title: Paradoxical effects of IFN-gamma in graft-versus-host disease reflect promotion of lymphohematopoietic graft-versus-host reactions and inhibition of epithelial tissue injury.
abstract: Interferon-gamma (IFN-gamma) inhibits graft-versus-host disease (GVHD) in lethally irradiated mice receiving allogeneic hematopoietic cell transplantation (allo-HCT) but promotes lethality in unirradiated and sublethally irradiated recipients. We investigated the role of IFN-gamma in GVHD in sublethally irradiated B6D2F1 recipients of B6 allo-HCT. B6D2F1 mice receiving wild-type B6 splenocytes alone died rapidly, whereas those receiving wild-type B6 splenocytes plus marrow survived long-term. Mice in both groups showed rapid elimination of host hematopoietic cells but minimal parenchymal tissue injury. However, mice receiving allo-HCT from IFN-gamma-deficient donors died rapidly regardless of whether donor marrow was given, and they exhibited severe parenchymal injury but prolonged survival of host hematopoietic cells. IFN-gamma plays a similar role in another model involving delayed B6 donor leukocyte infusion (DLI) to established mixed allogeneic (B6-->BALB/c) chimeras. IFN-gamma promotes DLI-mediated conversion from mixed to full donor chimerism while attenuating GVHD. Importantly, IFN-gamma enhances graft-versus-leukemia (GVL) effects in both models. Our data indicate that previously reported IFN-gamma-induced early mortality in allo-HCT recipients is due to augmentation of lymphohematopoietic graft-versus-host reaction (LGVHR) and can be avoided by providing an adequate source of donor hematopoietic stem/progenitor cells. Furthermore, the magnitude of GVL is correlated with the strength of LGVHR, and IFN-gamma reduces the potential of this alloreactivity to cause epithelial tissue GVHD.
authors.affiliation: Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical, Boston, MA 02129, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Wannee
authors.initials: W
authors.lastname: Asavaroengchai
authors.forename: Beow Yong
authors.initials: BY
authors.lastname: Yeap
authors.forename: Min-Guang
authors.initials: MG
authors.lastname: Wang
authors.forename: Shumei
authors.initials: S
authors.lastname: Wang
authors.forename: Megan
authors.initials: M
authors.lastname: Sykes
authors.forename: Yong-Guang
authors.initials: YG
authors.lastname: Yang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004848:Epithelium / Q000276:immunology / Q000473:pathology; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology*; D017708:Leukocyte Transfusion; D038041:Lymphopoiesis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011828:Radiation Chimera; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D007371:Interferon-gamma