ASSESSMENT OF THE CONTRIBUTION THAT DIRECT ALLORECOGNITION MAKES TO THE PROGRESSION OF CHRONIC CARDIAC TRANSPLANT REJECTION IN HUMANS

Background-Two populations of T cells contribute to allograft rejectio n. T cells with direct allospecificity are activated after recognition of intact MHC alloantigens displayed at the surface of donor passenge r leukocytes carried within the graft. In contrast, T cells with indir ect allospecificity recognize donor alloantigens as processed peptides associated with self (recipient)-MHC class II molecules. In small ani mal models of transplantation, direct pathway T cells dominate the acu te rejection process and are rendered tolerant to the graft after the loss of donor passenger leukocytes. It has been argued that indirect p athway T cells contribute substantially to continual graft damage afte r passenger cell loss. The purpose of this study was to determine whet her donor-specific tolerance could be detected in T cells with direct anti-donor allospecificity in human heart transplant recipients after prolonged graft residence.Methods and Results-Alloreactive helper (HTL f) and cytotoxic (CTLf) T cells were enumerated by use of limiting dil ution analysis, These assay systems were refined to make them specific for the direct pathway of allorecognition and more sensitive in the c ase of the HTLf assay, Recipient:anti-donor frequencies were generated in 10 long-term recipients of heart grafts with progressive chronic r ejection and compared with those against equivalently HLA mismatched r ecipient:third-party controls. For HTLf, direct pathway donor-specific hyporesponsiveness was detected in 5 of the 10 recipients (HTLf <1:10 0 000), Of these 5 recipients, 4 also had low anti-donor CTLf (<1:100 000), In the 5th recipient, although the CTLf was >1:100 000, it was s ignificantly lower than that estimated against the third-party control . Conclusions-Donor-specific hyporesponsiveness is demonstrated in 50% of recipients in both the HTLf and CTLf compartments of the direct al loresponse. Direct allorecognition therefore appears unlikely to be re sponsible for the progression of chronic rejection, implicating indire ct allorecognition as the predominant immunological driving force. Fur thermore, these data have potential implications for graft outcome, ad justment of immunosuppression, and recipient monitoring.