Lymphocyte Migration in Development of Type 1 Diabetes

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DESCRIPTION (provided by applicant): OBJECTIVES Type 1 diabetes (T1DM) is a T cell mediated autoimmune disease. In the early stages of the autoimmune response, naive autoreactive T cells migrate from blood into pancreatic lymph nodes where they meet Beta cell antigens; memory/effector offspring of these T cells then migrate from blood into islets to initiate the inflammation that leads to Beta cell destruction. The migration of lymphocytes from blood into tissues requires tissue-selective multistep cascades with sequential lymphocyte/endothelial adhesion and activation steps. Our goals are to identify the endothelial adhesion and activating molecules (such as chemokines) that are expressed in pancreatic lymph nodes and islets in the early stages of inflammation, to define the roles of these molecules in lymphocyte recruitment to these sites and in the initiation of the autoimmune response, and to determine which molecules are therapeutic targets for the prevention of T1DM. RESEARCH PLANS AND METHODS We will use tissue section immunohistology, suspension immunofluorescence staining with flow cytometry, and laser capture microdissection (LCM) with RT-PCR to determine which adhesion molecules, chemokines, and chemokine receptors are present in pancreatic lymph nodes (Aim 1) and islets (Aim 2) of nonobese diabetic (NOD) mice in the early stages of the autoimmune process. The physiologic roles of these molecules in the migration of naive autoreactive T cells into pancreatic lymph nodes (Aim 1) and in the production of memory/effector T cells which migrate to islets (Aim 2) will be defined using in vivo lymphocyte migration assays. In Aim 3, we will work closely with Dr. Hugh McDevitt to determine the effects of TNFalpha and anti- TNFalpha on lymphocyte migration pathways and on the development of autoimmunity or tolerance.