Induction of high levels of allogeneic hematopoietic reconstitution and donor-specific tolerance without myelosuppressive conditioning

Abstract

Donor-specific tolerance induced by bone marrow transplantation (BMT) would allow organ allografting without chronic immunosuppressive therapy. However, the toxicity 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 alloengraftment without toxic or myelosuppressive host conditioning. B6 mice received depleting anti-CD4 and anti-CD8 monoclonal antibodies, local thymic irradiation, and a high-dose (174 x 10(6)) of major histocompatibility (MHC)-mismatched B10.A bone marrow cells (BMCs) divided over days 0 through 4. High levels of donor cells were observed among white blood cells (WBCs) of all lineages. Permanent, multilineage mixed chimerism; donor-specific skin-graft tolerance; and in vitro tolerance were observed in most animals. Large numbers of donor class II(high) cells were detected in thymuses of long-term chimeras, and their presence was associated with intrathymic deletion of donor-reactive host thymocytes. The treatment was not associated with significant myelosuppression, toxicity, or graft-versus-host disease (GVHD). Thus, high levels of allogeneic stem-cell engraftment can be achieved without myelosuppressive host conditioning. As stem-cell mobilization and in vitro culture techniques have increased the feasibility of administering high doses of hematopoietic cells to humans, this approach brings hematopoietic cell transplantation closer to clinical use for the induction of central deletional T-cell tolerance.

Induction of Permanent Mixed Chimerism and Skin Allograft Tolerance Across Fully MHC-Mismatched Barriers by the Additional Myelosuppressive Treatments in Mice Primed with Allogeneic Spleen Cells Followed by Cyclophosphamide

“…More recently, repeated administration of high-dose allogeneic BMC could permit the induction of mixed chimerism in recipients treated with anti-T cell mAbs and thymic irradiation (37), although we showed that between 1.5 and 3 Gy is the minimum whole-body irradiation dose required to permit stable hematopoietic stem cell engraftment (performed by Y. Tomita in Transplantation Biology Research Center, Massachusetts General Hospital, Boston, MA; Ref. 37).…”

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

“…While split tolerance has been observed in some mixed chimerism strategies [7, 13], many current studies are specifically designed to avoid the issue by using donor and recipient combinations matched for minor histocompatibility antigens [14][15][16][17][18]. The prevention of split tolerance by minor antigen matching could result from a number of mechanisms, including reduced indirect reactivity to the donor or elimination of allelic tissuespecific antigens.…”

Donor double‐negative Treg promote allogeneic mixed chimerism and tolerance

“…5A, B). Hence, suppression of NK cells by adoptive transfer of DN-Treg provides a long-term benefit by achieving stable mixed chimerism and donorspecific tolerance.Following the first reports that described its use in a murine model [39,40], mixed chimerism was developed successfully in porcine and non-human primate models using immunosuppressive regimens [41][42][43][44][45][46][47][48]. More recently, mixed chimerism has produced clinical benefit in a number of transplant patients [49][50][51][52][53][54].…”