The TAM receptors (tyro 3, axl, mer) have emerged in recent years as master regulators of macrophage and dendritic cell activation and phagocytosis. Absence of one or more of these tyrosine kinases results in inflammation and autoimmunity. The TAM receptors are attractive targets for in vivo therapy with monoclonal antibodies or recombinant ligands. Stimulation through these molecules promotes a shift of cytokine production away from M1 inflammatory macrophages to M2 non- inflammatory, reparative cells, and decreases dendritic cell type I interferon secretion and activation. Such a modulation of macrophage and DC function may be desirable for inflammatory arthritis and diverse autoimmune conditions. In this proposal, we wish to explore the potential of antibodies to mer to modulate DC function in vitro, and to administer these antibodies in vivo to animals to assess their effects on the immune response. Through these preclinical studies, we expect to learn more about the biology of the receptors and to provide data to guide a parallel therapeutic approach in humans.
Control of inflammation is central to the treatment of most rheumatic diseases and of many other illnesses encountered throughout medicine. As our understanding of this process increases, so does the possibility of better and more specific ways to intervene in this process. Macrophages and dendritic cells are intimately involved in inflammation and recent discoveries of key receptors on these cells which control their activation opens the possibility of using them as targets for new therapeutics. We have a longstanding interest in the TAM receptors (tyro 3, mer, axl) expressed mostly on macrophages and on dendritic cells. These proteins control not only the ability of the cells to ingest debris, but also the nature and quantity of important mediators of inflammation (cytokines) produced by these cells. In this proposal, we wish to explore the use of novel antibodies we have made which activate the TAM receptors and - in principle - may direct macrophages and dendritic cells away from inflammation and toward healing and suppression of inflammation. We will use them in vitro and in animal models. If these antibodies have such an effect on models of arthritis and lupus in mice, a parallel approach to human inflammatory illnesses may open up, with the possibility of controlling many autoimmune and inflammatory diseases.
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