IL-3 and IL-4R in Mast Cell Growth and Hypersensitivity

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DESCRIPTION (provided by the applicant): Mast cells are of hematopoietic origin but complete their differentiation in peripheral connective tissues where they are thought to function as important effector cells in IgE-associated immune responses. Indeed, a large body of evidence indicates that mast cell mediator secretion significantly contributes to both allergic disorders, such as anaphylaxis and asthma, and to host resistance to certain parasites. The long-term objectives of this project are to understand to what extent the production of interleukin (IL)-3, and interactions between IL-3 and IL-4 receptor a chain (IL-4R alpha) signaling pathways, regulate the development and function of mast cells, and hypersensitivity responses in vivo. Studies using IL-3-deficient mice indicate that IL-3 contributes to increased numbers of tissue mast cells and immunity in mice infected with certain parasites. However, the ability of IL-3 to influence IgE- and mast cell-associated immune responses has not yet been examined in these mice. Therefore, we wish to employ IL-3-deficient mice to test the hypotheses that IL-3 is required for the full expression of local and systemic anaphylactic responses in vivo. Because mast cell-derived chemokines represent potentially important mediators in allergic inflammation, we also wish to test the hypothesis that exogenous IL-3 can regulate mast cell chemokine production either in the absence or presence of IgE and specific antigen. Numerous in vitro studies have suggested that IL-4 may act in concert with IL-3 to control mast cell development and function in vivo, and recent evidence suggests that IL-3 and IL-4, and perhaps IL-l3, are involved in regulating contact hypersensitivity. It would be advantageous to study mouse lines in which the expression of all of these cytokines is disrupted. Unfortunately, the close linkage of these genes precludes the generation by simple interbreeding of mouse lines that simultaneously lack these cytokines. To circumvent this difficulty we will take advantage of an exciting new opportunity to develop and analyze mice with a combined deficiency of IL-3 and IL-4Ra (IL-4Ra is also a component of IL-13R), thereby allowing us to investigate the potential compensatory roles of these cytokines in vivo. Specifically, we will use mice deficient in both IL-3 and IL-4Ra to analyze the requirement of IL-3, IL-4, and IL-13 for: 1) generating physiological levels of tissue mast cells, 2) gastrointestinal parasite-induced mast cell hyperplasia, and 3) regulating the expression of contact hypersensitivity reactions to haptens.