Induction of Heart Allograft Tolerance in Cynomolgus Macaques via En Bloc Thymus Transplantation

• Applicant: Dr. Ryan Chaban
• Subject Area: Cardiac and Vascular Surgery ; Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468485612

Induction of immune tolerance is the ultimate goal in the field of organ transplantation. Achieving a state of tolerance would lead to indefinite graft survival without chronic immunosuppression and its associated morbidity/ mortality and could lead to the prevention or reduction of chronic rejection. Strategies that have attained some degree of hematopoietic chimerism in organ receivers (a state in which one individual develops different blood cell lineage from different genomes after receiving bone marrow transplantation) through host conditioning and donor bone marrow co-transplantation have achieved tolerance in human kidney allograft recipients. While these groundbreaking results hold the promise of widespread application of tolerance to the entire field of organ transplantation, it is now clear, based on nonhuman primates (NHP) studies, that protocols which are successful in kidney recipients are ineffective in recipients of tolerance-resistant organs such as hearts and lungs. To extend the clinical applicability of donor hematopoietic chimerism to resistant thoracic organs, we will test the hypothesis that enhancing regulatory mechanisms in transient chimeras through donor thymus co-transplantation will achieve long-term stable heart allograft tolerance. Furthermore, in anticipation of rapid translation of a successful NHP protocol to clinical trials, we will test the substitution of experimental agents (anti-CD154 and anti-CD8 mAbs) with FDA-approved drugs: venetoclax (a Bcl-2 inhibitor) and tofacitinib (a JAK 1/3 inhibitor).

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Richard N. Pierson