T suppressor lymphocytes reverse ongoing acute allograft rejection

Abstract

(LEW × BN)F1 cardiac allografts are rejected within 8 days in untreated LEW recipients. At the critical time point of 5 days after transplantation, the obviously rejecting grafts are enlarged and maximally infiltrated by host cells as shown by 111In-labeled lymphocyte tracer studies. However, when such hearts were retransplanted back to naive (LEW × BN)F1 secondary hosts, they survive indefinitely, showing that even late rejection is reversible in the absence of sustained host immunological drive. Attempts were then made to abrogate this advanced immune responsiveness using Cyclosporine (CsA). CsA therapy (15 mg/kg/day for 7 days) starting from day 5 produced indefinite graft survival, similar as if initiated at the time of operation. Addition of exogenous IL-2, which drives the proliferation of Tc, could not reverse this effect. Serial changes in phenotype of lymphocyte subpopulations infiltrating both acutely rejecting and indefinitely functioning cardiac allografts in unmodified and CsA treated hosts, respectively, were then studied. Ratio of Th:Tc/s cells in acutely rejecting grafts was 1.6 by day 3; it inverted abruptly to 0.7 by day 5–6, suggesting predominance of Tc/s during the later stages of allograft rejection. Similarly, treatment with CsA produced a transient depression of Th, with recovery of original Th:Tc/s ratio during the next 2–3 weeks. Adoptive transfer experiments were then performed to investigate the functional significance of these findings. Survival of test grafts were prolonged (14–17 days, p < 0.001) when cells infiltrating the grafts were transferred during inversion of Th:Tc/s; before that period, test graft survival was shortened in a second set manner. Thus, suppressor cells may be responsible for resolution of rejection process as well as for host unresponsiveness seen after CsA treatment; they represent an important homeostatic host mechanism following immunological stimulation.