Immune regulation following allogeneic iPSC-derived cardiomyocyte transplantation in non-human primates

AIMS: This study explores the efficacy of immunosuppressive regimens commonly used in heart transplantation for promoting the survival of allogeneic induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) grafts in non-human primates, specifically cynomolgus monkeys. METHODS AND RESULTS: By combining methylprednisolone (MPL), calcineurin inhibitors (CNIs), and mycophenolate mofetil (MMF), we ensured adequate graft survival without acute rejection. Histological analysis showed iPSC-CM survival, vascularization, and minimal immune rejection, despite immaturity. Reducing the immunosuppressive regimen by omitting MPL and using only CNIs and MMF resulted in graft rejection, underscoring the need for all three immunosuppressants. Genetically modified hypo-immune iPSC-CMs had poor engraftment due to increased apoptosis, unrelated to immune rejection. Additionally, abatacept in combination with tacrolimus allowed MPL discontinuation without rejection, whereas amiodarone and ivabradine effectively prevented the occurrence of post-transplant ventricular arrhythmias and reduced the incidence of sudden cardiac death. CONCLUSION: These findings highlight the importance of optimized immunosuppressant regimens for iPSC-CM graft survival and the potential improvements in clinical outcomes in patients with severe heart failure.