Tolerance Induction Strategies in Organ Transplantation: Current Status and Future Perspectives

Achieving donor-specific immune tolerance has the potential to eliminate the need for lifelong immunosuppression in transplant recipients, but translating this goal into clinical practice remains challenging. Unlike laboratory rodents, humans are exposed to a variety of pathogens that generate memory T cells, which can interfere with tolerance induction. Establishing full donor hematopoietic chimerism, whether spontaneous or induced, can support robust immune tolerance. However, it often relies on graft-versus-host (GvH) reactivity, which carries significant risks, including graft-versus-host disease (GVHD) and infection. Although non-myeloablative conditioning protocols have shown promise, their broader use is limited by concerns about toxicity and the need to carefully balance GvH responses. Mixed and transient chimerism represents a less toxic alternative, but its effectiveness in humans is hindered by limited durability and resistance from memory T cells. Thymus transplantation offers another strategy by promoting central tolerance through donor-specific thymic education of developing T cells. Regulatory cell therapies combined with reduced immunosuppression have emerged as a safer approach. Early clinical trials have yielded encouraging results. Innovations in IL-2 pathway modulation and genetic engineering, including CAR-redirected regulatory T cells, may further enhance the precision, durability, and safety of strategies aimed at achieving transplantation tolerance.