A substantial level of mixed chimerism is required for the induction of permanent transplantation tolerance

The induction of donor-specific transplantation tolerance is a major goal in organ transplantation, in order to eliminate the requirement for lifelong immunosuppressive therapy. Previously, we have developed a murine bone marrow transplantation model in which recipient mice were treated with a single dose of anti-CD3 and low dose whole body irradiation (WBI). Transfusion of donor bone marrow cells across a full H-2 disparity resulted in induction of high levels of stable mixed chimerism, specific T cell non-responsiveness and indefinite skin allograft survival. The present study has focused on manipulation of the level of chimerism in this model by varying the number of infused bone marrow cells, varying the dose of WBI and addition of syngeneic bone marrow cells. Our results indicate that a substantial level of chimerism is needed for induction of transplantation tolerance. In addition, in the semi-allogeneic donor-recipient combination an even lower dose of WBI was sufficient of engraftment of bone marrow cells and subsequent tolerance induction. We suggest that sharing of MHC antigens between donor and recipient might play an important role in facilitating the development of chimerism and tolerance in organ transplantation.