Rapamycin-induced long-term allograft survival depends on persistence of alloantigen.
In this study the mechanism of rapamycin-induced long-term allograft tolerance was investigated in a rat model. We have demonstrated that the tolerance is strain specific, but is not organ specific. The tolerized rats failed to generate high levels of donor-specific cytotoxic Ab and cytotoxic cells in vivo. Removal of the alloantigen from the tolerized rats with or without concomitant thymectomy could break down the status of tolerance, and the rats regained the capability to reject the grafts and to develop specific cytotoxic Ab and cytotoxic cells. These results clearly indicate that the maintenance of the rapamycin-induced long-term tolerance to allografts depends on the persistence of alloantigens. Mechanistically, we have shown that the reduced IL-2 production and the reduced antigenicity of the graft in the tolerized rat contribute to, but are not solely responsile for, the tolerance. The results of adoptive transfer experiments suggest that regulatory cells or suppressive serum factors are not involved in the tolerance. The fact 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 TCR by persistent alloantigens is the major mechanism at the late stage of the rapamycin-induced allograft tolerance.
Chen
H
H
Laboratory of Experimental Surgery, Notre-Dame Hospital Research Center, Montreal, Quebec, Canada.
Luo
H
H
Daloze
P
P
Xu
D
D
Wu
J
J
D000818:Animals; D000917:Antibody Formation; D006085:Graft Survival / Q000187:drug effects*; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis; D007519:Isoantigens / Q000502:physiology*; D008297:Male; D009928:Organ Specificity; D011090:Polyenes / Q000494:pharmacology*; D051381:Rats; D011915:Rats, Inbred BUF; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D020123:Sirolimus; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007519:Isoantigens; D011090:Polyenes; D020123:Sirolimus