IL-12 AS AN IMMUNOPOTENTIATOR IN LEISHMANIASIS

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Leishmaniasis is a chronic infection that can cause severe disfiguring cutaneous lesions or fatal visceral disease. Chemotherapy is the only commonly practiced therapeutic intervention in this disease. The potential for such therapy is excellent, since major advances have been made in our understanding of the factors that regulate the immune system. The most notable advance has been the description of the major T helper cell subsets that control the immune system, namely CD4+ Th1 and Th2 cells. The understanding of how these T cell subsets are regulated has provided the potential to intervene in the disease state and potentiate appropriate immune responses. In leishmaniasis it is well established that disease progression in many cases is related to either the inappropriate expansion of the CD4+ Th2 cell subset, or a deficit in the development of CD4+ Th1 cells, which mediate protection. One of the principle cytokines that influences Th1 cell expansion and function is IL-12. This cytokine induces IFN-y, enhances Th1 cell differentiation, and preferentially expands the Th1 subset. In the proposed studies, a murine model of cutaneous leishmaniasis will be employed to develop an immunologically based therapy that incorporates IL-12 as an immunopotentiator. These studies are designed to evaluate basic questions of IL-12 biology, and apply that information towards the development of a prophylactic and therapeutic vaccine. To achieve this goal the first series of studies proposed is to define the mechanism(s) by which IL-12 functions. These experiments include characterization of the role of endogenous IL-12 in resistance to Leishmania major by comparative studies in resistant and susceptible mice, and an evaluation of the cells and cytokines associated with the response to IL-12 when it is used as an immunopotentiator. We will then assess the ability of IL- 12 administered in a therapeutic vaccine to induce resolution of disease. The first series of studies will determine if IL-12 can inhibit TH2 cells in vitro, and what inhibitors (such as monoclonal anti-cytokine antibodies) are required for expansion of Th1 cells. Studies will then directly address the potential to reverse disease development using IL-12 in a therapeutic vaccine. Parallel studies are also proposed to determine if IL-12 can augment the efficacy of chemotherapy. In a related series of experiments we will further define the optimal conditions for induction of protection using IL-12 as an immunopotentiator in a prophylactic vaccine. These experiments will delineate the optimal conditions for induction and expansion of protective CD4+ Th1 cells.