Significant progress in understanding the immunopathogenesis of Leishmania infection has been made using inbred strains of mice. Resistance of Leishmania major has been correlated with the ability to expand and activate CD4+ T cells that produce IFN-gamma, the major macrophage activating factor identified in this disease. In contrast, susceptible mice expand CD4+ T cells that produce IL-4 and IL-10, cytokines that interfere with the production of IFN-gamma and the ability of IFN-gamma to activate target macrophages to kill the intracellular amastigotes. The characteristics of these disparate CD4+ T cell populations suggest that these cells represent in vivo correlates of Th1 and Th2 subsets described in studies of murine T cell clones. Limited studies in human populations suggest that similar findings may accompany human visceral leishmaniasis and that Th1 and Th2 subsets also occur among human CD4+ T cell clones. Susceptibility is not related to deletion of the requisite IFN-gamma- producing T cell clones, since a variety of immunologic manipulations made at the time of infection enables susceptible mice to heal with the establishment of Th1 cell populations. Adoptive transfer of parasite- specific Th1 and Th2 lines and clones has demonstrated that these cells constitute stable cell populations capable of mediating the full spectrum of susceptibility and resistance, in large part through the effector functions of the lymphokines secreted by these cells. Although these types of effector CD4+ subsets are being incriminated in increasing numbers of parasitic diseases, the mechanisms by which these subsets become established remain unknown. Studies using neutralizing monoclonal antibodies have identified key cytokines that must be present during the early periods after infection in order for Th1 or Th2 development to proceed, although studies using recombinant cytokines have been unable to reverse genetically predetermined outcomes. This proposal seeks to use Leishmania major infection in inbred strains of mice to develop methods to examine closely the early events that are critical to the development of Th1 and Th2 effector subsets. The strategy involves both analysis of early cytokine requirements and a direct approach to the identification of antigens implicated in CD4+ subset activation. There are three specific goals: 1. to use parasites transfected with cytokine genes to target critical immune molecules directly to the infected macrophage; 2. to establish whether Th1 and Th2 cells arise from a common precursor; and 3. to begin studies to sequence directly critical peptides from the parasite that are complexed to MHC class II molecules that are involved in activation of important Th1 and Th2 clones. These studies should provide important insights towards the understanding of Th1 and Th2 cell subset maturation and the characteristics of critical parasite antigens involved in this process.
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