The thymic way to transplantation tolerance

Abstract

Within the past three decades, extensive research has been carried out with the aim to prevent graft rejection by minimizing the side effects related to the use of immunosuppressants. The major goal in transplantation research remains the development of strategies that would allow one to achieve a state of donor-specific unresponsiveness in order to promote a condition of true tolerance without the need of immunosuppressants. Recent evidence has been provided that this is a pursuing goal, at least in experimental animals. The thymus plays the major role in the development of self-tolerance, and initial work in the late 1960s indicated that the thymus also plays a critical role in the induction of acquired tolerance to exogenous antigens. Recently, the interest in acquired thymic tolerance has been renewed by the observation that, in the rat, the thymus is an immunologically privileged site in which isolated pancreatic islets can be engrafted and survive indefinitely. Moreover, intrathymic injection of the islets induced donor-specific unresponsiveness, which allowed survival of a second donor-strain islet cell allograft transplanted into an extrathymic site. These findings on cellular allografts have been extended to vascularized organ allografts. Studies have documented that, in rodents, the intrathymic injection of donor cells induces a state of tolerance and prolongs the survival of allografts, including kidney, heart, liver, and small bowel. Unresponsiveness to organ graft is donor but not tissue specific, and evidence is presented here that the thymus has a central role in such a phenomenon. The nature of the alloantigen(s) being recognized in the thymus and the possible mechanism(s) of acquired thymic tolerance are reviewed.