In utero bone marrow transplantation induces kidney allograft tolerance across a full major histocompatibility complex barrier in swine

Background. In utero hematopoietic stem-cell transplantation has been shown to induce donor-specific tolerance in small-animal models. However, tolerance has been difficult to achieve in large-animal studies. Methods. Outbred swine underwent in utero transplantation of fully major histocompatibility complex (MHC)mismatched CD3-depleted bone marrow mixed with fresh bone marrow to achieve a final CD3 content of 1.5%. Transplantation was performed at 50 to 55 days' gestation and two animals survived long term and demonstrated multilineage peripheral blood hematopoietic chimerism. These two long-term survivors were analyzed for in vitro evidence of donor-specific tolerance by mixed leukocyte reaction (MLR), cell-mediated lysis (CML), and antibody testing and in vivo by kidney transplantation. I Results. Both animals demonstrated in vitro donor-specific unresponsiveness by MLR and CML and did not demonstrate anti-donor antibody production. Donor matched kidney transplants were performed without immunosuppression and functioned for more than 100 days, with no evidence for rejection. Conclusions. The authors demonstrate conclusively that in utero transplantation of fully MHC-mismatched bone marrow in swine can lead to engraftment and stable multilineage hematopoietic chimerism and tolerance to postnatal donor MHC-matched kidney transplantation without the need for immunosuppression.