{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T22:19:33Z","timestamp":1793657973282,"version":"4.5.1"},"reference-count":121,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heart transplantation remains the gold-standard treatment for end-stage heart failure, yet long-term graft survival is hindered by chronic rejection and the morbidity and mortality caused by lifelong immunosuppression. While advances in medical and device-based therapies have reduced the overall need for transplantation, patients who ultimately require a transplant often present with more advanced disease and comorbidities. Recent advances in tolerance-inducing strategies offer promising avenues to improve allograft acceptance, while minimizing immunosuppressive toxicity. This review explores novel approaches aiming to achieve long-term immunological tolerance, including co-stimulation blockade, mixed chimerism, regulatory T-cell (Treg) therapies, thymic transplantation, and double-organ transplantation. These strategies seek to promote donor-specific unresponsiveness and mitigate chronic rejection. Additionally, expanding the donor pool remains a critical challenge in addressing organ shortages. Innovations such as ABO-incompatible heart transplantation are revolutionizing the field by increasing donor availability and accessibility. In this article, we discuss the mechanistic basis, clinical advancements, and challenges of these approaches, highlighting their potential to transform the future of heart transplantation with emphasis on clinical translation.<\/jats:p>","DOI":"10.3390\/ijms26093968","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T03:43:37Z","timestamp":1745379817000},"page":"3968","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Tolerogenic Therapies in Cardiac Transplantation"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4266-9321","authenticated-orcid":false,"given":"Laurenz","family":"Wolner","sequence":"first","affiliation":[{"name":"Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"William-Olsson","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4641-7202","authenticated-orcid":false,"given":"Bruno K.","family":"Podesser","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Zuckermann","sequence":"additional","affiliation":[{"name":"Department of Cardiac and Thoracic Aortic Surgery, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4071-9397","authenticated-orcid":false,"given":"Nina","family":"Pilat","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Cardiac and Thoracic Aortic Surgery, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1111\/j.1600-6143.2011.03539.x","article-title":"Solid organ allograft survival improvement in the United States: The long-term does not mirror the dramatic short-term success","volume":"11","author":"Lodhi","year":"2011","journal-title":"Am. J. Transplant."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.hfc.2007.02.005","article-title":"Tolerance in heart transplantation: The Holy Grail, or an attainable goal?","volume":"3","author":"Pierson","year":"2007","journal-title":"Heart Fail. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Unger, L.W., Muckenhuber, M., Mahr, B., Schwarz, C., Pilat, N., Granofszky, N., Regele, H., and Wekerle, T. (2022). Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1060576"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1111\/ajt.14217","article-title":"A Tale of Two Pathways: Renewing the Promise of Anti-CD40L Blockade","volume":"17","author":"Thomson","year":"2017","journal-title":"Am. J. Transplant."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1038\/nrneph.2010.110","article-title":"Transplantation tolerance through mixed chimerism","volume":"6","author":"Pilat","year":"2010","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1111\/ajt.16395","article-title":"Feasibility, long-term safety, and immune monitoring of regulatory T cell therapy in living donor kidney transplant recipients","volume":"21","author":"Harden","year":"2021","journal-title":"Am. J. Transplant."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/nri1027","article-title":"Regulatory T cells in transplantation tolerance","volume":"3","author":"Wood","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1097\/MOT.0000000000000206","article-title":"Organ-specific differences in achieving tolerance","volume":"20","author":"Madariaga","year":"2015","journal-title":"Curr. Opin. Organ. Transplant."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1097\/00007890-199611150-00016","article-title":"Pattern of liver, kidney, heart, and intestine allograft rejection in different mouse strain combinations","volume":"62","author":"Zhang","year":"1996","journal-title":"Transplantation"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1111\/cei.12981","article-title":"Operational tolerance in kidney transplantation and associated biomarkers","volume":"189","author":"Massart","year":"2017","journal-title":"Clin. Exp. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1097\/00007890-199912150-00026","article-title":"Prolongation of primate cardiac allograft survival by treatment with ANTI-CD40 ligand (CD154) antibody","volume":"68","author":"Pierson","year":"1999","journal-title":"Transplantation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/381434a0","article-title":"Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways","volume":"381","author":"Larsen","year":"1996","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1111\/j.1365-3083.2010.02387.x","article-title":"Monoclonal antibody treatment to prolong the secondary cardiac allograft survival in alloantigen-primed mice","volume":"71","author":"Xie","year":"2010","journal-title":"Scand. J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1111\/j.1600-6143.2005.00759.x","article-title":"Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion","volume":"5","author":"Pearl","year":"2005","journal-title":"Am. J. Transplant."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/35393","article-title":"CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells","volume":"391","author":"Henn","year":"1998","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1016\/j.ajt.2023.03.025","article-title":"TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate cardiac allograft survival","volume":"23","author":"Miura","year":"2023","journal-title":"Am. J. Transplant."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1097\/FTD.0000000000001275","article-title":"New Developments and Therapeutic Drug Monitoring Options in Costimulatory Blockade in Solid Organ Transplantation: A Systematic Critical Review","volume":"47","author":"Udomkarnjananun","year":"2025","journal-title":"Ther. Drug Monit."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1111\/ajt.13154","article-title":"Rapamycin and CTLA4Ig synergize to induce stable mixed chimerism without the need for CD40 blockade","volume":"15","author":"Pilat","year":"2015","journal-title":"Am. J. Transplant."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1056\/NEJMoa2201422","article-title":"Genetically Modified Porcine-to-Human Cardiac Xenotransplantation","volume":"387","author":"Griffith","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Fu, N., Xie, F., Sun, Z., and Wang, Q. (2021). The OX40\/OX40L Axis Regulates T Follicular Helper Cell Differentiation: Implications for Autoimmune Diseases. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.670637"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e90317","DOI":"10.1172\/jci.insight.90317","article-title":"Interruption of OX40L signaling prevents costimulation blockade-resistant allograft rejection","volume":"2","author":"Kitchens","year":"2017","journal-title":"JCI Insight"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"84","DOI":"10.21037\/atm.2019.12.146","article-title":"Blockade of OX40\/OX40L pathway combined with ethylene-carbodiimide-fixed donor splenocytes induces donor-specific allograft tolerance in presensitized recipients","volume":"8","author":"Lai","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.trim.2015.01.001","article-title":"Anti-OX40L monoclonal antibody prolongs secondary heart allograft survival based on CD40\/CD40L and LFA-1\/ICAM-1 blockade","volume":"32","author":"Dai","year":"2015","journal-title":"Transpl. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s10557-013-6502-9","article-title":"Memory T Cells Mediate Cardiac Allograft Vasculopathy and are Inactivated by Anti-OX40L Monoclonal Antibody","volume":"28","author":"Wang","year":"2014","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1002\/cpt.2539","article-title":"OX40L Inhibition Suppresses KLH-driven Immune Responses in Healthy Volunteers: A Randomized Controlled Trial Demonstrating Proof-of-Pharmacology for KY1005","volume":"111","author":"Saghari","year":"2022","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1615\/CritRevImmunol.v18.i5.10","article-title":"CD28\/B7 costimulation: A review","volume":"18","author":"Greenfield","year":"1998","journal-title":"Crit. Rev. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1111\/j.1600-6143.2005.01018.x","article-title":"Anti-CD28 antibody-induced kidney allograft tolerance related to tryptophan degradation and TCR class II B7 regulatory cells","volume":"5","author":"Haspot","year":"2005","journal-title":"Am. J. Transplant."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1056\/NEJMoa063842","article-title":"Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412","volume":"355","author":"Suntharalingam","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.jaci.2008.01.002","article-title":"Costimulation blockade in autoimmunity and transplantation","volume":"121","author":"Vincenti","year":"2008","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/j.1600-6143.2009.03005.x","article-title":"A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study)","volume":"10","author":"Vincenti","year":"2010","journal-title":"Am. J. Transplant."},{"key":"ref_31","first-page":"CD010699","article-title":"Belatacept for kidney transplant recipients","volume":"2014","author":"Masson","year":"2014","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e15251","DOI":"10.1111\/ctr.15251","article-title":"Utility of a fusion protein T-cell co-stimulation blocker Belatacept in heart transplant recipients: Real world experience from a high volume center","volume":"38","author":"Oren","year":"2024","journal-title":"Clin. Transplant."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e15249","DOI":"10.1111\/ctr.15249","article-title":"Effectiveness of combined plasma cell therapy and costimulation blockade based desensitization regimen in heart transplant candidates","volume":"38","author":"Fida","year":"2024","journal-title":"Clin. Transplant."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1161\/CIRCULATIONAHA.119.040563","article-title":"Notch-1 Inhibition Promotes Immune Regulation in Transplantation Via Regulatory T Cell-Dependent Mechanisms","volume":"140","author":"Magee","year":"2019","journal-title":"Circulation"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.ajt.2022.12.011","article-title":"TIGIT agonism alleviates costimulation blockade-resistant rejection in a regulatory T cell-dependent manner","volume":"23","author":"Hartigan","year":"2023","journal-title":"Am. J. Transplant."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/s41581-022-00600-0","article-title":"Activation and regulation of alloreactive T cell immunity in solid organ transplantation","volume":"18","author":"Duneton","year":"2022","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1111\/tri.13972","article-title":"T- and B-cell therapy in solid organ transplantation: Current evidence and future expectations","volume":"34","author":"Pilat","year":"2021","journal-title":"Transpl. Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/ni904","article-title":"Foxp3 programs the development and function of CD4+CD25+ regulatory T cells","volume":"4","author":"Fontenot","year":"2003","journal-title":"Nat. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.autrev.2011.05.004","article-title":"Human FoxP3+ regulatory T cells in systemic autoimmune diseases","volume":"10","author":"Miyara","year":"2011","journal-title":"Autoimmun. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/s41581-023-00733-w","article-title":"Regulatory T cells in autoimmune kidney diseases and transplantation","volume":"19","author":"Mikami","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3619","DOI":"10.1172\/JCI33185","article-title":"Conferring indirect allospecificity on CD4+CD25+ Tregs by TCR gene transfer favors transplantation tolerance in mice","volume":"118","author":"Tsang","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Pilat, N., Steiner, R., and Sprent, J. (2023). Treg Therapy for the Induction of Immune Tolerance in Transplantation-Not Lost in Translation?. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021752"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"ltad007","DOI":"10.1093\/immadv\/ltad007","article-title":"Treg-based immunotherapy for antigen-specific immune suppression and stable tolerance induction: A perspective","volume":"3","author":"Sakaguchi","year":"2023","journal-title":"Immunother. Adv."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1097\/TP.0000000000003617","article-title":"Ex Vivo Expanded Donor Alloreactive Regulatory T Cells Lose Immunoregulatory, Proliferation, and Antiapoptotic Markers After Infusion Into ATG-lymphodepleted, Nonhuman Primate Heart Allograft Recipients","volume":"105","author":"Ezzelarab","year":"2021","journal-title":"Transplantation"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Lee, L.M., Zhang, H., Lee, K., Liang, H., Merleev, A., Vincenti, F., Maverakis, E., Thomson, A.W., and Tang, Q. (2021). A Comparison of Ex Vivo Expanded Human Regulatory T Cells Using Allogeneic Stimulated B Cells or Monocyte-Derived Dendritic Cells. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.679675"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Zhao, L., and Cao, Y.J. (2019). Engineered T Cell Therapy for Cancer in the Clinic. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02250"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Lu, W., Liang, C.L., Chen, Y., Liu, H., Qiu, F., and Dai, Z. (2018). Chimeric Antigen Receptor (CAR) Treg: A Promising Approach to Inducing Immunological Tolerance. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02359"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s40472-020-00285-z","article-title":"CAR-Tregs as a Strategy for Inducing Graft Tolerance","volume":"7","author":"Wagner","year":"2020","journal-title":"Curr. Transplant. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"102986","DOI":"10.1016\/j.jaut.2022.102986","article-title":"Engineered Treg cells: The heir to the throne of immunotherapy","volume":"144","author":"Stucchi","year":"2024","journal-title":"J. Autoimmun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1172\/JCI82771","article-title":"Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor","volume":"126","author":"MacDonald","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1111\/ajt.15787","article-title":"Donor-specific chimeric antigen receptor Tregs limit rejection in naive but not sensitized allograft recipients","volume":"20","author":"Sicard","year":"2020","journal-title":"Am. J. Transplant."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Efimova, O.V., and Kelley, T.W. (2009). Induction of granzyme B expression in T-cell receptor\/CD28-stimulated human regulatory T cells is suppressed by inhibitors of the PI3K-mTOR pathway. BMC Immunol., 10.","DOI":"10.1186\/1471-2172-10-59"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.imlet.2019.05.003","article-title":"The UniCAR system: A modular CAR T cell approach to improve the safety of CAR T cells","volume":"211","author":"Bachmann","year":"2019","journal-title":"Immunol. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3145","DOI":"10.1182\/blood.2020009759","article-title":"Proof of concept for a rapidly switchable universal CAR-T platform with UniCAR-T-CD123 in relapsed\/refractory AML","volume":"137","author":"Wermke","year":"2021","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"101784","DOI":"10.1016\/j.xpro.2022.101784","article-title":"Generation of non-human primate CAR Tregs using artificial antigen-presenting cells, simian tropic lentiviral vectors, and antigen-specific restimulation","volume":"3","author":"Ellis","year":"2022","journal-title":"STAR Protoc."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/s41577-019-0232-6","article-title":"T(reg) cell-based therapies: Challenges and perspectives","volume":"20","author":"Raffin","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1002\/hep.28459","article-title":"A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation","volume":"64","author":"Todo","year":"2016","journal-title":"Hepatology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1016\/S0140-6736(20)30167-7","article-title":"Regulatory cell therapy in kidney transplantation (The ONE Study): A harmonised design and analysis of seven non-randomised, single-arm, phase 1\/2A trials","volume":"395","author":"Sawitzki","year":"2020","journal-title":"Lancet"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e061864","DOI":"10.1136\/bmjopen-2022-061864","article-title":"Transplantation Without Overimmunosuppression (TWO) study protocol: A phase 2b randomised controlled single-centre trial of regulatory T cell therapy to facilitate immunosuppression reduction in living donor kidney transplant recipients","volume":"12","author":"Brook","year":"2022","journal-title":"BMJ Open"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2290","DOI":"10.1016\/j.transproceed.2007.07.076","article-title":"Reduced numbers of blood natural regulatory T cells in stable liver transplant recipients with high levels of calcineurin inhibitors","volume":"39","author":"Fabrega","year":"2007","journal-title":"Transplant. Proc."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1097\/01.tp.0000229473.95202.50","article-title":"Calcineurin inhibitors, but not rapamycin, reduce percentages of CD4+CD25+FOXP3+ regulatory T cells in renal transplant recipients","volume":"82","author":"Segundo","year":"2006","journal-title":"Transplantation"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"7083","DOI":"10.1073\/pnas.1620835114","article-title":"IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors","volume":"114","author":"Whitehouse","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3404","DOI":"10.1111\/ajt.13872","article-title":"The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses","volume":"16","author":"Schwarz","year":"2016","journal-title":"Am. J. Transplant."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1097\/TP.0000000000001379","article-title":"Impact of Immune-Modulatory Drugs on Regulatory T Cell","volume":"100","author":"Furukawa","year":"2016","journal-title":"Transplantation"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/s41577-018-0046-y","article-title":"Biology and regulation of IL-2: From molecular mechanisms to human therapy","volume":"18","author":"Spolski","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.jhep.2022.08.035","article-title":"Low dose interleukin-2 selectively expands circulating regulatory T cells but fails to promote liver allograft tolerance in humans","volume":"78","author":"Lim","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1084\/jem.20082824","article-title":"In vivo expansion of T reg cells with IL-2-mAb complexes: Induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression","volume":"206","author":"Webster","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"13508","DOI":"10.1073\/pnas.1903165116","article-title":"Treg-mediated prolonged survival of skin allografts without immunosuppression","volume":"116","author":"Pilat","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1038\/s41591-018-0070-2","article-title":"A human anti-IL-2 antibody that potentiates regulatory T cells by a structure-based mechanism","volume":"24","author":"Trotta","year":"2018","journal-title":"Nat. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e173107","DOI":"10.1172\/JCI173107","article-title":"A humanized IL-2 mutein expands Tregs and prolongs transplant survival in preclinical models","volume":"134","author":"Efe","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.4049\/jimmunol.166.4.2311","article-title":"Peripheral deletion after bone marrow transplantation with costimulatory blockade has features of both activation-induced cell death and passive cell death","volume":"166","author":"Wekerle","year":"2001","journal-title":"J. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/bmt.2017.231","article-title":"Long-term outcome of mixed chimerism after stem cell transplantation for thalassemia major conditioned with busulfan and cyclophosphamide","volume":"53","author":"Fouzia","year":"2018","journal-title":"Bone Marrow Transplant."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/74731","article-title":"Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment","volume":"6","author":"Wekerle","year":"2000","journal-title":"Nat. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.healun.2013.11.004","article-title":"T-regulatory cell treatment prevents chronic rejection of heart allografts in a murine mixed chimerism model","volume":"33","author":"Pilat","year":"2014","journal-title":"J. Heart Lung Transplant."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"a015529","DOI":"10.1101\/cshperspect.a015529","article-title":"Induction of tolerance through mixed chimerism","volume":"4","author":"Sachs","year":"2014","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1097\/00007890-199908270-00006","article-title":"Combined histocompatibility leukocyte antigen-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: The induction of allograft tolerance through mixed lymphohematopoietic chimerism","volume":"68","author":"Spitzer","year":"1999","journal-title":"Transplantation"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S1074-7613(01)00122-4","article-title":"Mixed chimerism and transplant tolerance","volume":"14","author":"Sykes","year":"2001","journal-title":"Immunity"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0003-4975(00)01564-2","article-title":"Mixed hematopoietic chimerism induces long-term tolerance to cardiac allografts in miniature swine","volume":"70","author":"Schwarze","year":"2000","journal-title":"Ann. Thorac. Surg."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1097\/00007890-200206150-00011","article-title":"Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys","volume":"73","author":"Kawai","year":"2002","journal-title":"Transplantation"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1111\/ajt.12851","article-title":"Depletion of foxp3(+) T cells abrogates tolerance of skin and heart allografts in murine mixed chimeras without the loss of mixed chimerism","volume":"14","author":"Shinoda","year":"2014","journal-title":"Am. J. Transplant."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e705","DOI":"10.1097\/TXD.0000000000001150","article-title":"A Mixed-chimerism Protocol Utilizing Thymoglobulin and Belatacept Did Not Induce Lung Allograft Tolerance, Despite Previous Success in Renal Allotransplantation","volume":"7","author":"Sommer","year":"2021","journal-title":"Transplant. Direct"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"eads0255","DOI":"10.1126\/scitranslmed.ads0255","article-title":"Cardiac allograft tolerance can be achieved in nonhuman primates by donor bone marrow and kidney cotransplantation","volume":"17","author":"Tonsho","year":"2025","journal-title":"Sci. Transl. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"483856","DOI":"10.1155\/2013\/483856","article-title":"Heart allograft tolerance induced and maintained by vascularized hind-limb transplant in rats","volume":"2013","author":"Liu","year":"2013","journal-title":"Clin. Dev. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.1172\/JCI124218","article-title":"Post-transplantation cyclophosphamide prevents graft-versus-host disease by inducing alloreactive T cell dysfunction and suppression","volume":"129","author":"Wachsmuth","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1111\/tid.12365","article-title":"Infections after T-replete haploidentical transplantation and high-dose cyclophosphamide as graft-versus-host disease prophylaxis","volume":"17","author":"Crocchiolo","year":"2015","journal-title":"Transpl. Infect. Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1002\/cncr.30534","article-title":"Cardiomyopathy in patients after posttransplant cyclophosphamide-based hematopoietic cell transplantation","volume":"123","author":"Lin","year":"2017","journal-title":"Cancer"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/s41409-024-02237-y","article-title":"Low dose post-transplant cyclophosphamide and sirolimus induce mixed chimerism with CTLA4-Ig or lymphocyte depletion in an MHC-mismatched murine allotransplantation model","volume":"59","author":"Kabore","year":"2024","journal-title":"Bone Marrow Transplant."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S0022-5223(00)70001-8","article-title":"A clinical trial combining donor bone marrow infusion and heart transplantation: Intermediate-term results","volume":"119","author":"Pham","year":"2000","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.jaci.2022.05.006","article-title":"Introducing thymus for promoting transplantation tolerance","volume":"150","author":"Fitch","year":"2022","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.jaci.2021.06.028","article-title":"Experience with cultured thymus tissue in 105 children","volume":"149","author":"Markert","year":"2022","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1007\/s10875-021-01044-0","article-title":"Care of Children with DiGeorge Before and After Cultured Thymus Tissue Implantation","volume":"41","author":"Gupton","year":"2021","journal-title":"J. Clin. Immunol."},{"key":"ref_92","first-page":"e129983","article-title":"Cultured thymus tissue implantation promotes donor-specific tolerance to allogeneic heart transplants","volume":"5","author":"Kwun","year":"2020","journal-title":"JCI Insight"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1016\/j.jtcvs.2021.12.048","article-title":"Induction of donor-specific tolerance to heart transplantation: From concept to clinical translation","volume":"165","author":"Kang","year":"2023","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S0022-5223(96)70453-1","article-title":"Durability of donor-specific and organ-specific heart transplant tolerance induced by intrathymic pretreatment with allogeneic spleen cells","volume":"111","author":"Shen","year":"1996","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1016\/S0022-5223(12)70148-4","article-title":"Histocompatibility differences and cardiac transplant tolerance produced by intrathymic pretreatment","volume":"107","author":"Shen","year":"1994","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/j.1432-2277.2004.tb00447.x","article-title":"Intrathymic injection of anti-Fas monoclonal antibody prolongs murine non-vascularized cardiac allograft survival","volume":"17","author":"Djamali","year":"2004","journal-title":"Transpl. Int."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1046\/j.1600-6143.2003.00295.x","article-title":"Composite \u201cthymoheart\u201d transplantation improves cardiac allograft survival","volume":"4","author":"Menard","year":"2004","journal-title":"Am. J. Transplant."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1097\/01.tp.0000200368.03991.e0","article-title":"Long-term acceptance of fully allogeneic cardiac grafts by cotransplantation of vascularized thymus in miniature swine","volume":"81","author":"Nobori","year":"2006","journal-title":"Transplantation"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.jtcvs.2005.03.036","article-title":"Heart and en-bloc thymus transplantation in miniature swine","volume":"130","author":"Johnston","year":"2005","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"e1595","DOI":"10.1097\/GOX.0000000000001595","article-title":"Split Tolerance in a Murine Model of Heterotopic En Bloc Chest Wall Transplantation","volume":"5","author":"Oh","year":"2017","journal-title":"Plast. Reconstr. Surg. Glob. Open"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1097\/00007890-199703270-00012","article-title":"Outcomes in recipients of combined heart-kidney transplantation: Multiorgan, same-donor transplant study of the International Society of Heart and Lung Transplantation\/United Network for Organ Sharing Scientific Registry","volume":"63","author":"Narula","year":"1997","journal-title":"Transplantation"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"12750","DOI":"10.3389\/ti.2024.12750","article-title":"Simultaneous Heart and Kidney Transplantation: A Systematic Review and Proportional Meta-Analysis of Its Characteristics and Long-Term Variables","volume":"37","author":"Sampaio","year":"2024","journal-title":"Transpl. Int."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1097\/00007890-198004000-00002","article-title":"Distribution and quantitation of HLA-ABC and DR (Ia) antigens on human kidney and other tissues","volume":"29","author":"Williams","year":"1980","journal-title":"Transplantation"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/S0022-5223(00)70005-5","article-title":"Mechanisms of tolerance induction and prevention of cardiac allograft vasculopathy in miniature swine: The effect of augmentation of donor antigen load","volume":"119","author":"Yamada","year":"2000","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e139331","DOI":"10.1172\/jci.insight.139331","article-title":"Kidney-induced systemic tolerance of heart allografts in mice","volume":"5","author":"Yang","year":"2020","journal-title":"JCI Insight"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1097\/TP.0b013e3181ac60db","article-title":"Combined heart and liver transplantation: A single-center experience","volume":"88","author":"Raichlin","year":"2009","journal-title":"Transplantation"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"10036","DOI":"10.3389\/ti.2021.10036","article-title":"Adult Combined Heart-Liver Transplantation: The United States Experience","volume":"35","author":"Alexopoulos","year":"2021","journal-title":"Transpl. Int."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1097\/TP.0b013e31827eef7e","article-title":"Combined heart and liver transplant attenuates cardiac allograft vasculopathy compared with isolated heart transplantation","volume":"95","author":"Topilsky","year":"2013","journal-title":"Transplantation"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1016\/j.athoracsur.2014.04.100","article-title":"Combined heart and liver transplantation can be safely performed with excellent short- and long-term results","volume":"98","author":"Atluri","year":"2014","journal-title":"Ann. Thorac. Surg."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1016\/j.jacc.2021.01.039","article-title":"Toward Immunomodulation in Heart Transplantation: 2 Organs Are Better Than 1","volume":"77","author":"Dec","year":"2021","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1097\/MOP.0000000000000398","article-title":"ABO-incompatible heart transplantation","volume":"28","author":"Urschel","year":"2016","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1016\/j.healun.2024.03.019","article-title":"ABO-incompatible heart transplantation-evolution of a revolution","volume":"43","author":"Bansal","year":"2024","journal-title":"J. Heart Lung Transplant."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1161\/CIRCULATIONAHA.123.065450","article-title":"The Future of Pediatric and Adult Heart Transplantation: Perspective from the United States","volume":"149","author":"Bacha","year":"2024","journal-title":"Circulation"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.healun.2012.03.007","article-title":"Pushing the boundaries: The current status of ABO-incompatible cardiac transplantation","volume":"31","author":"Irving","year":"2012","journal-title":"J. Heart Lung Transplant."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2795","DOI":"10.1038\/s41467-024-47131-9","article-title":"Enzymatic conversion of human blood group A kidneys to universal blood group O","volume":"15","author":"MacMillan","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"eabm7190","DOI":"10.1126\/scitranslmed.abm7190","article-title":"Ex vivo enzymatic treatment converts blood type A donor lungs into universal blood type lungs","volume":"14","author":"Wang","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"548","DOI":"10.5500\/wjt.v6.i3.548","article-title":"Current techniques for AB0-incompatible living donor liver transplantation","volume":"6","author":"Rummler","year":"2016","journal-title":"World J. Transplant."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1002\/lt.22016","article-title":"Dual living donor liver transplantation with ABO-incompatible and ABO-compatible grafts to overcome small-for-size graft and ABO blood group barrier","volume":"16","author":"Song","year":"2010","journal-title":"Liver Transpl."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1177\/0267659120926895","article-title":"The Great Ormond Street Hospital immunoadsorption method for ABO-incompatible heart transplantation: A practical technique","volume":"36","author":"Issitt","year":"2021","journal-title":"Perfusion"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"10171","DOI":"10.3389\/ti.2022.10171","article-title":"Cardiac Xenotransplantation: Progress in Preclinical Models and Prospects for Clinical Translation","volume":"35","author":"Singh","year":"2022","journal-title":"Transpl. Int."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/s41591-024-03429-1","article-title":"Transplantation of a genetically modified porcine heart into a live human","volume":"31","author":"Griffith","year":"2025","journal-title":"Nat. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/3968\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:19:43Z","timestamp":1760030383000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/3968"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,23]]},"references-count":121,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26093968"],"URL":"https:\/\/doi.org\/10.3390\/ijms26093968","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,23]]}}}