title: 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.
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford Medical Center, 300 Pasteur Drive, Stanford, CA 94305-5166, USA.
authors.forename: Fengshuo
authors.initials: F
authors.lastname: Lan
authors.forename: Defu
authors.initials: D
authors.lastname: Zeng
authors.forename: Masanori
authors.initials: M
authors.lastname: Higuchi
authors.forename: John P
authors.initials: JP
authors.lastname: Higgins
authors.forename: Samuel
authors.initials: S
authors.lastname: Strober
mesh_terms: D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics / Q000276:immunology; D000961:Antilymphocyte Serum / Q000494:pharmacology*; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006649:Histocompatibility Antigens / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D015182:Lymphatic Irradiation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D036102:Peripheral Blood Stem Cell Transplantation / Q000009:adverse effects*; D011828:Radiation Chimera; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D013045:Species Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D019172:Transplantation Conditioning; D014916:Whole-Body Irradiation
chemical_list: D018949:Antigens, CD1; D000961:Antilymphocyte Serum; D006649:Histocompatibility Antigens; C038353:histocompatibility antigens RT, rat