title: Bone marrow graft-versus-host disease: early destruction of hematopoietic niche after MHC-mismatched hematopoietic stem cell transplantation.
abstract: Disrupted hematopoiesis and delayed immune reconstitution are life-threatening complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although graft-versus-host disease (GVHD) is a major risk factor for the bone marrow (BM) insufficiency, how GVHD impairs BM hematopoiesis has been largely unknown. We hypothesized that BM stromal niche could be a target of GVHD. In major histocompatibility complex (MHC)-mismatched murine models of GVHD, we have demonstrated the early destruction of osteoblasts that especially affected B-cell lineages. The defective B lymphopoiesis was due to the impaired ability of BM stroma and osteoblasts to support the hematopoiesis, as evidenced by the failure of GVHD-affected BM to reconstitute the hematopoietic cells. The administration of anti-CD4 monoclonal antibody (mAb) ameliorated these effects and improved B lymphopoiesis while preserving graft-versus-tumor effects. Genetic ablation of Fas-Fas ligand signaling also partially restored B lymphopoiesis. Our present study provided evidence of BM GVHD, with the identification of osteoblasts as the main target for GVHD in BM. Moreover, our data showed the potential for mAb therapies to enhance immune reconstitution in vivo for patients undergoing allo-HSCT.
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shono
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueha
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Abe
authors.forename: Makoto
authors.initials: M
authors.lastname: Kurachi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsuno
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagasawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Imamura
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology*; D015704:CD4 Antigens / Q000276:immunology; D002460:Cell Line; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D038041:Lymphopoiesis; D008285:Major Histocompatibility Complex; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens