Our central hypothesis is that induction of robust, reproducible and durable, tolerance to cardiac allograftswill 1) result in long-term graft sun/ival, 2) preserve normal graft function, and 3) prevent cardiac allograftvasculopathy (CAV) without long term immunosuppression. Recent studies have demonstrated that thecotrahsplantation of vascularized donor thymus induces rapid and stable tolerance to MHC disparate heartsin miniature swine. The goal of this Project is to extrapolate this innovative strategy to nonhuman primates.However, preliminary attempts to co-transplant vascularized thymus and heart allografts in nonhumanprimates resulted in early loss of the donor thymus followed by rejection of the heart. To explain this screpancy, we hypothesize that nonhuman primate thymus grafts are more susceptible to earlyimmune injury and inflammation than the porcine thymus grafts and that this early damage preventscyiniomolgus thymus grafts from contributing fully to the induction of tolerance. We furtherhypothesize that the three most likely causes of early thymus injury in cynomolgus recipients are: 1) the earlydepletion of salutary host Tregs by high-dose ATG therapy, 2) the homeostatic expansion of deleteriousmemory T ceils by high-dose ATG therapy, and 3) the inflammation associated with the surgical procedureOur goal is develop an innovative and integrated strategy to block each of these events, preserve earlythymic function and allow the transplanted thymus to participate fully in the induction of tolerance tocotransplanted cardiac allografts.
Our aims are 1) determine whether expanding host regulatory T cells invivo will abrogate early thymic loss, 2) determine whether depleting or inhibiting memory T cells will preventearly thymic rejection, and 3) determine if dampening the pro-inflammatory response will diminish earlythymus injury and promote tolerance in heart en bloc thymus allograft recipients.
Heart transplant recipients do not survive long enough because the drugs used to prevent the immunesystem from attacking the organs are not completely effective and they make transplant recipients moresusceptible to infections and cancer. We will find new ways to transplant organs without drugs usingtolerance which makes the organs immunologically invisible to the recipient.
|Madsen, Joren C (2017) Advances in the immunology of heart transplantation. J Heart Lung Transplant 36:1299-1305|
|Wang, Zhaohui; Zheng, Qian; Zhang, Huiping et al. (2017) Ontak-like human IL-2 fusion toxin. J Immunol Methods 448:51-58|
|Zheng, Qian; Wang, Zhaohui; Zhang, Huiping et al. (2017) Diphtheria toxin-based anti-human CD19 immunotoxin for targeting human CD19+ tumors. Mol Oncol 11:584-594|
|Purroy, Carolina; Fairchild, Robert L; Tanaka, Toshiaki et al. (2017) Erythropoietin Receptor-Mediated Molecular Crosstalk Promotes T Cell Immunoregulation and Transplant Survival. J Am Soc Nephrol 28:2377-2392|
|Hotta, Kiyohiko; Aoyama, Akihiro; Oura, Tetsu et al. (2016) Induced regulatory T cells in allograft tolerance via transient mixed chimerism. JCI Insight 1:|
|Wang, Zhaohui; Navarro-Alvarez, Nalu; Shah, Jigesh A et al. (2016) Porcine Treg depletion with a novel diphtheria toxin-based anti-human CCR4 immunotoxin. Vet Immunol Immunopathol 182:150-158|
|Wang, Zhaohui; Pratts, Shannon G; Zhang, Huiping et al. (2016) Treg depletion in non-human primates using a novel diphtheria toxin-based anti-human CCR4 immunotoxin. Mol Oncol 10:553-65|
|Nuñez, Sarah; Moore, Carolina; Gao, Baoshan et al. (2016) The human thymus perivascular space is a functional niche for viral-specific plasma cells. Sci Immunol 1:|
|La Muraglia 2nd, G M; O'Neil, M J; Madariaga, M L et al. (2015) A novel approach to measuring cell-mediated lympholysis using quantitative flow and imaging cytometry. J Immunol Methods 427:85-93|
|Matthews, Kristin A; Tonsho, Makoto; Madsen, Joren C (2015) New-Onset Diabetes Mellitus After Transplantation in a Cynomolgus Macaque (Macaca fasicularis). Comp Med 65:352-6|
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