Induction of specific unresponsiveness (tolerance) to experimental and clinical allografts using polyclonal antilymphocyte serum and donor-specific bone marrow

In their classic studies, Medawar and colleagues (1) first demonstrated that donor-specific antigen itself could be used to attenuate or eliminate the allograft rejection reaction. They injected living-replicating lymphoid cells in utero or into neonatal recipients — a time when the recipients were naturally immunosuppressed by virtue of their underdeveloped immune system — and demonstrated that such recipients were rendered specifically unresponsive to donor grafts as adults. They termed this phenomenon actively acquired immunological tolerance, and noted that tolerant adults were lymphoid cell chimeras, that they rejected third-party grafts, and could reject donor-specific grafts if their immune system was reconstituted with adult syngeneic lymphoid cells that had not been exposed in utero to the donor antigens. Although the exact immunological basis for this observation is still not completely defined, this experiment has served as a persistent goal to induce specific non-reactivity to tissue allografts without the use of chronically administered non-specific immunosuppression. All attempts to translate Medawar’s experiment to adult animals have been more or less based on the assumption that it would be done in immunologically mature, adult animals. Thus, most attempts to use donor-specific antigen to modulate the allograft response have utilized an initial period of transient non-specific immunosuppression (to mimic the neonatal state) during which exposure to donor-specific antigen is superimposed.