Simultaneous Protection Against Allograft Rejection and Graft-Versus-Host Disease After Total Lymphoid Irradiation: Role of Natural Killer T Cells

BACKGROUND: The use of combined organ and bone marrow transplantation has been studied extensively in rodent models to induce immune tolerance to organ grafts. However, bone marrow transplants with mature donor T cells can induce graft-versus-host disease even in human leukocyte antigen-matched humans. We determined whether total lymphoid irradiation can simultaneously protect against graft-versus-host disease while facilitating tolerance. METHODS: To more closely model clinical studies, we added mature donor T cells to bone marrow grafts combined with heart grafts, and compared murine graft and host survival after conditioning with nonmyeloablative total body or total lymphoid irradiation and depletive anti-T-cell antibodies. RESULTS: Conditioning with total lymphoid irradiation protected hosts against both graft-versus-host disease and organ graft rejection. Although nonmyeloblative total body irradiation prevented organ graft rejection, all hosts succumbed to lethal graft-versus host disease. Induction of tolerance with total lymphoid irradiation and anti-T-cell antibodies was dependent on the presence of regulatory host natural killer T cells, and expression of CD1d on donor marrow but not heart graft cells. CONCLUSION: Conditioning with total lymphoid irradiation and anti-T-cell antibodies prevented host-versus-donor and donor-versus-host alloimmune responses. Tolerance required host natural killer T-cell recognition of CD1d on donor marrow cells.