AMPLIFICATION OF NATURAL REGULATORY IMMUNE-MECHANISMS FOR TRANSPLANTATION TOLERANCE

There is a need to derive donor-specific tolerance in clinical organ t ransplantation, where potential benefits remain overshadowed by chroni c rejection and side effects of continual immunosuppressive therapy, I t is known that the mature immune system in mice can be reprogrammed t o accept a foreign graft as if it were ''self.'' Here we show that, on ce generated, this state of operational tolerance becomes self-sustain ing, imposing itself on new cohorts of lymphocytes as they arise, Thes e new cohorts retain specificity for the tolerizing antigen and can be selectively amplified to tolerate new antigens that have linked expre ssion with the original tolerogen, Regulation is critically dependent upon the continuous presence of tolerizing antigen and is mediated by the CD4(+) lymphocyte population, We propose that such natural mechani sms of immune regulation may eventually be exploited for transplantati on tolerance, even in fully immune-competent recipients.