This is a multidisciplinary program designed to study mechanisms of cell mediated immunity and how it is subverted in leprosy. In particular, we will define the cellular mechanisms necessary to mount a cell mediated response to M. leprae in cutaneous macrophages. For this purpose we will examine the structural and functional phenotypes of emigrating, blood borne T cells and monocytes as well as resident Langerhans cells and keratinocytes. Using immunocytochemistry, electron microscopy, cell proliferation, activation and cytotoxicity assays as well as Northern blotting and in situ hybridization we will evaluate the nature, interaction and secretory repertoire of the cells which accumulate in lepromatous skin. We will compare the host response to antigenic challenge with Lepromin and PPD to that obtained with the recombinant human lymphokines IFNY, IL-2 and GM-CSF. The ability of these agents to modify host macrophages and dispose of M. leprae in situ will be compared with the generation and function of cytotoxic T cells against monocytes in vitro. The ability of these immune modulators to kill M. leprae will be evaluated using mouse foot pad injection. The role of M. leprae macromolecules in inhibition of the function of T cells and their subsets will be dissected with purified M. leprae components, and various triggers. Each of these modalities will be followed temporally, in selected patient populations, obtained through collaborative efforts in Brazil, India, Ethiopia and the Phillipines.