Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disorder that destroys selectively the insulin-producing beta cells of pancreas. The only possible cure for IDDM is the replacement of the destroyed beta cell mass. Technical problems related to pancreatic islet isolation no longer limit the therapeutic use of pancreatic islets obtained from allogeneic donors. However, the immunosuppressive drugs employed to prevent rejection of allogeneic islets induce generalized immunosuppression and harmful side-effects. Rejection of islet cell allografts occurs mainly because allo-antigen (Ag)-specific T cells react against the transplanted tissue. Dendritic cells (DC) are the Ag-presenting cells (APC) that activate the recipient na?ve T cells that trigger the transplant rejection. Galectin-1 is a potent T cell counterstimulator that interferes with the formation of the immunological synapse at the early stages of DC-T cell interaction during Ag presentation. As a consequence, galectin-1 induces T cell apoptosis. In this proposal, we hypothesize that donor-derived DC expressing transgenic galectin-1 can be used as """"""""tolerogenic DC"""""""" to induce Ag-specific T cell tolerance in a murine model of islet cell transplantation. DC will be transduced with a recombinant adenovirus (rAd) vector encoding human galectin-1 plus the reporter gene enhanced green fluorescent protein (EGFP) (rAd-GaI-1 -EGFP).
The aims of this proposal are the following:
Aims 1 and 2) to investigate the interaction of DC expressing transgenic galectin-1 with na?ve T cells in vitro and in vivo;
and Aim 3) to determine whether transfer of donor-derived rAd-Gal-1-EGFP-transduced DC can reverse hyperglycemia and promote long-term pancreatic islet allograft survival.These studies will explore novel ways to generate allo-Ag specific 1-cell tolerance combining two promising tools in the transplantation field: tolerogenic DC and T cell counterstimulators (i.e. galectin-1). The mechanisms by which DC activate recipient I cells during rejection of islet cell allografts will be investigated. This approach may achieve significant prolongation of allograft survival and minimize the need for immunosuppressive drugs with side-effects and toxicity against pancreatic islets. The results may have an important impact on regulation of beta-cell autoimmunity and in other areas of transplantation.
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