Previous studies in partially inbred miniature swine have demonstrated that primarily vascularized transplants across class I plus minor histocompatibility antigen differences lead to systemic tolerance in about one-third of cases without the need for exogenous immunosuppression. Based on the hypothesis that tolerance induction in these situations may involve a limitation of T-cell help at the time of first antigen exposure, we have recently evaluated the effect of a brief course of Cyclosporin A immediately following renal allografts in this model. Such treatment increased the percentage of class I plus minor antigen mismatched transplant recipients that develop long-term tolerance to 100%. The major goals of this proposal are to study the early immunologic parameters which lead to tolerance induction in this experimental system and to examine the applicability of these findings to additional organs (heart) and species (primate) as a prelude to future clinical applications. Specifically, we shall: 1) Investigate the role of an active immune process in generating tolerance following class I mismatched renal transplants; 2) Study the cell populations present in the graft at critical times following transplantation by histology, by cell culture analysis and by patterns of cytokine gene expression: 3) Examine the basis of differences in the immune response to cardiac versus renal allografts in this model and determine whether or not our findings can be extended to cardiac transplants; and 4) Perform renal transplants between pairs of MLR-negative cynomolgus monkeys with or without a brief course of immunosuppression aimed at elimination of T cell help. These studies should provide valuable insight into the mechanism by which tolerance to a primarily vascularized transplant is induced. In addition, if the cynomolgus monkey studies are successful, a similar clinical protocol for HLA matched organ transplants is envisioned in the future. Although rodent models have been of great importance to studies of transplantation, it has proved much more difficult to induce specific transplantation tolerance in man than in rodents. Of possible relevance to these studies is the difference in expression of class II MHC antigens on vascular endothelium between rodents and large animals. For preclinical studies on the induction of tolerance across selected MHC barriers it is therefore important to utilize a large animal model.
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| Sasaki, Hajime; Oura, Tetsu; Spitzer, Thomas R et al. (2018) Preclinical and clinical studies for transplant tolerance via the mixed chimerism approach. Hum Immunol 79:258-265 |
| Tanimine, Naoki; Turka, Laurence A; Priyadharshini, Bhavana (2018) Navigating T-Cell Immunometabolism in Transplantation. Transplantation 102:230-239 |
| Michel, S G; Madariaga, M L L; LaMuraglia 2nd, G M et al. (2018) The effects of brain death and ischemia on tolerance induction are organ-specific. Am J Transplant 18:1262-1269 |
| Smith, R N; Adam, B A; Rosales, I A et al. (2018) RNA expression profiling of renal allografts in a nonhuman primate identifies variation in NK and endothelial gene expression. Am J Transplant 18:1340-1350 |
| Chatterjee, Debanjana; Moore, Carolina; Gao, Baoshan et al. (2018) Prevalence of polyreactive innate clones among graft--infiltrating B cells in human cardiac allograft vasculopathy. J Heart Lung Transplant 37:385-393 |
| Gonzalez-Nolasco, Bruno; Wang, Mengchuan; Prunevieille, Aurore et al. (2018) Emerging role of exosomes in allorecognition and allograft rejection. Curr Opin Organ Transplant 23:22-27 |
| Smith, R N; Matsunami, M; Adam, B A et al. (2018) RNA expression profiling of nonhuman primate renal allograft rejection identifies tolerance. Am J Transplant 18:1328-1339 |
| Fan, Martin Y; Low, Jun Siong; Tanimine, Naoki et al. (2018) Differential Roles of IL-2 Signaling in Developing versus Mature Tregs. Cell Rep 25:1204-1213.e4 |
| Benichou, Gilles; Prunevieille, Aurore (2018) Graft-derived exosomes. When small vesicles play a big role in transplant rejection. Am J Transplant 18:1585-1586 |
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