The ability to avoid autoimmunity is a cardinal feature of the immune system. In healthy individuals, this is achieved by several mechanisms of """"""""immunological tolerance."""""""" Dendritic Cells (DCs) play a critical role in the induction of immunological tolerance. DCs express an elaborate system of pathogen recognition receptors (PRRs), that enable them to sense conserved molecular signatures contained in microbes, and then decode this information to elicit an appropriate immune response. In this context, the present proposal focuses on the potent anti inflammatory effects of the yeast cell wall, zymosan, which is recognized by dectin-1, a C-type lectin receptor for beta-glucans, and by TLR 2, expressed in murine and human DCs. Our preliminary data suggests that zymosan induces regulatory dendritic cells and macrophages which secrete copious amounts of the anti-inflammatory cytokines IL-10 and TGF-beta but little pro-inflammatory cytokines, and induce tolerogenic T cell responses. In this context, the overarching goals of the present proposal are: 1) to determine the molecular mechanism(s), including the recognition receptors and intracellular signaling networks by, which zymosan exerts its anti-inflammatory, tolerogenic effects; 2) to determine whether the anti-inflammatory effects of zymosan can be exploited in the immune therapy of autoimmune diabetes. This will be achieved in the following aims:
Aim 1 : To determine the receptor(s) and signaling pathway(s) by which zymosan induces IL-10 in DCs Aim 2: To determine the principal cell type(s) and receptors that mediate TGF-beta production in response to zymosan Aim 3: To determine whether injection of soluble antigen + zymosan into mice, induce regulatory T cells, via a mechanism dependent on IL-10 and TGF-beta Aim 4: To determine whether injections of antigen + zymosan into diabetic prone mice can protect from autoimmune Th1 responses Successful completion of these goals promises to provide us with novel insights into the critical intracellular signaling components within DCs that mediate the induction of tolerogenic T cells. Such insights should be of great value in the design of novel therapeutic approaches in the control and prevention of autoimmune diseases.
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