Biomedical subjects
Publications and source records attributed to V Mehra.
The first of a series of epidemiological studies in progress in India has shown a strong association between risk of cataract and remembered episodes of dehydrational crises from severe cholera-like diarrhoeal disease. The findings suggest that severe diarrhoea is a major risk factor in early development of cataract and might account for about 36% of cases in the study area.
The various forms of leprosy form a clinical and immunological spectrum which offers extraordinary possibilities for insight into immunoregulatory mechanisms in man. At one pole, tuberculoid leprosy, patients develop high levels of cell-mediated immunity which ultimately results in killing of bacilli in the tissues, albeit often with damage to nerves. At the lepromatous pole, patients exhibit selective immunological unresponsiveness to antigens of M. leprae. Even though all currently known protein species of M. leprae and BCG are cross-reactive, lepromatous patients unreactive to M. leprae antigens frequently respond strongly to tuberculin. In vitro experiments suggest the existence of lepromin-induced suppressor activity, mediated by both monocytes and T cells. The T suppressor cells have the T8 phenotype of which 50% express the activation markers, Ia and FcR. The one unique species of antigen of the leprosy bacillus is a phenolic glycolipid, and it appears that the TS cells largely recognize the terminal trisaccharide of this unique antigen. Depletion of the TS cells restores in vitro reactivity of lymphocytes to lepromin in a portion of lepromatous patients, and addition of IL-2-containing supernatants partially restores responsiveness to M. leprae antigens. Vaccination of lepromatous patients with a mixture of M. leprae and live BCG restores cell-mediated immunity in the majority of lepromatous patients, and concomitantly reduces the in vitro suppressor activity and number of activated T8 cells. These experiments suggest the existence of stage-of-disease related suppressor cells in leprosy which appear to block the responsiveness of TH capable of responding to either specific or cross-reactive mycobacterial antigens. The mode of action of these TS appears to be the inhibition of production of IL-2 and other lymphokines. Successful immunotherapeutic vaccination appears to overcome this block in the majority of patients.
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A patient with acquired agammaglobulinemia had an antihelper T cell factor that was identified as an immunoglobulin of the IgG class. The factor specifically bound to the TH2- T cell subset and, in the presence of complement, abolished the helper effect of normal T cells. The antihelper T cell antibody preceded by several years the appearance of suppressor TH2+Ia+ T cells, at which time the clinical course rapidly deteriorated. Plasmapheresis resulted in lymphocytosis and reappearance of a functionally intact helper T cell population. It did not affect the suppressor cells. Conversely, total thymectomy resulted in a temporary disappearance of the TH2+Ia+ suppressor cells, but did not decrease the levels of the autoantibody to helper T cells. Neither of these treatments reversed the state of agammaglobulinemia.
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Guinea pigs immunized with intact or disrupted armadillo-grown human Mycobacterium leprae administered in aqueous or oil vehicles were tested with various dilutions of M. leprae suspended in saline, water-soluble M. leprae extract, purified protein derivative, and a water-soluble extract of normal armadillo tissue. The results demonstrated the following. (i) Under no conditions was any skin test reactivity found to normal armadillo tissue extract. (ii) Positive sensitization to both M. leprae and its water-soluble extract was achieved by sensitizing guinea pigs with M. leprae suspended in Hanks solution or saline. Autoclaved M. leprae in Hanks solution or saline inoculated intradermally was an effective immunogen. Oil suspensions or emulsions were effective at sensitization, but appeared to be no better and, in general, slightly weaker, than simple inoculation in aqueous suspension. (iii) Living BCG failed to reveal a significant adjuvant effect on sensitization to M. leprae. However, cord factor appeared to potentiate slightly the sensitization to M. leprae in aqueous suspension. (iv) The minimum dose required for sensitization with M. leprae in aqueous suspension was 55 micrograms of purified bacilli. (v) Animals inoculated with M. leprae in saline or with M. leprae together with BCG showed positive skin test reactivity to the first skin test application made fully 1 year after the initial sensitization. The efficacy of autoclaved, irradiated M. leprae in aqueous, oil-free medium suggests a relatively safe approach to human vaccination studies.
The possibility of an active mechanism of immunologic suppression in leprosy was explored by assessing the in vitro lymphocyte responses of 61 leprosy patients and 30 normal individuals to the mitogen Con A in the presence or absence of Dharmendra lepromin. Lepromin-induced suppression of Con A stimulation was found in 32 of 35 lepromatous patients and 15 of 15 borderline patients, but only 2 of 15 tuberculoid patients and 2 of 30 normal controls. Cell fractionation studies indicated at least two cell populations involved in the in vitro lepromin-induced suppressor activity, adherent cells and T gamma-cells.
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The lambda gt 11 expression vector permitted us to survey protein antigens of Mycobacterium leprae and Mycobacterium tuberculosis expressed in Escherichia coli. Using monoclonal antibodies, recombinant clones were detected producing three major antigens of M. tuberculosis and five major protein antigens of M. leprae. These recombinant antigens produced in E. coli should prove useful for diagnosis, epidemiology and possibly the development of recombinant mycobacterial vaccines.
Leprosy remains a significant medical and social problem in many developing countries. The varied forms of the disease form a spectrum. At one pole, tuberculoid leprosy, patients develop high levels of cell-mediated immunity which results in the killing and clearing of bacilli in the tissues. At the lepromatous pole, patients exhibit a selective immunological unresponsiveness to antigens of Mycobacterium leprae so that the organisms inexorably multiply in the skin. We have suggested that in lepromatous leprosy one or a small number of unique antigenic determinants present on M. leprae might induce specific suppressor cells that inhibit the reactivity of helper T-cell clones capable of recognizing other specific or cross reactive determinants. Although unique epitopes have been identified by monoclonal antibodies on a small number of M. leprae proteins, the only unique species of antigen present in M. leprae, and not on any other species of mycobacteria so far examined, is a phenolic glycolipid (gly-I). We show here that this unique antigen of M. leprae is capable of inducing suppression of mitogenic responses of lepromatous patients' lymphocytes in vitro and provide evidence that the suppressor T cells recognize the specific terminal trisaccharide moiety.
Leprosy, a chronic infectious disease afflicting between 10 and 15 million people, is caused by the obligate intracellular parasite Mycobacterium leprae. Although M. leprae was the first identified bacterial pathogen of man, basic biochemical, immunological, diagnostic and therapeutic investigations have been severely limited because it remains one of the few human pathogens that have not been cultured in vitro. An M. leprae recombinant DNA expression library was constructed to provide a source of genes encoding proteins relevant for such studies. Monoclonal antibodies directed against M. leprae specific antigens have been used to isolate the genes encoding the five most immunogenic protein antigens of the leprosy bacillus. We report here that M. leprae specific epitopes recognized by all of 13 monoclonal antibodies tested were produced by recombinant phage in Escherichia coli.
Leprosy is a chronic infectious disease caused by Mycobacterium leprae. As with other intracellular parasites, protective immunity is dependent on T cells and cell-mediated immunity. In animal models, immunization with killed armadillo-derived M. leprae elicits strong T-cell responses, delayed-type hypersensitivity and protection against viable challenge. We have recently shown that killed M. leprae can induce delayed-type hypersensitivity in healthy human volunteers. Identification of the M. leprae antigens that are recognized by T cells and may be involved in protection has been hampered by the inability to cultivate the organism in vitro and by difficulties in antigen purification from limited quantities of armadillo-derived bacillus. Because genes for the major protein antigens of M. leprae as seen by mouse monoclonal antibodies have been isolated, it has become possible to test whether these individual antigens are recognized by T cells. We screened crude lambda gtll phage lysates of Escherichia coli containing individual M. leprae antigens using M. leprae-specific T-cell clones isolated from M. leprae-vaccinated volunteers. Using this method, we find that nearly half of the M. leprae-specific T-cell clones are stimulated to proliferate by lysates containing an epitope of a M. leprae protein of relative molecular mass 18,000 (18K).
Leprosy is a spectral disease in which immune responses to Mycobacterium leprae correlate with the clinical, bacteriological and histopathological manifestations of disease, so study of its pathology provides insights into immunoregulatory mechanisms in man. At the tuberculoid pole, patients have few lesions in the skin which contain rare organisms and are able to mount strong cell-mediated immune responses to M. leprae antigens. In contrast, at the lepromatous pole, patients have disseminated skin lesions containing large numbers of acid-fast bacilli and are selectively unresponsive to antigens of M. leprae. M. leprae-induced suppressor cells derived from peripheral blood have been reported to be active in vitro, yet their in vivo significance has remained unclear. Because the focal point of the immune response to M. leprae is the skin lesion consisting of lymphocytes and macrophages, we have recently developed methods for isolating lymphocytes from skin biopsies of leprosy patients. We report here that two T8 clones derived from lepromatous leprosy skin biopsies, in the presence of lepromin, suppress concanavalin A (Con-A) responses both of peripheral blood mononuclear cells and of T4 clones in an HLA-D (HLA, histocompatibility locus antigen)-restricted manner. Moreover, these T8 clones suppressed responses of HLA-D-matched, but not HLA-D-mismatched antigen-responsive T4 clones to M. leprae antigens, indicating that T-cell suppression is major histocompatibility complex (MHC)-restricted at some level in man.
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