INDUCTION OF HIGH-LEVELS OF ALLOGENEIC HEMATOPOIETIC RECONSTITUTION AND DONOR-SPECIFIC TOLERANCE WITHOUT MYELOSUPPRESSIVE CONDITIONING

Donor-specific tolerance induced by bone marrow transplantation (BMT) would allow organ allografting without chronic immunosuppressive thera py. However, the toxicity(1) of conditioning regimens used to achieve marrow engraftment has precluded the clinical use of BMT for tolerance induction. We have developed a BMT strategy that achieves alloengraft ment without toxic or myelosuppressive host conditioning. B6 mice rece ived depleting anti-CD4 and anti-CD8 monoclonal antibodies, local thym ic irradiation, and a high-dose (174 x 10(6)) of major histocompatibil ity (MHC)-mismatched B10.A bone marrow cells (BMCs) divided over days 0 through 4. High levels of donor cells were observed among white bloo d cells (WBCs) of all lineages. Permanent, multilineage mixed chimeris m; donor-specific skin-graft tolerance; and in vitro tolerance were ob served in most animals. Large numbers of donor class IIhigh cells were detected in thymuses of long-term chimeras, and their presence was as sociated with intrathymic deletion of donor-reactive host thymocytes. The treatment was not associated with significant myelosuppression, to xicity, or graft-versus-host disease (GVHD). Thus, high levels of allo geneic stem-cell engraftment can be achieved without myelosuppressive host conditioning. As stem-cell mobilization(2) and in vitro culture t echniques' have increased the feasibility of administering high doses of hematopoietic cells to humans, this approach brings hematopoietic c ell transplantation closer to clinical use for the induction of centra l deletional T-cell tolerance.