Tolerance induced by bone marrow chimerism prevents transplant vascular sclerosis in a rat model of small bowel transplant chronic rejection

Background. The major impediment to success in solid organ transplantation is chronic rejection (CR), The characteristic lesion of CR is transplant va scular sclerosis (TVS), Although the mechanism of TVS is thought to have an immunologic basis, in humans immunosuppression does not prevent or reverse it. One possible therapy to prevent TVS is induction of donor-specific tol erance. Bone marrow chimerism has been successful in inducing tolerance in acute and chronic rejection heart and kidney transplant models. The highly immunogenic small bowel (SB) allograft provides a rigorous test of the effi cacy of this tolerance regimen. We examined whether induction of tolerance by bone marrow chimerism could prevent TVS in a model of Fisher 344 (F344) to Lewis (LEW) rat SB transplantation. Methods. Done marrow chimeras (BMC) were created by transplantation of T-ce ll-depleted F344 bone marrow into irradiated LEW rats. Chimerism was assess ed by flow cytometric method. F344 SB, heterotopically transplanted into th e chimeras, was clinically and histologically assessed for CR. F344 SB graf ts, transplanted into cyclosporine-A-treated LEW recipients, served as cont rol grafts for CR. Results. Cyclosporine-A-treated LEW rats chronically rejected F344 SB graft s. By contrast, the BMC group demonstrated tolerance and had long-term SB g raft survival (>120 days) without TVS. The BMC demonstrated immunocompetenc e by prompt rejection of third party ACI (RT1(av1)) SB allografts. Conclusions. Bone marrow chimerism prevents chronic graft failure secondary to TVS in a model of chronic SB rejection. TVS fails to develop when toler ance is established, suggesting that the mechanisms involved in TVS are, in part, immunologically mediated.