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OBJECTIVE-Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing β-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes.
RESEARCH DESIGN AND METHODS-We adoptively transferred HLA-A2-matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/γc^sup null^/HLA-A*0201 (NOD-scid/ γc^sup null^/A2) mice. At various times after adoptive transfer, we determined the ability of these nuce to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node and islets of NOD-scid/γc^sup null^/A2 mice after transfer.
RESULTS-Human T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining pancreatic lymph node, and most importantly, islets of NOD-scid/γc^sup null^/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/γc^sup null^/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2-matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8^sup +^ T cells among the islet infiltrates.
CONCLUSIONS-We show that insulitis is transferred to NOD-scid/γc^sup null^/A2 mice that received HLA-A2-matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8^sup +^ T cells are epitope-specific and produce interferon-γ after in vitro peptide stimulation. This indicates that NOD-scid/γc^sup null^/A2 mice transferred with HLA-A2-matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell-mediated responses in patients with type 1 diabetes. Diabetes 60:1726-1733, 2011
NOD mice develop spontaneous diabetes due to autoimmune destruction of pancreatic ?-cells. These mice have served as a useful tool for understanding many aspects of type 1 diabetes (1,2). For example, the identification of certain pathogenic epitopes were originally found in NOD mice and subsequently observed in the blood of type 1 diabetic patients (3). The major shortcoming of these studies is their inability to evaluate the...