PROGRESSIVE ACCUMULATION OF CTL WITH HIGH AVIDITY FOR DONOR ANTIGENS DURING THE DEVELOPMENT OF ACUTE CARDIAC REJECTION

To study the importance of cytotoxic T lymphocytes (CTL) with high avi dity for donor antigens (Ag) in the development of acute cardiac allog raft rejection, their appearance within the graft in relation to rejec tion was analyzed. For this study, donor directed CTL propagated from sequentially taken endomyocardial biopsies (EMB) were enumerated by li miting dilution analysis (LDA). Subsequentially, the fraction of these CTL having high avidity for donor Ag was determined by addition of a CD8 monoclonal antibody (mAb) to the cytotoxic phase of the LDA. Analy sis of 37 EMB cultures obtained from 11 heart transplant (HTx) patient s before, during, or after they experienced rejection, revealed the ki netics of donor specific CTL in relation to rejection for HTx patients in general. For 5 individual recipients, a more detailed analysis was performed. The kinetics found for individual patients confirmed the p attern found for the total group of HTx recipients tested. Frequencies of donor specific precursor CTL (pCTL) as well as of in vivo primed d onor reactive CTL (committed CTL or cCTL) increased towards rejection and decreased after successful rejection therapy. More than 2 weeks be fore rejection was diagnosed, only a small fraction of the graft infil trating donor specific pCTL and cCTL had high avidity for donor Ag (me dian=35% and 11%, respectively). Within 2 weeks preceding rejection, t his fraction increased gradually (median=52% and 55%, respectively) an d became dominant during rejection (median=87% and 78%, respectively). After successful rejection therapy, a decrease to basal levels (media n=18% and 24%, respectively) was observed. Conclusively, intragraft ac cumulation of high avidity, donor specific pCTL and cCTL may cause tra nsplant rejection.