DESCRIPTION (adapted from application abstract): Interleukin-4 (IL-4) plays an important role in promoting the differentiation of naive T cells into IL-4- secreting Th2 cells. The balance of Th1 (IFN) cytokine responses versus Th2 responses in vivo is thought to be involved in several infectious diseases and allergic responses. The prototypic in vivo model used to study Th1/Th2 responses is infection with the protozoan parasite Leishmania major. Infection of susceptible BALB/c mice induces strong IL-4 and Th2-associated cytokine responses, but L. major infection in resistant strains of mice is associated with a Th1 cytokine profile. The long-term goal of this research is to study the role of IL-4 in Th2 responses, and specifically, in determining susceptibility to L. major in BALB/c mice. To that end, genetically pure BALB/c IL-4 and IL-4R deficient mouse strains were generated through gene- targeting in BALB/c embryonic stem cell lines. Infection of these mice have revealed differences in susceptibility depending on the parasite substrain and indicated that there are alternative pathways for at least some L. major parasite strains to escape immune mechanisms in the absence of IL-4. The goal of the proposed research is to identify the mechanism that allows the substrain L. major LV39 to continue to cause disease in both IL-4-/- and IL-4R -/- mice. The hypothesis is that a factor other than IL-4 or IL-13 is induced by L. major LV39, but not by IR173, in IL-4R -/- mice. In order to explain the difference between anti-IL-4 treatment in vivo and the results with genetically-deficient mice, the hypothesis is that anti-IL-4 affects Th2 responses as well as cellular infiltration. In Specific Aim 1, the cytokine profiles induced by LV39 and IR173 infections will be characterized at the sight of inoculation in an ear dermal model of infection. In Specific Aim 2, the role of IL-10 compensation will be addressed by neutralizing IL-10 in vivo and infecting BALB/c IL-10 x IL-4R -/- double knockout mice with L. major LV39. In Specific Aim 3, the action of anti-IL-4 treatment on cellular infiltration will be tested in a dermal infection model. These studies will provide novel insights into the properties of different L. major parasites and will offer alternative theories to the Th1/Th2 paradigm in general. These studies also will lead to new interpretations of the action of anti-IL-4 treatment in vivo.