Preclinical and clinical developments in Treg therapy for heart transplantation: Critical assessment and translational challenges

Regulatory T cells (Tregs) represent a promising approach to induce donor-specific tolerance in cardiac transplantation, potentially reducing reliance on chronic immunosuppression. This review critically evaluates preclinical and clinical evidence. Preclinical studies demonstrate that adoptively transferred Tregs prolong cardiac allograft survival and prevent chronic allograft vasculopathy (CAV) in murine models through multiple suppressive mechanisms. Phase I/II trials in kidney and liver transplantation have already confirmed safety and feasibility of polyclonal Treg cell therapy, with evidence of immunosuppression reduction in selected patients. However, no cardiac-specific trials have been completed in adults, and critical translational barriers persist including limited in vivo persistence, phenotypic instability under inflammatory conditions, manufacturing complexity and incompatibility with deceased donor timelines. Emerging approaches show promise: CAR-engineered Tregs targeting HLA-A2 demonstrate enhanced specificity and establish infectious tolerance in preclinical cardiac transplant models, with preliminary data from the first-in-human kidney transplant data suggesting safety and efficacy. Thymus-derived Tregs offer advantages for pediatric recipients, with the first treated cardiac transplant patient showing preserved Treg homeostasis. This review identifies key research priorities necessary to translate Treg therapy into clinical cardiac transplantation practice.