Long-term survival of intestinal allografts induced by costimulation blockade, busulfan and donor bone marrow infusion.
Tolerance-inducing strategies that infuse donor bone marrow cells in conjunction with costimulation blockade have not been applied to intestinal transplantation. Intestines from BALB/c mice were transplanted into C57BL/6 recipients treated with anti-CD40L mAb, CTLA4-Ig, donor bone marrow, and busulfan. The majority of mice transplanted after completion of this regimen developed hematopoietic macrochimerism, although the degree of chimerism varied widely between recipients, and experienced long-term allograft survival. T cells from these mice demonstrated donor-specific hyporesponsiveness in vitro. However, T cells from chimeric mice proliferated to donor alloantigen in vivo. Furthermore, chimeric mice bearing intestinal allografts were capable of rejecting subsequently placed donor-strain skin grafts. These data suggest that although long-term allograft survival occurs in the absence of acute or chronic rejection, recipient mice are not completely unresponsive to donor alloantigens. When intestinal transplantation was performed at the time of initial bone marrow infusion (initiation of the chimerism protocol), most recipients failed to develop chimerism and promptly rejected the intestinal allograft. Although this is the most effective protocol that we have tested using this stringent model of transplantation, our observations suggest that modifications will be necessary before it can be reliably applied to the transplantation of highly immunogeneic organs like the intestine.
Guo
Zhong
Z
Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA.
Wang
Jun
J
Dong
Ying
Y
Adams
Andrew B
AB
Shirasugi
Nozomu
N
Kim
Oliver
O
Hart
John
J
Newton-West
Marvin
M
Pearson
Thomas C
TC
Larsen
Christian P
CP
Newell
Kenneth A
KA
D000069594:Abatacept; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002066:Busulfan / Q000627:therapeutic use*; D006084:Graft Rejection; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D018796:Immunoconjugates / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007422:Intestines / Q000473:pathology / Q000637:transplantation*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D018183:Transplantation Chimera; D014184:Transplantation, Homologous / Q000276:immunology* / Q000379:methods / Q000473:pathology
D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D002066:Busulfan