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Exp Hematol. 2015 Feb;43(2):79-88.e1-4. doi: 10.1016/j.exphem.2014.10.008. Epub 2014 Oct 30.

Effective treatment against severe graft-versus-host disease with allele-specific anti-HLA monoclonal antibody in a humanized mouse model.

Author information

1
Division of Stem Cell Therapy, Centre for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
2
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.
3
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.
4
Department of Nephrology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
5
Department of Pathology, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
6
Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
7
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.

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.

PMID:
25448490
DOI:
10.1016/j.exphem.2014.10.008
[Indexed for MEDLINE]
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