title: Effective treatment against severe graft-versus-host disease with allele-specific anti-HLA monoclonal antibody in a humanized mouse model.
abstract: Graft-versus-host disease (GVHD), mediated by donor-derived alloreactive T cells, is a major cause of nonrelapse mortality in allogeneic hematopoietic stem cell transplantation. Its therapy is not well-defined. We established allele-specific anti-human leukocyte antigen (HLA) monoclonal antibodies (ASHmAbs) that specifically target HLA molecules, with steady death of target-expressing cells. One such ASHmAb, against HLA-A*02:01 (A2-kASHmAb), was examined in a xenogeneic GVHD mouse model. To induce fatal GVHD, non-irradiated NOD/Shi-scid/IL-2Rγ(null) mice were injected with healthy donor human peripheral blood mononuclear cells, some expressing HLA-A*02:01, some not. Administration of A2-kASHmAb promoted the survival of mice injected with HLA-A*02:01-expressing peripheral blood mononuclear cells (p < 0.0001) and, in humanized NOD/Shi-scid/IL-2Rγ(null) mice, immediately cleared HLA-A*02:01-expressing human blood cells from mouse peripheral blood. Human peripheral blood mononuclear cells were again detectable in mouse blood 2 to 4 weeks after A2-kASHmAb administration, suggesting that kASHmAb may be safely administered to GVHD patients without permanently ablating the graft. This approach, different from those in existing GVHD pharmacotherapy, may open a new door for treatment of GVHD in HLA-mismatched allogeneic hematopoietic stem cell transplantation.
authors.affiliation: Division of Stem Cell Therapy, Centre for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakauchi
authors.affiliation: Division of Stem Cell Therapy, Centre for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan. Electronic address: y-sato4@ims.u-tokyo.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy, Centre for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Napier
authors.affiliation: Department of Nephrology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
authors.forename: Jo-ichi
authors.initials: J
authors.lastname: Usui
authors.affiliation: Department of Pathology, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Ota
authors.affiliation: Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy, Centre for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Division of Stem Cell Therapy, Centre for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
mesh_terms: D000208:Acute Disease; D000483:Alleles; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen