Approaches to the Study of T-Lymphocytes in Transplantation Tolerance

Basic research into the cellular and molecular mechanisms leading to transplantation tolerance has undergone a renaissance during the past decade. A number of elegant and ingenious experimental approaches have been developed and utilized to study, both in vitro and in vivo, the changes in T-lymphocytes that accompany tolerance induction. In this article, we emphasize mechanisms that accomplish T-cell-dependent transplantation tolerance via "passive" (clonal deletion/anergy) and "active" (suppression/priming of IL-4-producing T cells) mechanisms. Evidence is summarized from the recent literature describing several different and important experimental models of transplantation tolerance:intravenous injection of allogeneic cells, direct intrathymic injection of allogeneic cells, transgenic mice expressing genomically incorporated alloantigens, antibody-mediated depletion of T-cell subsets, and neonatal transplantation tolerance. At the present state of our understanding it is clear that only rarely does a single mechanism take sole responsibility for the tolerant condition; neonatal transplantation tolerance is an excellent example of a model that is induced and maintained by a coalition of tolerance-promoting processes. It is also apparent that induction of unresponsiveness among individual T-cells, once thought to occur exclusively in the thymus gland, can occur extrathymically, even among immunocompetent T-cells. This realization has revived optimism among basic and clinical transplanters who have long held the aspiration that prolonged, even indefinite, allograft survival can be achieved in adult human beings with only minimal perturbation of the immune system.