Mycobacterium leprae is an obligate human intracellular pathogen which has not been cultivated successfully in vitro. Experimental models of this disease do not provide a close parallel, either histopathologically or immunologically. Several atypical Mycobacteria (M. Simiae, M. avium) produce chronic, non-fatal systemic infections in normal immunocompetent mice which offer a number of parallels to lepromatous leprosy, whilst providing the great advantage of ready culturability in vitro. Such mice develop a persistent anergic state to the specific footpad sensitin(s) and fail to express and obvious cell-mediated immunity (CMI). The proposed studies will examine the in vivo interactions between T-cell and macrophage populations within the heavily infected spleen as the infection progresses, using an adoptive cell transfer system which will allow various purified T-cell subpopulations to be tested quantitatively for their expressor/suppressor activities in vivo. These studies should lead to a better understanding of the role played by these cells in the establishment of the persistent M. avium-intracellulare infections in vivo and further establish this infection as a realistic model with which to study the immunology of lepromatous leprosy. The effect of various chemotherapeutic and immunomodulatory agents on this process can then be determined. The second objective will be to study the bactericidial (or bacteriostatic) mechanisms associated with activated macrophages harvested from hypersensitive and anergic donors. In particular, the role played by activated oxygen intermediates and lysosomal enzymes on this process and the expression of resistance to this process by the persister (but not the non-persister) strains of atypical Mycobacteria will be explored. Finally, attempts will be made to isolate and characterize the protein sensitin released by actively multiplying Mycobacteria in vitro (and by inference, by the same organisms growing in vivo) and presumed to be responsible for the induction of both DTH and CMI. Development of the specific monoclonal antibodies will be used to purify the sensitin(s) which will be tested as a potential immunogen and immunotherapeutic agent in vivo by restoring cell-mediated reactivity to the anergic, chronically infected host.
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