Autoimmune diseases such as Type 1 diabetes (T1D) manifest themselves clinically when insulin producing cells are already completely lost. At this point, the only cure for diabetes is the replacement of these insulin-producing cells. However, patients receiving such grafts suffer from lifetime immunosuppressive treatments, leading to increased propensity to infection. If functional resistance.- to allograft rejection could be conferred on these grafts the requirement for immunosuppression would be avoided aid the quality of life for those receiving allografts would be greatly enhanced. In this exploratory R21 application we propose a new hypothesis for the induction of resistance to islet allograft rejection. Since these grafts are destroyed by cytokines produced by infiltrating cells, we proposed to engineer islets that are unresponsive to these pathogenic cytokines. Two different experimental designs are proposed in this application. In the first set of studies we will determine whether targeted expression of SOCS-1, a protein that inhibits interferon signaling, can ameliorate graft responses. We present compelling preliminary data stating that this aim is feasible and shows promising results. In the second set of studies we plan to down-modulate SOCS-3 gene expression to determine if modulation of IL-6 responses, with increased responses to IL-10, could play a pro-survival role in graft survival. Extensive mechanistic studies, to understand both systemic and localized allograft responses, are proposed for each paradigm. These studies should lead to new methods for inducing resistance to islet allograft rejection.
