In the last 2 years, islet cell transplants were successfully undertaken in a small series of patients though rejection, need for ongoing immunosuppression, logistic and other problems currently limit this as an option in type I diabetics. This application will analyze mechanisms underlying islet allograft rejection and test ways in which such islet rejection may be overcome in normal recipients as well as those with pre-existing autoimmune responses which, if unregulated, lead to islet destruction. The focus of these studies will be on the leukocyte recruitment to inflamed islets which precedes islet injury.
Aim 1 will determine the mechanisms underlying recruitment of host immune cells to an islet allograft, with a particular focus on the role of chemokines and their receptors. We have a unique collection of knockout (KO) mice and neutralizing monoclonal antibodies (mAbs) directed against ligands or receptors in each of the pathways expressed during islet allograft rejection. Based on the preliminary effects of chemokine receptor targeting in this model using (mAbs), we hypothesize that blockade of the chemokine receptor, CXCR3, will be particularly important to preventing islet allograft rejection, alone or in conjunction with sub-therapeutic, limited immunosuppression. Accordingly, Aim 2 will focus on analysis of the effects of modulation of chemokine receptor pathways leading to recruitment of activated T cells, with a particular focus on the CXCR3/IP-10 pathway. As necessary, additional pathways known to be expressed during islet rejection can also be dissected by our approach using in-house KO (CCR1, CCR2, CCR5) and corresponding blocking antibodies.
Aim 3 will test the hypothesis that one or more of the same chemokine-dependent pathogenetic mechanisms that underlie islet allograft rejection is key to T cell recruitment and activation during development of autoimmune diabetes in NOD mice. Data from these studies may lead to the establishment of new methods to achieve long-term islet allograft survival without toxic levels of immunosuppression, and also ways to prevent development of autoimmune diabetes in experimental animals. Success in this work would provide a rationale for testing in non-human primates and, ultimately, in patients with Type 1 diabetes.
| Nanji, Sulaiman A; Hancock, Wayne W; Luo, Bin et al. (2006) Costimulation blockade of both inducible costimulator and CD40 ligand induces dominant tolerance to islet allografts and prevents spontaneous autoimmune diabetes in the NOD mouse. Diabetes 55:27-33 |
| Lee, Iris; Wang, Liqing; Wells, Andrew D et al. (2005) Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor. J Exp Med 201:1037-44 |
| Wang, Liqing; Fraser, Christopher C; Kikly, Kristine et al. (2005) B7-H3 promotes acute and chronic allograft rejection. Eur J Immunol 35:428-38 |
| Lee, Iris; Wang, Liqing; Wells, Andrew D et al. (2003) Blocking the monocyte chemoattractant protein-1/CCR2 chemokine pathway induces permanent survival of islet allografts through a programmed death-1 ligand-1-dependent mechanism. J Immunol 171:6929-35 |
