Induction of immunological tolerance in full major and multiminor histocompatibility-disparate mice using a mixed bone marrow transplantation model.

Bone marrow transplantation (BMT) has been used to induce and maintain immunological tolerance. Such tolerance could facilitate tissue and organ transplantation between the donor and the recipient without need for continuous immune suppression. A protocol employing transplantation of a mixture of T-cell depleted (TCD) syngeneic plus TCD-allogeneic bone marrow cells has been successfully used for induction of transplantation tolerance between mice that differ at components of the major histocompatibility barrier (MHC), or for crossing the xenogenic barrier. We examined the production of specific immunological tolerance using mixed syngeneic plus allogeneic TCD-BMT to cross the entire major plus multiminor histocompatibility barriers. The transplanted mice were repopulated in a stable manner with a mixture of both donor and recipient phenotypes. On histological examination, the mice were reconstituted with hemopoietic and immunocompetent lymphocytes as assayed by their responses to the thymus-dependent cellular antigen, sheep red blood cells (SRBC) in an in vivo plaque-forming cell assay. The transplanted mice were found to be stable chimeras and expressed long lasting tolerance of both donor and recipient cells and yet they were fully reactive to third party cells in mixed lymphocyte culture. These results provide evidence that "supportive" or accessory cells in the syngeneic marrow facilitate maturation of donor marrow cells into fully functioning immunocytes in an allogeneic environment crossing the MHC barrier, which represents the greatest known challenge to allogeneic marrow transplantation in mice. The MHC-mismatched mixed allogeneic transplantation method may improve organ engraftment in human recipients of BMT from a partially mismatched donor or from a cadaver donor, and may significantly improve graft acceptance from a fully matched sibling donor.