EVIDENCE THAT HUMAN CARDIAC ALLOGRAFT ACCEPTANCE IS ASSOCIATED WITH ADECREASE IN DONOR-REACTIVE HELPER T-LYMPHOCYTES

We have reported that acute cardiac allograft rejection is associated with increased numbers of donor-reactive helper T lymphocytes (HTL) in the peripheral blood of patients. Further, increased frequencies of c irculating donor-reactive HTL may predict allograft rejection episodes diagnosed by endomyocardial biopsy. The present study evaluates the r elationship between donor-reactive HTL and allograft ''acceptance'' in cardiac transplant recipients bearing long-term allografts (>1 year). Patients were categorized as either long-term accepters or persistent rejecters based on the number of rejection episodes and the ability t o withdraw steroid therapy. Limiting dilution analysis for IL-2-produc ing HTL was utilized, with cadaver donor splenocytes as a source of do nor alloantigens. Donor-reactive HTL frequencies were determined from peripheral blood samples obtained before transplant, and at 1 month an d 1 year after transplant. Individuals who accommodated their allograf ts and were withdrawn from steroid therapy had reduced numbers of dono r-reactive HTL at 1 year after transplant as compared with earlier tim e points. Further, PBMC obtained from these individuals at 1 year afte r transplant responded weakly to donor alloantigens in a mixed lymphoc yte response (MLR). This relationship between donor-reactive HTL and a llograft accommodation was exemplified in a cardiac/liver transplant p atient who was diagnosed with progressive multifocal leukoencephalopat hy and removed from all immunosuppression, No subsequent rejection epi sodes were diagnosed. Donor-reactive HTL were not detectable and this individual failed to mount an MLR to donor alloantigens, However, a vi gorous donor-reactive response was observed when MLR cultures were sup plemented with exogenous IL-2. Therefore, nonresponsiveness to the all ograft appeared to be due to a deficit in IL-2 production, In contrast , patients who experienced persistent rejection episodes and required continued steroid therapy maintained large numbers of donor-reactive H TL at 1 year after transplant, PBMC from these individuals responded v igorously to donor alloantigens in an MLR. Hence, monitoring donor-rea ctive HTL may identify individuals who have accommodated their graft a nd may tolerate a reduction in immunosuppression.