Alloreactive (CD4-Independent) CD8+ T Cells Jeopardize Long-Term Survival of Intrahepatic Islet Allografts |
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Authors: | K. E. Lunsford K. Jayanshankar A. M. Eiring P. H. Horne M. A. Koester D. Gao G. L. Bumgardner |
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Affiliation: | Department of Surgery, Division of Transplantation, The Ohio State University Medical Center, Columbus, OH;Integrated Biomedical Science Graduate Program, College of Medicine and Public Health, The Ohio State University, Columbus, OH |
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Abstract: | Despite success of early islet allograft engraftment and survival in humans, late islet allograft loss has emerged as an important clinical problem. CD8+ T cells that are independent of CD4+ T cell help can damage allograft tissues and are resistant to conventional immunosuppressive therapies. Previous work demonstrates that islet allografts do not primarily initiate rejection by the (CD4-independent) CD8-dependent pathway. This study was performed to determine if activation of alloreactive CD4-independent, CD8+ T cells, by exogenous stimuli, can precipitate late loss of islet allografts. Recipients were induced to accept intrahepatic islet allografts (islet 'acceptors') by short-term immunotherapy with donor-specific transfusion (DST) and anti-CD154 mAb. Following the establishment of stable long-term islet allograft function for 60–90 days, recipients were challenged with donor-matched hepatocellular allografts, which are known to activate (CD4-independent) CD8+ T cells. Allogeneic islets engrafted long-term were vulnerable to damage when challenged locally with donor-matched hepatocytes. Islet allograft loss was due to allo specific immune damage, which was CD8- but not CD4-dependent. Selection of specific immunotherapy to suppress both CD4- and CD8-dependent immune pathways at the time of transplant protects islet allografts from both early and late immune damage. |
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Keywords: | CD40 ligand CD4+ T cells CD8+ T lymphocytes cell-mediated cytotoxicity cellular transplantation costimulation blockade cytotoxic T cells delayed-type hypersensitivity donor-specific transfusion effector mechanisms hepatocyte transplantation islet transplantation |
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