Host conditioning with total lymphoid irradiation and antithymocyte globulin prevents graft-versus-host disease: the role of CD1-reactive natural killer T cells

Abstract

Our previous studies in mice showed that the nonmyeloablative conditioning regimen of fractionated irradiation of the lymphoid tissues (total lymphoid irradiation; TLI) and depletive anti-T-cell antibodies (anti-thymocyte serum) markedly increased the percentage of regulatory DX5 + and natural killer 1.1 + T cells in the mouse spleen, and prevented acute lethal graft-versus-host disease (GVHD) in BALB/c mice (H-2 d) following the transplantation of bone marrow (BM) and peripheral blood mononuclear cells (PBMC) from C57BL/6 (H-2 b) donors. The object of the current study was to determine whether the TLI and anti-thymocyte serum regimen protected natural killer T-cell deficient CD1 −/− BALB/c mice against GVHD after BM and PBMC transplantation from C57BL/6 donors, and whether a similar conditioning regimen of TLI and anti-thymocyte globulin (ATG) can prevent GVHD in Lewis rat (RT1 l) hosts after BM and PBMC transplantation from ACI rat (RT1 a) donors. The experimental results in mice showed that, although wild-type BALB/c hosts are protected in association with a marked increase in CD1- reactive T cells expressing the invariant TCR identified with a CD1 tetramer reagent; CD1 −/− BALB/c hosts are not. Studies of chimeric donor cells in mice protected from GVHD showed donor T-cell polarization to a Th2 cytokine pattern. Results in rats showed that approximately 1000 fold more donor PBMC cells were required to induce a similar incidence of lethal GVHD in TLI and ATG conditioned hosts as compared with hosts conditioned with single-dose total-body irradiation or total-body irradiation and ATG. Surviving TLI and ATG conditioned rat hosts were complete chimeras. In conclusion, the TLI and ATG/anti-thymocyte serum conditioning regimen protects against GVHD in rats and mice, and regulatory natural killer T cells are required for protection.