THE ROLE OF CYCLOSPORINE-INDUCED AUTOREACTIVE T-LYMPHOCYTES IN SOLID-ORGAN ALLOGRAFT SURVIVAL AND CHRONIC REJECTION

Cyclosporine (CsA) has profound but paradoxical effects on the immune system, CsA can facilitate the induction of transplantation tolerance in some animal systems but it inhibits the clonal deletion of MHC clas s II autoreactive T cells, The present studies evaluated whether the a utoreactive T cells participate in the induction of facilitated graft acceptance after CsA treatment by recognizing and eliminating activate d allograft responsive T cells that express MHC class II determinants. Transfer of autoreactive T cells into naive Lewis rats pretreated wit h cyclophosphamide significantly prolonged the survival of heterotopic cardiac allografts from MHC-disparate BN strain donors, Following tra nsfer of the autoreactive T cells, there was a marked reduction in the frequency of alloreactive T lymphocytes responsive to donor alloantig ens, The role of MHC class II autoreactive CD8(+) V beta 8.5(+) T cell s in facilitated graft acceptance was also supported by the findings t hat (1) treatment with anti-MHC class II antibody abrogated prolonged allograft survival after CsA therapy and (2) V beta 8.5(+) lymphocytes , infiltrate the allograft during CsA therapy but are absent in the gr aft in non-CsA-treated control animals, Although these data are consis tent with the hypothesis that autoreactive T cells prolong cardiac all ograft survival after CsA treatment, the autoaggressive cells failed t o inhibit the development of chronic rejection of both heart and skin allografts, These data suggest either that the autoreactive T cells do not inhibit immune mechanisms responsible for chronic graft rejection or that the autoaggressive lymphocytes may participate in and exacerb ate chronic rejection of allografts, Taken together, the induction of MHC class II autoreactive T cells may provide a common fundamental mec hanism explaining the paradoxical effects of CsA.