RAPAMYCIN-INDUCED LONG-TERM ALLOGRAFT SURVIVAL DEPENDS ON PERSISTENCEOF ALLOANTIGEN

In this study the mechanism of rapamycin-induced long-term allograft t olerance was investigated in a rat model. We have demonstrated that th e tolerance is strain specific, but is not organ specific. The toleriz ed rats failed to generate high levels of donor-specific cytotoxic Ab and cytotoxic cells in vivo. Removal of the alloantigen from the toler ized rats with or without concomitant thymectomy could break down the status of tolerance, and the rats regained the capability to reject th e grafts and to develop specific cytotoxic Ab and cytotoxic cells. The se results clearly indicate that the maintenance of the rapamycin-indu ced long-term tolerance to allografts depends on the persistence of al loantigens. Mechanistically, we have shown that the reduced IL-2 produ ction and the reduced antigenicity of the graft in the tolerized rat c ontribute to, but are not solely responsible for, the tolerance. The r esults of adoptive transfer experiments suggest that regulatory cells or suppressive serum factors are not involved in the tolerance. The fa ct that the removal of the alloantigen in the thymectomized rat could reverse the tolerance, indicates that there is no clonal deletion. We propose that chronic desensitization due to prolonged engagement of TC R by persistent alloantigens is the major mechanism at the late stage of the rapamycin-induced allograft tolerance.