Counter Regulatory Receptors and Allergic Inflammation

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Asthma is a chronic inflammatory process characterized by activation of resident mast cells and infiltrating Th2 cells, eosinophils, and neutrophils with consequent changes in the structural elements of the airways. Strategies to downregulate the inflammatory response are of critical importance in the management of asthma. The objective of this Project is to test the hypothesis that the activation of mast cells, eosinophils, and neutrophils may be modulated by the leukocyte immunoglobulin- like receptors (LIRs), a family of cell surface receptors that are homologous to mouse gp49 and that possess immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic domain. Specific Aim 1 is to confirm the expression of LIR-5 in peripheral blood neutrophils and eosinophils and in culture- derived mature human mast cells and to determine the expression of other LIRs in these cells. Specific Aim 2 investigates the inhibitory actions of LIR-5 in mast cells and eosinophils and will be extended to a study of other LIRs as based on the results of Specific Aim 1. Because of the potential importance of regulated expression of LIRs in inflammatory conditions and as a therapeutic approach to modulating effector cell function, Specific Aim 3 will focus on the developmental regulation of LIRs in eosinophils and mast cells derived by in vitro culture from cord blood, and the expression and function of LIRs in peripheral blood eosinophils treated with interleukin (IL) 3, IL-5, or GM- CSF to inhibit apoptosis and increase inflammatory mediator generation. Again, our focus will be on LIR-5 and will be extended to other members of the LIR family as we find evidence that they are expressed in these critical effector cells of allergic inflammation. These studies will reveal the potential of this novel family of molecules in regulating the allergic response and provide the impetus to pursue these molecules as novel therapeutic targets in the treatment of allergic disease and asthma.