Active role of chimerism in transplantation tolerance induced by antilymphocyte serum, sirolimus, and bone-marrow-cell infusion.
BACKGROUND
A regimen consisting of antilymphocyte serum (ALS), sirolimus, and donor bone-marrow-cell (BMC) infusion induces indefinite skin allograft survival across fully mismatched mouse strain combinations. We investigated the role of chimerism in this transplantation tolerance model.


METHODS
B10.A (H-2a) mice were treated with ALS on day -1 and 2, sirolimus, and infusion of (C57BL/6xDBA/2)F1 (B6D2F1, H-2(b/d)) BMCs on day 7 relative to DBA/2 (D2) skin grafting on day 0. At postgraft days 30, 50 and 120, the recipient mice were injected intravenously with splenocytes prepared from either naive or D2 mixed chimeric B10.A mice that had been sensitized in vivo to B6. Changes in chimerism and graft survival were monitored.


RESULTS
Although D2 skin grafts were rejected with a median survival time of 63.8 days in B10.A mice given ALS and sirolimus alone, they survived more than 200 days in all B10.A mice given ALS, sirolimus, and B6D2F1 BMCs. Chimerism became evident 21 days postgrafting and progressively increased thereafter to 20% at postgraft day 200. Infusion of anti-B6 presensitized cells resulted in depletion of chimeric donor cells and subsequent graft rejection regardless of the timing of injection. Injection of presensitized cells in mice given ALS and sirolimus alone had no effect on graft survival. Injection of presensitized cells that were cytotoxic to alloantigen expressed by BMCs but tolerant to skin reduced, but did not deplete, established chimerism and allowed continued allograft survival.


CONCLUSIONS
Chimeric donor cells play a major role in both the early and late phases of transplantation tolerance induced by the ALS, sirolimus, and BMC regimen.
Kanamoto
Akira
A
Transplant Center, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Monaco
Anthony P
AP
Maki
Takashi
T
D000818:Animals; D000961:Antilymphocyte Serum / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D008285:Major Histocompatibility Complex; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D020123:Sirolimus / Q000627:therapeutic use*; D016038:Skin Transplantation / Q000276:immunology*; D013997:Time Factors; D018183:Transplantation Chimera / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*
D000961:Antilymphocyte Serum; D020123:Sirolimus