Beta-cell replacement therapy in Type 1 diabetes is hampered by two potentially distinct immune obstacles: (1) conventional transplantation rejection and, (2) recurrence of established autoimmune pathogenesis. While a variety of intervention strategies have proven successful in preventing the onset of autoimmune diabetes in animal models, prevention of islet transplant destruction in such recipients has proven to be quite challenging. Importantly, the actual mechanism(s) of islet transplant damage is (are) not clear. The goal of this proposal will be to determine the relative contribution of major candidate effector pathways in islet injury mediated by defined alloreactive or auto- reactive T cells in vivo. We will test the general working hypothesis that the effector mechanism of islet damage inflicted by alloreactive CD8 T cells is distinct from islet-specific, autoimmune CD4 T cells is cytokine-dependent in vivo. The continued development of intervention strategies for islet transplantation, design of surrogate Beta cell lines, and the application of immunoisolation technology in Type 1 diabetes will be aided by determining the mechanisms of islet destruction triggered by alloreactive versus autoreactive T cells. This proposal has the defined focus of systematically comparing alloreactive CD8 T cells with islet-specific CD4 T cells for their respective requirements for inflicting injury to pancreatic islet transplants. This will be performed through the following specific aims: (1) Determine the requirement for TNF receptor expression on islet transplants for islet injury, (2) Determine the requirement for islet IFN gamma receptor expression, (3) Determine the requirement for islet Fas (CD95) expression, and (4) Determine whether islet damage is sensitive to oxygen free radical scavenging.
|Sleater, M; Diamond, A S; Gill, R G (2007) Islet allograft rejection by contact-dependent CD8+ T cells: perforin and FasL play alternate but obligatory roles. Am J Transplant 7:1927-33|
|Kupfer, Tinalyn M; Crawford, Megan L; Pham, Kim et al. (2005) MHC-mismatched islet allografts are vulnerable to autoimmune recognition in vivo. J Immunol 175:2309-16|
|Wiseman, A C; Pietra, B A; Kelly, B P et al. (2001) Donor IFN-gamma receptors are critical for acute CD4(+) T cell-mediated cardiac allograft rejection. J Immunol 167:5457-63|
|Diamond, A S; Gill, R G (2000) An essential contribution by IFN-gamma to CD8+ T cell-mediated rejection of pancreatic islet allografts. J Immunol 165:247-55|