Specific tolerance induction after recipient conditioning with donor stem cells: A relevant clinical model of living-organ donation for solid organs

Background: High mortality and graft loss rates after allogeneic transplant ation of intestinal organs are the main reasons for the strong efforts to i nduce tolerance strategies which bear clinical relevance. The presented exp erimental study investigated the possibility to induce donor-specific toler ance by use of myeloablative therapy (mTh) in conjunction with donor stem c ell transplantation (SCTx), hereby chosing a model with clinical applicabil ity for the transplantation setting of living-related donor donation. Methods: mTh was performed by administration of cyclophosphamid, i.v. (90 m g/kg body weight, on days -2 and -1) together with i.v.-injection of busulf an (35 mg/kg b.w., on day -1). Hereafter, hematopoietic reconstitution of t he recipient (LEW) rat was achieved by transplantation of 5 x 10(8) CD2-dep leted donor (DA) bone marrow stem cells. After establishment of 100 percent donor chimerism las validated by flow cytometry), a secondary small bowel allograft was transferred. Results: The described protocol achieved full donor-chimeric reconstitution of hematopoietic tissues in syngeneic recipients which otherwise died. In the high-responder strain combination DA --> LEW or CAP --> LEW all recipie nt demonstrated specific tolerance and long-term graft acceptance of small bowel and skin grafts without signs of acute graft-versus-host disease. Conclusions: These findings indicate the possibility to achieve the goal of donor-specific tolerance induction in the clinical setting of living-donat ion with appropriate conditioning of recipients by the use of peripheral st em cell transplantation.