CXCR3 Chemokines in Type I Diabetes

La Jolla Institute For Immunology, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Our goal is to mechanistically understand the role of IP-10 (interferon-induced protein of 10kDa, CXCL10) and its receptor CXCR3 in the pathogenesis of type 1 diabetes (T1D) and islet allograft rejection. Based on this insight we wish to analyze the therapeutic potential of IP-10 blockade in experimental models of induced and spontaneous autoimmune diabetes (RIP-LCMV and NOD mice) and islet transplantation. We believe that this focused analysis will unravel novel interventive avenues to prevent destruction of insulin producing beta-cells and restore long-term tolerance to islets. Encouraging preliminary data demonstrate a profound amelioration of virally induced T1D in RIPLCMV mice after systemic IP-10 blockade. Importantly, this clinically beneficial effect was obtained without any detectable side effects. An intriguing observation is that IP-10 blockade appears to predominantly affect migration/attraction of aggressive T lymphocytes into the islets rather than overall reduction of immune responsiveness. Thus, we hypothesize that IP-10 is a unique immunological target in that its blockade will selectively affect lymphocyte accumulation in the islets of Langerhans. Indeed, in vivo administration of antibodies against other chemokines did not have a similarly profound effect. Aim 1: Importance of IP-10 in the pathogenesis of T1D - therapeutic blockade and mechanistic analyses. Aim 2: Importance of IP-10 during islet allograft rejection - therapeutic blockade and mechanistic analyses.