Tolerance to kidney allografts has been achieved in nonhuman primates (NHPs) and, for the first time, in humans using a combination of nonmyeloablative conditioning and donor bone marrow transplantation that results in transient donor chimerism. However, mixed chimerism protocols that induce long term tolerance to kidney allografts in NHPs fail to do so in recipients of cardiac allografts. The goal of Project 1 is to use new agents and novel strategies to optimize mixed chimerism so that it will induce tolerance to cardiac allografts and prevent cardiac allograft vasculopathy (CAV). We hypothesize that 1) targeting newly recognized barriers to tolerance will allow us to alter the balance of an alloresponse away from alloaggression and towards deletion/regulation leading to long-term tolerance, 2) humoral responses and proinflammatory states are particularly detrimental to tolerance induction in cardiac allograft recipients and may be important confounding factors limiting the duration of the state of mixed chimerism, and 3) durable mixed chimerism will likely be required for tolerance in heart recipients because, unlike kidneys, cardiac allografts do not appear capable of maintaining tolerance once chimerism disappears. In the specific aims of each Project, the contributions of allo-, auto- and natural antibodies to graft loss after mixed chimerism induction are recognized and addressed in an innovative and complementary manner. Likewise, the deleterious effects of proinflammatory molecules are considered throughout the program and addressed with innovative and complementary approaches. We anticipate ongoing progress will continue to contribute to a reduction in the morbidity and mortality associated with solid organ transplantation.
(Seeinstructions): The survival of human recipients of heart transplants is limited by rejection and by the complications of anti- rejection drugs. The objective of this proposal is to induce a state of immune tolerance in the recipient, which """"""""tricks"""""""" the immune system into seeing the foreign graft as its own tissue, so that the organ is not rejected without the need for drugs. This would greatly improve the outcomes of heart transplants.
|Zwang, N A; Zhang, R; Germana, S et al. (2016) Selective Sparing of Human Tregs by Pharmacologic Inhibitors of the Phosphatidylinositol 3-Kinase and MEK Pathways. Am J Transplant 16:2624-38|
|Newton, Ryan; Priyadharshini, Bhavana; Turka, Laurence A (2016) Immunometabolism of regulatory T cells. Nat Immunol 17:618-25|
|Madariaga, M L L; Spencer, P J; Michel, S G et al. (2016) Effects of Lung Cotransplantation on Cardiac Allograft Tolerance Across a Full Major Histocompatibility Complex Barrier in Miniature Swine. Am J Transplant 16:979-86|
|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|
|Hotta, Kiyohiko; Aoyama, Akihiro; Oura, Tetsu et al. (2016) Induced regulatory T cells in allograft tolerance via transient mixed chimerism. JCI Insight 1:|
|Sihag, Smita; Haas, Michael S; Kim, Karen M et al. (2016) Natural IgM Blockade Limits Infarct Expansion and Left Ventricular Dysfunction in a Swine Myocardial Infarct Model. Circ Cardiovasc Interv 9:e002547|
|Madariaga, M L; Michel, S G; La Muraglia 2nd, G M et al. (2015) Kidney-induced cardiac allograft tolerance in miniature swine is dependent on MHC-matching of donor cardiac and renal parenchyma. Am J Transplant 15:1580-90|
|Huynh, Alexandria; DuPage, Michel; Priyadharshini, Bhavana et al. (2015) Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol 16:188-96|
|Priyadharshini, Bhavana; Turka, Laurence A (2015) T-cell energy metabolism as a controller of cell fate in transplantation. Curr Opin Organ Transplant 20:21-8|
|Aoyama, A; Tonsho, M; Ng, C Y et al. (2015) Long-term lung transplantation in nonhuman primates. Am J Transplant 15:1415-20|
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