Significant improvement in early post-transplant survival rates has been achieved over the last decade for recipients of all types of allografts. Nevertheless, the need for further refinement of currently available nonspecific immunosuppression is emphasized by the morbidity and the annual attrition rate of at least 3-5% which are observed in chronically suppressed allograft recipients and the complete failure of such therapy for xenogeneic transplantation. The objective of this Program Project is to improve the outcome following organ transplantation by defining the essential conditions for and clarifying the mechanisms involved in donor specific tolerance induction. The ultimate goal is to induce specific and long-lasting inhibition of only those elements of the immune response responsible for allograft or xenograft rejection without the need for long-term administration of immunosuppressive agents. The rationale linking the objectives of the 4 interrelated and even in some human allograft recipients, it should be possible to identify and then reproducibly provide the immunologic perturbations which lead to this state. Preliminary observations have confirmed that one approach, employing mixed chimerism, can be successfully extended from murine models to non-human primate allo and concordant xenograft recipients. Our hypothesis is that definition of an approach to tolerance induction can be applied clinically will not only improve the long-term results of allotransplantation, but also provide a means of utilizing xenogeneic donors.
The specific aims are to characterize, in a continuum of models including mice selected for specific MHC incompatibilities or genetically engineered defects, partially inbred swine, and non-human primates, the mechanisms of action of conditioning regimens, with or without donor bone marrow transplantation, that induce tolerance and the state of reactivity of anergy that results from their application. The methodology of the studies includes genetic manipulation, renal or cardiac allo and xenografts in large animal models, thymus transplantation, and flow cytometry and functional analyses of peripheral blood and graft infiltrating cells. Subsequent translation of these developments to clinical protocols for treatment of allograft recipients will be of immediate relevance and should contribute to a reduction in the costs and morbidity associated with transplantation and should ultimately provide a realistic approach to even discordant xenotransplantation.
| Wang, Zhaohui; Louras, Nathan J; Lellouch, Alexandre G et al. (2018) Dosing optimization of CCR4 immunotoxin for improved depletion of CCR4+ Treg in nonhuman primates. Mol Oncol 12:1374-1382 |
| Newton, Ryan H; Shrestha, Sharad; Sullivan, Jenna M et al. (2018) Maintenance of CD4 T cell fitness through regulation of Foxo1. Nat Immunol 19:838-848 |
| Hotta, Kiyohiko; Oura, Tetsu; Dehnadi, Abbas et al. (2018) Long-term Nonhuman Primate Renal Allograft Survival Without Ongoing Immunosuppression in Recipients of Delayed Donor Bone Marrow Transplantation. Transplantation 102:e128-e136 |
| Robinson, Kortney A; Orent, William; Madsen, Joren C et al. (2018) Maintaining T cell tolerance of alloantigens: Lessons from animal studies. Am J Transplant 18:1843-1856 |
| 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 |
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