MACROPHAGE ACTIVATION IN EXPERIMENTAL LEISHMANIASIS

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The proposed study on macrophage activation in experimental leishmaniasis will attempt to define the role of macrophages bearing Ia in the response of genetically susceptible and resistant strains of mice toward Leishmania major infections. Whereas Balb/c mice develop visceralizing, fatal infections which have been used as experimental models both for diffuse cutaneous and systemic leishmaniasis in man, the C57B1/6 mice are resistant to severe disease and recover completely following the development of local lesions. The reasons for the different immune responses to the parasite in these two strains of mice is not well understood but may be related to the tendency of the susceptible Balb/c mouse strain to undergo an inappropriate, nonprotective expansion of T lymphocytes following infection. This expansion of T cells apparently leads to the inability to control or develop immunity to the parasite, a theory substantiated by the fact that various immunomodulatory strategies including prophylactic cyclosporine A treatment allows for protection and the development of immunity against L. major in the susceptible mouse model. As lymphocytes may be stimulated to expand by activated, Ia bearing macrophages, it may be that an over-abundance of these stimulatory macrophages become activated during infection in non-immunosuppressed, infected Balb/c mice. Indeed, preliminary data has shown a very high level of Ia-bearing peritoneal exudate cells does develop in infected Balb/c mice as compared to non- infected controls. It is hoped that this study will help to clarify the role of activated macrophages in the susceptibility or resistance of mice to L. major and their relation to the disease process. Specifically, the levels of Ia bearing macrophages of the periotoneal cavities of C57B1/6, Balb/c and cyclosporine treated Balb/c mice will be compared at different times following infection. In addition, infected Balb/c mice will be prophylactically treated with anti-Ia antibody in order to further analyze the possible immunoregulatory role of macrophage activation in systemic disease development. All animals will be followed for disease progression at each time point by determinations of lesion size, cell numbers and weights of the draining lymph node and spleen, metastasis of Leishmania to the spleen and lymph node and levels of anti-leishmanial antibodies and delayed type hypersensitivity toward a leishmanial antigen.