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.
| Coppieters, Ken T; Amirian, Natalie; Pagni, Philippe P et al. (2013) Functional redundancy of CXCR3/CXCL10 signaling in the recruitment of diabetogenic cytotoxic T lymphocytes to pancreatic islets in a virally induced autoimmune diabetes model. Diabetes 62:2492-9 |
| Van Belle, Tom L; Juntti, Therese; Liao, Jeanette et al. (2010) Pre-existing autoimmunity determines type 1 diabetes outcome after Flt3-ligand treatment. J Autoimmun 34:445-52 |
| Hintermann, Edith; Christen, Urs (2007) Viral infection--a cure for type 1 diabetes? Curr Med Chem 14:2048-52 |
| Barral, Ana Maria; Thomas, Helen E; Ling, Eleanor M et al. (2006) SOCS-1 protects from virally-induced CD8 T cell mediated type 1 diabetes. J Autoimmun 27:166-73 |
| Christen, Urs; von Herrath, Matthias G (2005) Infections and autoimmunity--good or bad? J Immunol 174:7481-6 |
