INHIBITION OF HUMAN IN VIVO CYTOTOXIC T LYMPHOCYTE GENERATION BY CYCLOSPORINE FOLLOWING ORGAN TRANSPLANTATION

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Abstract
The effect of Cyclosporine (CsA) on the in vivo cell-mediated immune response to donor antigens was examined sequentially following cadaveric renal transplantation in both immunologically naive and specifically sensitized allograft recipients. Cytotoxic T lymphocytes (CTL) exhibiting preferential specificity for donor antigens were detected in the peripheral blood of all patients receiving azathioprine (AZA) immunosuppression by two weeks posttransplant, disappearing progressively over the first three months with clinical quiescence. In contrast, the generation of donor-reactive CTL was significantly diminished in incidence (P=0.05) and in magnitude (P=0.004) in subjects receiving CsA. CTL were detected in only 36% of patients by two weeks posttransplant, and were not detectable in any CsA-treated patient after the sixth posttransplant week. The ability of CsA to inhibit clonal reexpansion of CTL was examined both in vitro and in vivo in subjects exhibiting prior sensitization to donor antigens. In vitro, CsA caused a dose-dependent inhibition of accelerated (72-hr MLC) CTL generation following restimulation with donor spleen cells, which was quantitatively identical to that in parallel cultures using responder PBL from non-sensitized individuals. In vivo, CsA produced a rapid disappearance of circulating CTL posttransplant in patients who exhibited specific cell-mediated sensitization to the graft donor, as evidenced by the presence of circulating donor-reactive CTL prior to transplantation. In contrast, in patients receiving AZA there was a rapid increase in donor-reactive CTL in the peripheral blood following transplantation. CTL persisted for six weeks or longer, and two of four patients lost the graft to irreversible acute rejection within the first four weeks.