Evolving approaches of hematopoietic stem cell-based therapies to induce tolerance to organ transplants: the long road to tolerance

摘要

The immunoregulatory properties of hematopoietic stem cells (HSC) have been recognized for over 60 years, beginning when Owen (1945) reported that genetically disparate freemartin cattle sharing a common placenta were red blood cell chimeras, and subsequently when Billingham, Brent, and Medawar (1953) demonstrated that murine neonatal chimeras prepared by infusion of donor-derived hematopoietic cells exhibited donor-specific tolerance to skin allografts. Various approaches using HSC in organ transplantation have gradually brought the dream of inducing donor-specific tolerance in organ transplant recipients closer to reality. Several hurdles needed to be overcome, especially avoiding graft-versus-host disease, the toxicity of ablative conditioning and eliminating the need for close donor/recipient matching. For wide acceptance, HSC therapy must be safe and reproducible in mismatched donor/recipient combinations. Discoveries in other disciplines have often unexpectedly and synergistically contributed to progress. This review presents an historic perspective of the quest for tolerance in organ transplantation, highlighting current clinical approaches.