IMMUNOSUPPRESSIVE THERAPY ABROGATES UNRESPONSIVENESS TO RENAL-ALLOGRAFT INDUCED BY THYMIC RECOGNITION OF DONOR ANTIGENS

This laboratory and others have previously shown that the intrathymic injection of donor cells or major histocompatibility complex allopepti des induced indefinite survival of a subsequent graft without immunosu ppression. This approach may open interesting new perspectives for tra nsplant medicine. Studies to explore the feasibility of the technique in humans can only be designed with some form of concomitant immunosup pression to avoid the risk of irreversible rejection in the case that the thymus approach fails. Thus, one of the first issue to address is whether conventional immunosuppression interfered with the process of thymus tolerance. This study was designed to investigate the above iss ue. In transplanted Lewis control rats, cyclosporin A (CsA) (10 mg/kg per day) and methylprednisolone (MP) (10 mg/kg twice daily) for 3 days were invariably followed by kidney graft rejection within 10 days. In subsequent experiments, five groups of Lewis rats were injected with medium alone or Brown-Norway (BN) leukocytes into the thymus, and 24 h later, they were orthotopically transplanted with major histocompatib ility complex-incompatible kidneys from BN rats. At the time of transp lantation, Lewis rats received MP (10 mg/kg twice daily) CsA (10 mg/kg per day), or the combination of the two (MP + CsA at the same dose) f or 3 days, Lewis rats injected intrathymically with BN leukocytes but not receiving immunosuppressants had indefinite survival of their kidn ey graft. The effect of the intrathymic injection of donor cells of in ducing unresponsiveness to a subsequent kidney graft was abolished by concomitant immunosuppression. All animals given immunosuppressants re jected their graft within 12 days after surgery. These findings indica te that, at least in rats, steroids and CsA interfere with the mechani sm(s) that promote thymic recognition of alloantigens. These results h ave major implications for future studies aimed at exploring whether t he thymus technique was a feasible antirejection strategy in human tra nsplantation.