PROPHYLAXIS OF L. TROPICA INFECTIONS WITH CYCLOSPORINES

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The proposed study on the prophylaxis of Leishmania tropica infections in Balb/c mice with the known immunosuppressant Cyclosporine A and its analogue, B-5-49, will attempt to elucidate the drug-induced alteration in the host response to the parasite which enables this highly susceptible mouse strain to mount an effective curative immune response to the infecting protozoa. Leishmania tropica infections in Balb/c mice have been used as experimental models of both diffuse cutaneous and the frequently fatal systemic leishmaniasis in man. Our understanding, treatment and prevention of these two world-wide infections is strikingly incomplete or inadequate. It is hoped that this study will help to clarify the important immunomodulatory effects of the two cyclosporines which apparently prevents leishmania specific immunosuppression from developing during the infectious process. After determining the optimum protective treatment regimen for both drugs, the antigen-specific and non-specific immune responsiveness of infected, treated animals will be monitored and compared to non-treated controls. Specifically, the development and level of: 1) delayed type hypersensitivity, 2) anti-leishmanial antibodies and 3) resistance to parasite challenge will be determined over time as well as level of immune responsiveness in vitro in response to unrelated antigens (SRBC) and mitogens. Of particular interest will be the ability of lymphocytes from the experimental animals to produce lymphokines which are capable of stimulating macrophage cidal activity toward intracellular leishmania. The level of immunosuppression in treated, non-infected animals will also be determined to clearly establish the level of immunocompetence following the chosen treatment regimen for both drugs.