Nature of pancreatic islet and cardiac allograft immunity and tolerance: These studies deal with the cellular and molecular mechanisms by which transplanted islets are destroyed by alloreactive CD8 T cells and the nature of CD4 T cell augmentation of the response. In parallel, a major emphasis is on the study o the induction of tolerance to transplanted islets. These studies involve the induction of peripheral tolerance to islet allografts by targeting varied cell-surfaice molecules such as LFA-1, CD154, and CD45RB. The hypothesis being explored is that peripheral tolerance to islet transplants is largely controlled by regulatory T cells rather than due to the deletion of potentially graft-destructive cells. Nature of islet xenograft immunity: This area of research focuses on the nature of T cell immunity to islets transplanted from other species (xenografts) with particular emphasis on comparing this process with the response to islets from the same species (allografts). These studies have indicated that xenograft and allograft immunity are quite different processes, in that allograft responses appear to depend particularly on CD8 T cells, whereas the xenograft response is more dependent on CD4 T cells. One implication of this research is that it could ultimately enable us to use islets from other species as a treatment for human diabetes and thus to solve the problem of finding adequate numbers of islets to treat all patients with this disease.

Nature of islet damage in autoimmune diabetes: These studies address the mechanism of islet damage initiated by autoimmune T cells derived from non-obese diabetic (NOD) mice. Such studies chiefly analyze the nature of CD4 T cell-dependent islet-specific autoimmunity in the pathogenesis of the disease. Several results suggest that the mechanism of damage in this system is similar to the type of damage proposed for islet xenograft destruction. We will continue to examine the mechanisms by which autoimmune T cells actually recognize and destroy islet transplants. In parallel, newer studies are exploring the use of bone marrow transplantation as a means of correcting both the intrinsic autoimmune phenotype in NOD mice as well as generating a tolerance-prone immune environment for islet transplants.

Bibliography

• Wiseman, AC, BA Pietra, BP Kelly, GR Rayat, M Rizeq, RG Gill. 2001. Donor IFN-gamma receptors are critical for acute CD4+ T cell-mediated cardiac allograft rejection J. Immunol. 167:5457-5463
• Nicolls, MR, M Coulombe, AS Diamond, J Beilke, RG Gill. 2002. Interferon-gamma is not a universal requirement for islet allograft Survival. Transplantation 74:472-477
• Nicolls, MR, M Coulombe, J Beilke, RG Gill. 2002. CD4 dependent generation of dominant transplantation tolerance induced by simultaneous perturbation of CD154 and LFA-1 pathways. J. Immunol. 169:4831-4839.
• Gill RG. 2003. Animal models of pancreatic islet xenotransplantation. Curr. Opin. Organ Transplantation 8:64-69
• Nicolls, MR, JM D'Antonio, JC Hutton, RG Gill, JL Czwornog, MW Duncan. 2003. Proteomics as a tool for discovery: Proteins implicated in Alzheimer's disease are highly expressed in normal pancreatic islets. J. Proteome Res. 2:199-205
• Rayat, GR, ZA Johnson, JN Beilke, GS Korbutt, RV Rajotte, RG Gill. 2003. The degree of phylogenetic disparity of islet grafts dictates the reliance of indirect CD4 T cell antigen recognition for rejection. Diabetes 52:1433-1440
• Moriyama, H, N Abiru, J Paronen, K Sikora, E Liu, D Miao, D Devendra, J Beilke, R Gianani, RG Gill, GS Eisenbarth. 2003. Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the NOD mouse. Proc. Natl. Acad. Sci. (USA 100: 10376-10381
• Johnson, Z, J Beilke, B Pietra, B. Kelly, RG Gill. Distinct requirements for host CD80/CD86 costmulatory molecules in cardiac versus islet rejection. Transplant. Proc. (in press)
• TJ. Grazia, BA. Pietra, ZA Johnson, BP. Kelly, RJ. Plenter, RG Gill. A two-step model of acute CD4-mediated cardiac allograft rejection J. Immunol. (in press).

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