before the year 2010.

In the 11 counties with downward trends of the detection rates, the WHO target can be met in eight to ten counties within this century when the duration of disease was determined with the WHO definition. If the MB proportion among new cases increased by 10%, the target would be met one year later. However, at the same MB proportion, the change of fixed treatment schedules from PB six months and MB two years to PB nine months and MB three years will cause achievement of the goal to be postponed by two to ten years.

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67.) [Global leprosy, current status and a future outlook].

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Nihon Hansenbyo Gakkai Zasshi 1999 Jul;68(2):87-90

Yuasa Y

Sasakawa Memorial Health Foundation.

Successful "Leprosy Elimination Programme" since 1991 managed to reduce global case load to nearly 1/10 in 10 years. However, this rapid fall of case detection/incident rate. This means that even after year 2,000, control effort of leprosy as an infectious disease must be sustained, while adequate control/care of leprosy as a deformity/disability causing disease need more attention.

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68.) Lot quality assurance sampling (LQAS) for monitoring a leprosy elimination program.

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Int J Lepr Other Mycobact Dis 1999 Jun;67(2):143-9

Gupte MD, Narasimhamurthy B

Institute for Research in Medical Statistics, Tamil Nadu, India.

In a statistical sense, prevalences of leprosy in different geographical areas can be called very low or rare. Conventional survey methods to monitor leprosy control programs, therefore, need large sample sizes, are expensive, and are time-consuming. Further, with the lowering of prevalence to the near-desired target level, 1 case per 10,000 population at national or subnational levels, the program administrator's concern will be shifted to smaller areas, e.g., districts, for assessment and, if needed, for necessary interventions. In this paper, Lot Quality Assurance Sampling (LQAS), a quality control tool in industry, is proposed to identify districts/regions having a prevalence of leprosy at or above a certain target level, e.g., 1 in 10,000.

This technique can also be considered for identifying districts/regions at or below the target level of 1 per 10,000, i.e., areas where the elimination level is attained. For simulating various situations and strategies, a hypothetical computerized population of 10 million persons was created. This population mimics the actual population in terms of the empirical information on rural/urban distributions and the distribution of households by size for the state of Tamil Nadu, India. Various levels with respect to leprosy prevalence are created using this population.

The distribution of the number of cases in the population was expected to follow the Poisson process, and this was also confirmed by examination. Sample sizes and corresponding critical values were computed using Poisson approximation. Initially, villages/towns are selected from the population and from each selected village/town households are selected using systematic sampling. Households instead of individuals are used as sampling units.

This sampling procedure was simulated 1000 times in the computer from the base population. The results in four different prevalence situations meet the required limits of Type I error of 5% and 90% Power. It is concluded that after validation under field conditions, this method can be considered for a rapid assessment of the leprosy situation.

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69.) Patient contact is the major determinant in incident leprosy: implications for future control.

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Int J Lepr Other Mycobact Dis 1999 Jun;67(2):119-28

van Beers SM, Hatta M, Klatser PR

Department of Biomedical Research, Royal Tropical Institute, Amsterdam, The Netherlands.

Not with standing the elimination efforts, leprosy control programs face the problem of many leprosy patients remaining undetected. Leprosy control focuses on early diagnosis through screening of household contacts, although this high-risk group generates only a small proportion of all incident cases. For the remaining incident cases, leprosy control programs have to rely on self-reporting of patients.

We explored the extent to which other contact groups contribute to incident leprosy. We examined retrospectively incident leprosy over 25 years in a high-endemic village of 2283 inhabitants in Sulawesi, Indonesia, by systematically reviewing data obtained from the local program and actively gathering data through interviews and a house-to-house survey. We investigated the contact status in the past of every incident case. In addition to household contact, we distinguished neighbor and social contacts. Of the 101 incident cases over a 25-year period, 79 (78%) could be associated to contact with another leprosy patient. Twenty-eight (28%) of these 101 cases were identified as household contacts, 36 (36%) as neighbors, and the remaining 15 (15%) as social contacts.

Three patients had not had a traceable previous contact with another leprosy patient, and no information could be gathered from 19 patients. The median span of time from the registration of the primary case to that of the secondary case was 3 years; 95% of the secondary cases were detected within 6 years after the primary case. The estimated risk for leprosy was about nine times higher in households of patients and four times higher in direct neighboring houses of patients compared to households that had had no such contact with patients. The highest risk of leprosy was associated with households of multibacillary patients.

The risk of leprosy for households of paucibacillary patients was similar to the risk of leprosy for direct neighboring houses of multibacillary patients, indicating that both the type of leprosy of the primary case and the distance to the primary case are important contributing factors for the risk of leprosy.

Contact with a leprosy patient is the major determinant in incident leprosy; the type of contact is not limited to household relationships but also includes neighbor and social relationships. This finding can be translated into a valuable and sustainable tool for leprosy control programs and elimination campaigns by focusing case detection and health promotion activities not only on household contacts but also on at least the neighbors of leprosy cases.

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70.) A continuing focus of Hansen's disease in Texas.

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Am J Trop Med Hyg 1999 Mar;60(3):449-52

Taylor JP, Vitek I, Enriquez V, Smedley JW

Tuberculosis Elimination Division and Hansen's Disease Program, Texas Department of Health, Austin 78756, USA.

To describe epidemiologic and clinical characteristics of Hansen's disease cases in Texas, information was abstracted from records of 810 patients reported from 1973 through 1997. Annually, from 18 to 54 patients were reported. Average annual incidence rates ranged from 1.9 to 2.4 cases per million population. A majority of the patients were male (63%) and white (77%). More than half (53%) of the patients were born in the United States; a majority (83%) of the patients born in the United States were born in Texas. Most (76%) patients were diagnosed with multi-bacillary leprosy. Foreign-born patients were more likely to be younger at onset and have multi-bacillary disease compared with patients born in the United States. Within Texas, an endemic focus of Hansen's disease exists along the Gulf of Mexico coast.

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71.) An epidemiological study on Mycobacterium leprae infection and prevalence of leprosy in endemic villages by molecular biological technique. =========================================================================

Indian J Lepr 1999 Jan-Mar;71(1):37-43

Izumi S, Budiawan T, Saeki K, Matsuoka M, Kawatsu K Ternate Leprosy Hospital, Maluku, Indonesia.

One of the most important unsolved questions in epidemiology of leprosy is the highly uneven geographic distribution of the disease. There are many hyperendemic "pockets" in endemic countries. Little is known about the reasons why leprosy is hyperendemic in these areas. We conducted, therefore, a series of epidemiological studies on Mycobacterium leprae infection and prevalence of leprosy in North Maluku district, Maluku Province, Indonesia where leprosy is highly endemic. It was found that considerable number of general inhabitants are seropositive to various mycobacterial antigens and 27% of the villagers were carrying leprosy bacilli on their surface of nasal cavity.

These results suggested the importance of M. leprae in the residential environment in infection of the leprosy bacillus and the resulting transmission of the disease. Based on these observations, we conclude that new preventive measures are essential for global elimination of leprosy in addition to early diagnosis and multidrug therapy (MDT).

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72.) Antimycobacterial activities of riminophenazines.

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J Antimicrob Chemother 1999 May;43(5):615-23

Reddy VM, O'Sullivan JF, Gangadharam PR

Department of Biomedical Sciences, UIC College of Medicine at Rockford, IL 61107, USA.

Riminophenazines were specifically developed as drugs active against Mycobacterium tuberculosis but extensive research over several decades has shown that these compounds are also active against many other mycobacterial infections, particularly those caused by Mycobacterium leprae and the Mycobacterium avium complex (MAC).

Clofazimine, the lead compound in this series, is included in the regimens that are approved by the WHO for the treatment of leprosy and has contributed significantly to the control of that disease, particularly that caused by dapsone-resistant bacteria. Despite early problems, clofazimine has shown clinical efficacy in tuberculosis, in particular that caused by multiple drug resistant strains.

Clofazimine does not induce resistance and also inhibits emergence of resistance to isoniazid in M. tuberculosis. The efficacy of clofazimine against MAC is more varied and the availability of better drugs has limited its use. Newer riminophenazines, such as B746 and B4157, not only showed increased anti-mycobacterial activity but also produced less skin pigmentation, which is the main drawback of this group of compounds.

The most important virtues of riminophenazines, such as intracellular accumulation in mononuclear phagocytic cells, anti-inflammatory activity, a low incidence of drug resistance and slow metabolic elimination, make them attractive candidates for the treatment of mycobacterial infections. It is essential, however, to investigate the newer analogues clinically, while continuing the pursuit of alternate candidates that demonstrate higher anti-mycobacterial activity and lower rates of skin pigmentation.

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73.) Nasal mucosa and skin of smear-positive leprosy patients after 24 months of fixed duration MDT: histopathological and microbiological study.

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Int J Lepr Other Mycobact Dis 1999 Sep;67(3):292-7

Ebenezer GJ, Job A, Abraham S, Arunthathi S, Rao PS, Job CK

Department of Histopathology and Experimental Pathology, Schieffelin Leprosy Research and Training Center, Tamil Nadu, India. The skin and nasal mucosa of 10 lepromatous leprosy patients who had completed 24 doses of fixed duration multidrug therapy (MDT) but who continued to be skin-smear positive for acid-fast bacilli (AFB) were examined histopathologically.

The nasal mucosa showed granuloma fractions that exceeded those seen in the skin specimens, signifying that activity in this region subsides much more gradually than the activity in the skin. Mouse foot pad studies done using T900r mice with an inoculum from the nasal mucosa biopsy specimens of these patients did not demonstrate any growth of Mycobacterium leprae, indicating that these bacilli were not viable.

A skin specimen from one patient grew significant amounts of bacteria in the T900r mouse foot pad. These results show that 2 years of treatment with MDT would prevent dissemination of M. leprae from the nasal mucosa and, therefore, should preclude further transmission of the disease. It also indicates that viable bacteria might persist in the skin of patients, especially those with an initial bacterial index of > or = 4+ who have completed 24 doses of regular MDT. Therefore, a more cautious approach to administering only 12 doses of MDT to highly positive multibacillary patients is suggested.

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74.) Resolution of lepromatous leprosy after a short course of amoxicillin/clavulanic acid, followed by ofloxacin and clofazimine.

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Int J Dermatol 1999 Jul;38(7):558-60

Villahermosa LG, Walsh DS, Fajardo TT Jr, Abalos RM, dela Cruz EC,

Veerasubramanian P, Walsh GP

Publication Types:

letter

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75.) Effect of zafirlukast on leprosy reactions.

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Int J Lepr Other Mycobact Dis 1999 Mar;67(1):71-5

Vides EA, Cabrera A, Ahern KP, Levis WR

Publication Types:

Clinical trial

Clinical trial, phase ii

Letter

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76.) Immunochemotherapy with interferon-gamma and multidrug therapy for

multibacillary leprosy.

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Acta Trop 1999 Mar 15;72(2):185-201

Barral-Netto M, Santos S, Santos I, von Sohsten R, Bittencourt AL, Carvalho EM, Barral A, Waters M

Servico de Immunologia HUPES, Universidade Federal da Bahia, Brazil.

barral@svn.com.br

Treatment for multibacillary leprosy is presently performed with a multidrug therapy (MDT) scheme maintained for 2 years. Leprosy treatment however can benefit from the reduction of length. The lack of interferon-gamma (IFN-gamma) production by lepromatous leprosy (LL) patients' lymphocytes lead us to use this cytokine in the treatment of multibacillary leprosy associated with MDT in the treatment of multibacillary leprosy, and monitor several clinical and immunological parameters during the course of treatment.

A total of 20 multibacillary leprosy patients were evaluated, 10 treated with MDT alone, and 10 treated with MDT + 10 daily doses of 2 x 10(6) international units (IU) of recombinant human IFN-gamma/m2 followed by 10 daily doses of 10(7) IU IFN-gamma/m2, intramuscularly, during the first 20 days of MDT. IFN-gamma was well tolerated and did not cause any increase in the rate of leprosy reactions development during treatment. Decrease of bacillary load, fall of anti-Mycobacterium leprae IgG serum antibodies, changes of histological pattern, as well as changes in lymphocyte proliferation assay in response to mitogens (PHA or PWM), M. leprae antigen or PPD was similar in both groups of patients.

Among several soluble immunological markers measured before and 30 days after beginning of treatment, levels of soluble IL-2R receptor increased in patients treated with MDT plus IFN-gamma whereas decreased in patients treated with MDT alone. Soluble ICAM-1 levels decreased in the MDT group but did not change in the MDT + IFN-gamma treated patients. Soluble CD4 and soluble CD8 markers did not change significantly in either group of patients. Neopterin, a marker of macrophage activation, increased in all but one patient treated with MDT + IFN-gamma but in none treated with MDT alone, indicating that IFN-gamma was active in vivo.

Our findings indicate that despite being able to promote macrophage activation in multibacillary leprosy patients a short course of systemically administered IFN-gamma is not able to change the clinical course of a long standing disease such as leprosy.

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77.) Thalidomide's effectiveness in erythema nodosum leprosum is associated with a decrease in CD4+ cells in the peripheral blood.

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SO - Lepr Rev 1992 Mar;63(1):5-11

AU - Shannon EJ; Ejigu M; Haile-Mariam HS; Berhan TY; Tasesse G

AD - Pharmacology Research Department, G.W. Long Hansen's Disease Center,

Carville, La 70721. MJ - CD4-CD8 Ratio; Erythema Nodosum [drug therapy]; Leprosy, Lepromatous [drug therapy]; Thalidomide [therapeutic use] MN - Adult; Erythema Nodosum [immunology]; Leprosy, Lepromatous [immunology] MT - Human; Male; Support, Non-U.S. Gov't PT -JOURNAL ARTICLE

AB - Thalidomide is well documented as being an effective drug in the treatment of erythema nodosum leprosum (ENL). The mechanism of action of thalidomide in ENL as well as the pathogenesis of ENL are yet to be fully determined. Lepromatous leprosy patients experiencing ENL have been reported to have an increase in the ratio of CD4+ to CD8+ cells in their blood and ENL skin lesions. Thalidomide has been shown to cause a decrease in the ratio of CD4+ to CD8+ lymphocytes in the blood of healthy males. This decrease was due to a significant reduction in the numbers of Cd4+ lymphocytes and an apparent increase in the numbers of CD8+ lymphocytes. In this study, thalidomide's effectiveness in halting chronic ENL and arresting a relapse into ENL was consistently associated with a decrease in the numbers of CD4+ lymphocytes in the blood of 2 male lepromatous leprosy patients.

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78.) La lepra, Evolucion Historia, epidemiológica y medidas de control. Autor: Zulueta R, Ana M

Dermatologia Venezolana, Vol. 2 No. 4, 1.992

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79.) Leprosy in infants.

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Baker B. et al.

In J leprosy 53:517-23

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80.) Leprosy in a child of less than two months of age.

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Benerjee, K, Meyers W.M.,

Clinical Dermatology, The CMD Case collection, World Congress Of Dermatology Berlin (West),

May 24-29-1.987,: 149.

History. Patient was a less than 2 months oid male baby belonging to one of the trained nurses of our Institute. The chud had close, intimate contact with a relative who suffered from dimorphous leprosy and who had taken treatment for only 6 months before discontinuing it on his own. Examination. A round, elevated, red-dish lesion was detected on the face (see attach). Investigations. KOH mount of scrap-ings showed no fungus.

A slit smear for acid fast bacilli was negative. Histopathology. Skin biopsy material was sent to 4 different centres. Ah of them confirmed it to be Hansen's disease of a tuberculoid nature. Treatment. The lesion resolved completely within three months' treatment with D.D.S. 2.5 mg for 5 days each week.

Conclusion. To my knowledge leprosy at less than 2 months of age has not yet been reported and may be disputed. Two cases of leprosy at 6 months of age were reported by Bruce Baker et al. The precise mode of natural transmission, the incubation period and clinical manifestation have not yet been established. Early signs and diagnosis may be missed in the mistaken belief that leprosy is non-existent in the very young.

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DATA-MÉDICOS/DERMAGIC-EXPRESS No 2-(87)  26/01/2000 DR. JOSÉ LAPENTA R. 

UPDATED 07 JULY 2025

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Produced by Dr. José Lapenta R. Dermatologist

Venezuela 1.998-2.025

Producido por Dr. José Lapenta R. Dermatólogo Venezuela 1.998-2.025

Tlf: 0414-2976087 - 04127766810