The mer/axl/tyro3 subfamily of tyrosine kinases (TAM kinases) plays a powerful role in regulating activation of macrophages, dendritic cells, and NK cells by diverting cytokine production from inflammatory to noninflammatory cytokines. These receptor kinases bind to phospholipid-binding proteins which in turn bind to phospholipids, notably phosphatidylserine on apoptotic cells. These signaling molecules can thus down regulate innate immunity when they bind to dying cells or other phospholipid-containing debris. We propose to perform the first studies of these important molecules in humans and in human disease. The central hypothesis of this proposal is that these key regulatory molecules can be harnessed as potential targets for immunotherapy of lupus and other inflammatory and autoimmine disorders. The first Specific Aim is to define which human immune cells - and subsets of cells - express these molecules. In the second Aim, we will ask how expression is regulated during immune activation and cell maturation. We are especially interested in the possibility that the immunomodulatory role of immune complexes might be mediated through mer, and that the composition of immune complexes, notably their phospholipid content, may be of importance in mer cross linking. In the third Specific Aim, we will test whether cross linking of mer/axl/tyro3 (individually and together) leads to down regulation of macrophage, dendritic cell, NK cell, and lymphocyte activation in vitro. These studies will lead the way to developing an important potential therapeutic target for treatment of autoimmune and inflammatory disorders. In the fourth Specific Aim, we will examine expression of these molecules in human SLE peripheral blood, hypothesizing that this autoimmune condition may be characterized by increased expression of these kinases. We will ask whether the overexpression of type I interferon-related genes (the lupus """"""""signature"""""""") can be diminished by cross linking of these immunoregulatory kinases. Such experiments may give support to the notion that therapeutic ligation of these receptor kinases could be used to control autoimmunity and inflammation.
These studies are relevant to the overall mission of the ACE as they will contribute to understanding of a specific autoimmune disorder but will very likely have applications to other disases and to immunoregulation in humans in general. They are related to the T-cell cytokine polarization studies in that macrophage and DC activation is key to this process;and to the proposed stem cell transfer experiments looking at SLE immunoregulatiory disorders.
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