Mechanisms of CML hyporesponsiveness in long-term renal allograft recipients

Long-term, HLA disparate, renal allograft recipients were assessed by a dose-dependent CML (cell-mediated lympholysis) assay for evidence of donor-specific CML hyporesponsiveness. The frequency of cytolytic T-cell (CTL) precursors capable of responding to donor alloantigen was also examined by a limiting-dilution assay and application of Poisson distribution statistics. Four recipients were found to have depressed CML responses against donor class I HLA antigens (mean 2-5% specific lysis), whereas significant responses against third party targets were noted (15-60% specific lysis). These data are consistent with an antigen-specific defect in the recipient CTL effector mechanism. To determine whether or not this may be due to a deletion of anti-donor alloreactive cells, a sensitive limiting-dilution assay was developed in conjunction with Poisson distribution statistics to obtain the frequency of both anti-donor and anti-third party CTLp present in recipient PBLs. A simultaneous reduction in the number of alloreactive clones and the presence of an active suppressor population were defined, suggesting that several mechanisms may operate concurrently in long-term renal allograft recipients with well-functioning grafts.