title: Evidence that human cardiac allograft acceptance is associated with a decrease in donor-reactive helper T lymphocytes.
abstract: 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 circulating donor-reactive HTL may predict allograft rejection episodes diagnosed by endomyocardial biopsy. The present study evaluates the relationship between donor-reactive HTL and allograft "acceptance" in cardiac transplant recipients bearing long-term allografts (> 1 year). Patients were categorized as either long-term acceptors or persistent rejecters based on the number of rejection episodes and the ability to withdraw steroid therapy. Limiting dilution analysis for IL-2-producing HTL was utilized, with cadaver donor splenocytes as a source of donor alloantigens. Donor-reactive HTL frequencies were determined from peripheral blood samples obtained before transplant, and at 1 month and 1 year after transplant. Individuals who accommodated their allografts and were withdrawn from steroid therapy had reduced numbers of donor-reactive HTL at 1 year after transplant as compared with earlier time points. Further, PBMC obtained from these individuals at 1 year after transplant responded weakly to donor alloantigens in a mixed lymphocyte response (MLR). This relationship between donor-reactive HTL and allograft accommodation was exemplified in a cardiac/liver transplant patient who was diagnosed with progressive multifocal leukoencephalopathy and removed from all immunosuppression. No subsequent rejection episodes were diagnosed. Donor-reactive HTL were not detectable and this individual failed to mount an MLR to donor alloantigens. However, a vigorous donor-reactive response was observed when MLR cultures were supplemented with exogenous IL-2. Therefore, nonresponsiveness to the allograft 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 HTL at 1 year after transplant. PBMC from these individuals responded vigorously to donor alloantigens in an MLR. Hence, monitoring donor-reactive HTL may identify individuals who have accommodated their graft and may tolerate a reduction in immunosuppression.
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor 48109.
authors.forename: L A
authors.initials: LA
authors.lastname: DeBruyne
authors.forename: D G
authors.initials: DG
authors.lastname: Renlund
authors.forename: D K
authors.initials: DK
authors.lastname: Bishop
mesh_terms: D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D006680:HLA Antigens / Q000235:genetics; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D018655:Lymphocyte Count; D007959:Lymphocyte Culture Test, Mixed; D010641:Phenotype; D013154:Spleen / Q000166:cytology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology*; D014019:Tissue Donors; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D006680:HLA Antigens