THE AVIDITY, NOT THE MERE PRESENCE, OF PRIMED CYTOTOXIC T-LYMPHOCYTESFOR DONOR HUMAN-LEUKOCYTE CLASS-II ANTIGENS DETERMINES THEIR CLINICALRELEVANCE AFTER HEART-TRANSPLANTATION

Background: To analyze the relevance of CD4-positive cytotoxic T-lymph ocytes (CTL) in clinical heart rejection, we studied the frequency and avidity of donor human leukocyte antigen class II-specific CTL presen t within the graft during a rejection episode and during a period with out rejection. Methods: For this analysis endomyocardial biopsies of h eart transplant recipients were cultured to obtain graft-infiltrating lymphocytes (GIL). GIL cultures exhibiting donor class II-directed cyt otoxicity were considered for this study. With limiting dilution analy sis, the frequency of donor class II-specific CTL that had been primed by donor antigens in vivo (designated cCTL) was determined in GIL cul tures established from endomyocardial biopsies taken during a rejectio n episode (n = 10) or during a period without rejection (n = 11). Addi tion of anti-CD4 to the limiting dilution analysis revealed the fracti on of donor class II-specific cCTL having a high avidity for donor ant igen. Results: During a rejection episode, 196 (median) donor class II -specific cCTL/106 GIL were present. In a period without rejection, th e frequency of donor class II-specific cCTL was not significantly diff erent (median = 330/10(6); p = 0.1). Addition of anti-CD4, however, re vealed that donor class II-specific cCTL with a high avidity for donor antigen are predominant during a rejection episode (median = 100%) bu t are in minority during a period without rejection (median = 35%; p < 0.0001). Conclusions: These results suggest that graft-infiltrating C D4(+) CTL can mediate heart rejection provided they have a high avidit y for donor antigen.