Cellular and Molecular Mechanisms that Contribute to Ocular Surface Allergy

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PROJECT SUMMARY Allergic conjunctivitis (AC) affects nearly 30 million Americans, thereby constituting a major health problem and causing significant health care costs in the United States. In addition to perennial and seasonal forms of AC which can diminish quality of life, advanced forms of vernal or atopic AC can be sight-threatening as well. Unfortunately, current pharmacotherapies are only transiently effective and incapable of abolishing signs and symptoms. Antihistamines and mast cells stabilizers, for example, target IgE mediated released proinflammatory cytokines and histamines. However, this is preceded by important upstream activities not targeted by these drugs, namely the stimulation of T helper 2 lymphocytes by dendritic cells (DC). Thus, it is likely that novel strategies targeting DC function, may serve as a better means to treat AC. To this end, the overall goal of these proposed studies is to better understand conjunctival (conj) DCs and the mechanisms employed toward AC immunopathogenesis. It is currently understood that DCs originate from different lineages which yield distinct subsets and perform intrinsic or specialized functions and recent work from our lab has initiated the classification of subsets and respective ontogenies that constitute the conj DC network. This, for one, permits comparisons to DC subsets previously identified in other mucosal tissues, such as those constituting lung or gut, which also sustain allergic inflammation. Furthermore identification of such DC subsets in conj will facilitate Aim 1 of this study, which is to discern which DC subset(s) is immunopathogenic in AC and whether this is accomplished via proficient T cell stimulation and/or enhanced allergen uptake and presentation. Regarding T cell stimulation mediated by conj DCs, preliminary studies presented in this proposal demonstrate that thrombospondin (TSP)-1, a matricellular glycoprotein with immunoregulatory functions, inhibits DC maturation required for consequent T cell stimulation. Thus, Aim 2 of this proposal seeks to explore the role of TSP-1 deficiency in the immunopathogenesis of AC. In summary, results from these studies will provide further understanding of conj DC subsets and function, an area which is not only applicable to allergy but also to infectious diseases and other immune-related conditions afflicting the ocular surface. Furthermore identification of the immunopathogenic DC subset(s) in AC and their mechanisms will provide important insights for development of much needed therapeutic strategies to better treat AC.