Insulin Dependent Diabetes Mellitus (IDDM) results from the autoimmune destruction of the pancreas. An ideal therapy to overcome diabetes would be the transplantation of a pancreas or islet graft. Currently, the one-year success rate for pancreas and islet grafts is around 70 percent and 10 percent respectively. A better understanding of how the immune response to the graft can be modified is critical for the design of novel therapeutic strategies. A number of T cell-derived cytokines have been implicated in both allograft rejection and protection. The cytokine IFN-gamma is secreted by the Thl-type T cell subset. This cell subset is the dominant cell subset activated during acute rejection. However, the absence of IFN-gamma is detrimental to some models of transplantation tolerance. These data suggest that IFN-gamma is involved in acute rejection but that it is also required for long-term survival of the graft. Likewise IL-10, a cytokine secreted by the Th2- type T cell subset, has been associated with allograft, rejection and has also been shown to be required for long-term allograft survival. A second Th2-type cytokine, IL-4 has been shown to be present in many long-term surviving grafts, but has also been shown to be present during acute rejection. The picture which emerges would suggest that each cytokine has different roles depending on the state of the graft and the period of engraftment. Using mouse strains which have mutations in the genes which code for these cytokines we will transfer T cells which are differently cytokine-deficient into immunocompromized (RAG-2-deficient) recipients in the presence of a pancreas graft. Since the cytokines are only secreted by the T cells after stimulation, infusing T cells has the advantage that the selected cytokines will be secreted at the site of graft antigens and therefore be targeted to the graft site. We will determine how each of the cytokines and T cells subsets interact in response to the allograft. We will use this information to manipulate the ratios of each cytokine in order to optimize the timing and dose of each cytokine with the ultimate goal of obtaining allograft protection.
| Hall, De Shon; Roberts, Edda M; Ferguson, Sharon et al. (2003) Increasing transplant mass results in long-term allograft survival and recovery from transplant vasculopathy. J Clin Immunol 23:162-74 |
