Molecular mechanisms underlying ACAID-induction

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Thrombospondin (TSP-1) is essential for maintaining ocular immune privilege and preventing potentially blinding effects of ocular inflammation. An extracellular matrix protein TSP-1 is synthesized by several ocular epithelia as well as resident antigen presenting cells (APCs), which contribute to the immune privilege status of the eye. The anti-inflammatory effects of TSP-1 in ocular inflammation are apparent from the spontaneous development of chronic ocular surface inflammation in TSP-1 deficient mice. The studies described in this proposal seek to elucidate immunologic mechanisms underlying such inflammatory responses noted in the absence of TSP-1. The first specific aim seeks to determine the significance of thrombospondin-1 (TSP-1) in the prevention of ocular inflammation. Experiments in this aim will allow us to characterize immune effectors developed in the absence of TSP-1 that lead to ocular surface inflammation. The second aim seeks to investigate the specific contribution of local TSP-1 in the lacrimal glands towards altering immune effectors. Considering the multidomain structure of a large molecule like TSP-1 with multiple cell type specific biological effects, these investigations will clarify mechanisms by which TSP-1 contributes to the prevention of chronic ocular inflammation. Since TSP-1 is known to be important in maintaining immune privilege these studies can build further on the existing knowledge of ocular immune responses and provide insights into novel potential therapeutic strategies.