B Cell Traffic in Type I Diabetes Mellitus

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DESCRIPTION (provided by applicant): Type I diabetes mellitus (T1DM) is a devastating disorder resulting from autoimmune destruction of insulin-producing pancreatic beta cells. TIDM is T cell mediated; B cells are also essential. Our long term goal is to elucidate the mechanisms by which B lymphocytes migrate to and are retained at sites of autoimmune attack and to use this information to design therapeutic options to disrupt those pathways and alter the pathological process. The specific hypothesis is that chemokines recruit B cells to pancreatic islets, where they contribute inflammatory signals driving benign insulitis to overwhelming disease. We base that hypothesis on the observations that: 1) we find large, well-organized B cell infiltrates in the islets, 2) an experimental technique which redistributes B cells away from islets is protective, 3) B cell receptor specificity (BCR) profoundly impacts disease as well as islet localization of B cells. The specific aims of this proposal are to: 1) identify the molecular signals that attract B lymphocytes to the islets of Non-Obese Diabetic mice and use this information to block B cell entry into the site of inflammation. We will investigate the effects of CXCL13 on B cell migration to the islets using transwell migration and adoptive transfer studies. In-vivo blockade of these signals to determine effects on native B cell localization and disease will follow. 2) Determine the effects of B cell specificity and activation status on entry into and retention in inflamed islets. We have engineered two NOD mouse lines expressing BCRs specific for insulin (disease-promoting), or a non-islet antigen (protective). We will compare the islet chemokine responses of naive, antigen-engaged, and T-cell-activated B cells from these mice using adoptive transfer, transwell migration, and confocal imaging. 3) Develop a mouse model of TIDM in which B cell chemoattraction is altered to further clarify the effects of B cell localization in this disease. These studies will identify the mechanims that mediate entry of B lymphocytes into a site of autoimmune attack and may identify novel targets of intervention in TIDM.