The objectives of this project are to (a) extend our analysis of how Leishmania donovani achieves its state of intracellular parasitism, and thus, causes persistent visceral infection, and (b) determine what cellular immune mechanisms are available to the host to control or eradicate visceral leishmaniasis. To accomplish these two long-term objectives, whose ultimate intent is to improve the treatment of patients with leishmaniasis, we will examine host-parasite interaction at the cellular and tissue level and at the level of the intact animal host. The specific aims of this project are to (1) determine the source and role of interferon (IFN)-gamma and interleukin 2 (IL2) in macrophage activation in experimental visceral leishmaniasis, (2) analyze the cellular immune response to L. donovani at tissue (granuloma) level, (3) determine how suppressor cell mechanisms provoked by L. donovani infection inhibit the cellular immune response and T cell secretion of IFN-gamma and IL2, and thus, prevent macrophage activation and leishmanicidal activity, (4) test the in vitro efficacy and tissue effects of treatment with IFN-gamma, IL2 and indomethacin (antisuppressor) agent in experimental visceral leishmaniasis, and finally (5) determine if immunotherapy (with IFN-gamma or IL2) can act synergistically in vivo with antileishmanial chemotherapy to achieve superior therapeutic results. These studies and models have been designed to address key but as yet unresolved immunopathogenetic issues in leishmaniasis. We anticipate that the proposed detailed analysis, to be conducted at the cellular, tissue, and intact-host levels, will provide a sound and rationale basis for approaching the future pharmacologic or immunologic management of world-wide infections caused by L. donovani, other strains of Leishmania, and other intracellular pathogens as well.