DIFFERENTIAL AVIDITY AND CYCLOSPORINE SENSITIVITY OF COMMITTED DONOR-SPECIFIC GRAFT-INFILTRATING CYTOTOXIC T-CELLS AND THEIR PRECURSORS - RELEVANCE FOR CLINICAL CARDIAC GRAFT-REJECTION

We have used limiting dilution analysis to study the qualitative and q uantitative differences between graft-infiltrating cytotoxic T cell po pulations propagated from endomyocardial biopsies of heart transplant patients who experienced one or more acute rejection episodes and pati ents who never showed signs of rejection. Limiting dilution cultures w ere stimulated with autologous or donor cells both in the absence or i n presence of cyclosporine and of CD8 in the cytotoxic phase. Almost a ll antigen-primed, committed cytotoxic T cells (cCTL) present in the g raft of patients with rejections were CsA resistant. In contrast, in m ost patients of the nonrejector group, a substantial part of the cCTL could be inhibited by CsA. The CTL precursors (pCTL) in both groups we re predominantly CsA sensitive. Addition of CD8 mAb during the cytotox icity phase of the limiting dilution analysis was used to differentiat e between CTL populations with high avidity for donor antigens and pop ulations with low avidity. The predominant subpopulation in the graft of rejectors was a CsA-resistant cCTL with high avidity, while in the graft of most nonrejector, cCTL with low avidity dominated. In most re jectors, CD8 mAb had only a minor influence on the pCTL frequency esti mates, and thus on T cells with high avidity. CsA-sensitive pCTL with high avidity might represent an intermediate stage between the naive p CTL and mature, functional, CsA-insensitive cCTL with high avidity for donor antigens.