. Studies with Leishmania major, which visceralizes in susceptible mice to produce a disease much like human kala-azar, have shown that the inability to control the parasite correlates with the inability to activate and expand CD4+ T cells to produce IFN-gamma. Although resistant mice successfully activate CD4+ cells that produce IL-4, a cytokine that interferes with both the production of IFN-gamma and the capacity of IFN-gamma to activate macrophages to kill the intracellular parasite. The inability of susceptible mice to heal is not due to a deletion of the requisite IFN-gamma-producing CD4+ T cells, since various immunologic manipulations, including anti-IL-4 monoclonal antibody, enable susceptible animals to control infection. These immunologic manipulations must be made at the onset of infection, however, suggesting that the early interactions of parasite antigens with the immune system are most important in determining the outcome of disease. These experiments, together with various reconstitution experiments into defined recipient mice using parasite-specific CD4+ lines and clones, implicate CD4+ cells centrally in the response of leishmania. This proposal seeks to analyze CD4+ T lymphocytes at the molecular level in order further insights into genetic determinants of susceptibility with the potential for the development of unique therapeutic approaches. There are four specific goals: 1). to assess T cell receptor (TcR) usage that occurs in susceptible BALB/c mice during infection with Leishmania and after interventions (anti-CD4, anti-IL-4) that allow these mice to heal and develop immunity; 2) to characterize CD4+ cell lines and clones established from these mice for TcR type, antigen specificity, cytokine profiles and the capacity to mediate protection or progressive infection when transferred into scid mice; 3) to clone and sequence TcR beta and alpha cDNA from CD4+ clones implicated in mediating disease outcome; 4) to clone the genomically rearranged TcR genes and established transgenic mice in order to examine directly the role of TcR in mediating susceptibility and Th cell development.
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