UNIQUE ENDOTHELIAL MOLECULES IN AUTOIMMUNE INFLAMMATION

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The migration of autoreactive and effector lymphocytes from blood into target organs is a key event in the initiation and maintenance of target organ damage in autoimmune diseases. This migration involves a complex adhesion cascade with sequential lymphocyte/endothelial adhesion and activation events. Our goals are to identify adhesion triggering chemokines and novel activating and adhesion molecules expressed by high endothelial venules (HEV) in sites of autoimmune-mediated inflammation and tissue destruction, and to define the roles of these molecules in lymphocyte migration to these sites. We will use nonobese diabetic (NOD) mice, a well-characterized model for human insulin dependent diabetes mellitus (IDDM) and Sjogren's syndrome, as a model to define the unique endothelial molecules involved in lymphocyte migration to inflamed pancreatic islets, salivary gland and lacrimal gland. In Specific Aim 1, we shall use laser capture microdissection (LCM) and gene analysis techniques to define the patterns of chemokine expression by HEV endothelial cells in inflamed islets, salivary gland and lacrimal gland. The roles of these chemokines (and their receptors) in lymphocyte migration to inflamed tissues will be assessed in functional studies, including in vitro assays of lymphocyte adhesion and in vivo migration studies with mAb- inhibition or chemokine desensitization. Under Specific Aim 2, we shall use LCM and gene microarray analyses to identify and characterize genes that are expressed in a tissue-selective or inflammation-specific manner by HEV in sites of autoimmune- mediated target organ damage. We are most interested in genes encoding novel adhesion or activating molecules that may mediate lymphocyte migration into inflamed pancreatic islets and salivary and lacrimal gland. These studies will define novel therapeutic targets for the prevention of inflammation and target organ damage in autoimmune diseases including IDDM and Sjogren's syndrome.