Type 1 diabetes (T1 D) is a tissue specific autoimmune disease characterized by the T mediated destruction of the insulin producing b cells of the islets of Langerhans. Treatment of diabetes has focused on the use of insulin replacement. However, th is treatment can be difficult to regulate and has many shortcomings. While the surgical techniques for transplanting pancreatic islets is now at hand, problems remain. First and foremost is that fact that even syngeneic grafts are rejected due to the same autoimmune mechanisms that caused the initial islet cell loss. This process must be controlled to promote effective transplant function. This proposal will use two new approaches to remove autoantigen reactive T cells. We will use MHC-tetramer based constructs loaded with self peptides and coupled with the plant toxin, saporin. We will use the toxin coated tetramers to delete self-reactive T cell. This approach will be validated in vitro and them in vivo. We will also adapt a new class of nanoparticles, PRINT (Particle Replication in Non-wetting Templates) to be targeted to specific T cells by MHC coating and to carry Iymphotoxic drugs. The combination of targeting by antibody and drug selectivity will provide a new level of efficiency in targeting to autoimmunity.
This research will adapt a new technology to selectively delete autoimmune T cells. It will use two parallel approaches. The first will use toxin-couple peptide loaded histocompatibility molecules to suicide the self reactive T cells. The other will use novel molded nanoparticles similar targeted, but carrying lymphocyte selective drugs to kill the autoreactive T cells.
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