Insulin-dependent diabetes (IDD) is an autoimmune disease. the characterization of autoreactive T lymphocytes in IDD is fundamental to the development of future diagnostic and therapeutic strategies to study and treat early diabetics and prediabetics. Due to limitations peculiar to IDD, characterization of these autoreactive cells in IDD has remained elusive. We propose to conduct human (iso or HLA identical allograft pancreas recipients with recurrent disease) and animal (BB rat) studies to isolate, expand, clone and characterize the beta cell autoreactive T lymphocytes. We will focus on the molecular characterization of the T cell antigen receptor (TcR) rearrangements used by these cells in view of preliminary work suggesting restricted TcR usage by CD8+ cells isolated from a graft with recurrent disease. Specifically we will: a) accumulate additional immunopathological, immunological and molecular information from retrospective and prospective cases of human graft recurrent IDD (GRIDD) with different HLA backgrounds; b) ask whether TcR rearrangements identical or similar to those predominant in isletites can also be found in peripheral blood T cells of prediabetics or early diabetics, but not in normals; c) whether T cells with anti- idiotypic TcR specificities exist in peripheral blood of patients who underwent GRIDD that cannot be answered by the human studies. Vascularized whole pancreas transplants in diabetic BB rats will be performed in order to reproduce the anamnestic autoimmune process seen in human GRIDD. In the animal model, the following questions will be addressed: a) whether isletites in grafts are representative of the autoimmune response in native isletites; b) whether TcR anti-idiotypic immunization prevents native IDD in animals and thus, whether it is likely to be feasible in humans. If limited TcR diversity is confirmed in human IDD, preparation and use of peptide vaccines could have major impact on prevention/treatment of IDD.
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