INTERLEUKIN-12 AS IMMUNOTHERAPY IN LEISHMANIASIS

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The long-term goal of these studies is to understand cytokine-based mechanisms responsible for curative and noncurative immune responses during leishmaniasis. A well-characterized model of murine leishmaniasis has already provided important insights into the cytokine pathology of this disease. Progression of L. major infection from cutaneous to visceral sites in susceptible BALB/c mice is mediated by expansion of the Th2 CD4+ lymphocyte subset and production of IL-4. Although IFN-gamma and Th1 CD4+ cell development are necessary for cure in resistant C57BL/6 mice and in BALB/c mice protectively treated with anti-IL-4 antibodies, IFN-gamma therapy does not restore curative immunity in BALB/c mice. Based on our preliminary data, we propose that IL-12 may be a more effective immunotherapeutic agent for Th2-mediated illnesses. IL-12 is a heterodimeric T-cell growth and IFN-gamma stimulatory cytokine that is produced by B-cells and macrophages and that is known to promote Th1 and suppress Th2 cell responses in vitro. Our preliminary studies confirm the ability of IL-12 to cure susceptible BALB/c mice and to durably suppress Th2 immune responses when administered early during infection with L. major. Treatment of resistant C57BL/6 mice with anti-IL-12 antibodies exacerbates disease. We hypothesize that IL-12 strongly inhibits Th2 T cell responses, that suppression of IL-12 synthesis and function during infection causes Th2- mediated progression of disease, and that IL-12 has potential as an immunotherapeutic agent in leishmaniasis and other Th2-mediated parasitic diseases. We propose experiments to explore further the basic biology of IL-12 production and function during leishmaniasis and to identify immunotherapeutic uses in the mouse model that may suggest clinical applications. Specific aims are to: 1) Examine the role of IL-12 in regulating CD4+ subset selection and curative immunity in disease-susceptible BALB/c mice and resistant C57BL/6 mice infected with Leishmania major. 2) Identify differences in the production of IL-12 by BALB/c and C57BL/6 mice during leishmaniasis. 3) Develop uses for IL-12 as a therapeutic modulator of immune responses during established leishmaniasis.