In vivo cell-mediated effector mechanisms of allograft destruction were investigated in a canine single-lung transplantation model. This large animal model permits direct longitudinal studies of immune effector cells from the grafts of individual recipients by bronchoalveolar lavage (BAL). Evidence was obtained that two types of cytolytic lymphocytes act as effectors of allograft destruction. Typical allospecific cytolytic T lymphocytes, were detected late in the course of rejection in nonimmunosuppressed recipients and in cyclosporine-treated recipients during the latter stage of drug tapering. The other type of intragraft cytolytic lymphocyte was observed in the early stages of CsA dose tapering and was characterized by ability to lyse xenogeneic targets in a lectin-dependent cytotoxicity assay but inability to kill allogeneic target cells from the lung donor. These cytolytic cells were also detected in the initial stage of lung rejection in non immunosuppressed recipients and in the early period (3 days) of mixed lymphocyte culture. Current interpretation of these data is that these latter effector cells have the characteristics of IL-2-activated killer cells (IAK). Substantial delays in the detection of intragraft donor-specific CTL relative to IAK activity were observed in recipients undergoing CsA dose tapering compared with nonimmunosuppressed recipients. This finding suggests that appropriate CsA treatment may lead to prolonged inhibition of the generation of donor-specific CTL compared with induction of IAK activity. Delayed detection of intragraft donor-specific CTL paralleled the absence of such activity in donor-specific MLC of tolerant lung allograft recipients. The result of CsA therapy may, therefore, be characterized as a state of “partial unresponsiveness,” since certain pathways of immune effector activity remain intact after termination of treatment. The differential effect of CsA on various pathways of allograft destruction may have important implications regarding concepts of alloreactivity and T cell-mediated immune responses.