Cellular basis of long-term organ transplant acceptance: pivotal role of intrathymic clonal deletion and thymic dependence of bone marrow microchimerism-associated tolerance.

Long-term acceptance of MHC-incompatible organ allografts without chronic immunosuppressive therapy has been achieved in experimental animals. There are also reports, mainly in liver transplant, of patients who after complete withdrawal of immunosuppressants still have a functioning graft. It has been proposed that organ transplant implies a migratory flux of donor "passenger" leukocytes out of the graft into the recipient tissues or organs, serving to establish a persistent condition of "microchimerism," and being a tolerogenic precursor of chimeric cells. Although there is evidence that the same migratory mechanisms apply to all organ grafts, migration of passenger leukocytes is less in organs other than the liver, such as the kidney and heart. To enhance the acceptance of organs less tolerogenic than the liver, perioperative infusion of donor bone marrow has been attempted to increase the migration of donor leukocytes of bone marrow origin. It has been suggested that such peripheral donor microchimerism is not only associated with long-term acceptance of the organ graft but that it plays an active role in induction and maintenance of unresponsiveness. However, the intimate mechanisms(s) responsible for prolonged organ survival in this setting remains speculative. Experimental evidence that the thymus plays the major role in the development of self-tolerance and is also critical in the induction of acquired tolerance to exogenous antigens has focussed the attention on the intrathymic events that lead to donor-specific unresponsiveness to allograft. Data are available showing that after direct intrathymic injection of donor cells, clonal deletion of maturing host thymocytes occurs and is the major mechanism in the induction of donor-specific tolerance. The central role of the thymus in transplant tolerance is also supported by more recent findings that in mixed allogeneic bone marrow chimeras in mice with a nonmyeloablative conditioning regimen, migration of donor bone marrow-derived dendritic cells to the thymus serves to negatively select newly developing host T cells. Therefore, the peripheral T-cell component would be devoid of alloreactive population. Thus, lifelong intrathymic clonal deletion is the only significant mechanism involved in the maintenance of donor-specific T-cell tolerance that would allow the subsequent vascularized organ from the same donor to survive indefinitely.