Nakauchi Yusuke, Yamazaki Satoshi, Napier Stephanie C, Usui Jo-ichi, Ota Yasunori, Takahashi Satoshi, Watanabe Nobukazu, Nakauchi Hiromitsu
Division of Stem Cell Therapy, Centre for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Division of Stem Cell Therapy, Centre for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Exp Hematol. 2015 Feb;43(2):79-88.e1-4. doi: 10.1016/j.exphem.2014.10.008. Epub 2014 Oct 30.
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-A02:01 (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-A02:01, some not. Administration of A2-kASHmAb promoted the survival of mice injected with HLA-A02:01-expressing peripheral blood mononuclear cells (p < 0.0001) and, in humanized NOD/Shi-scid/IL-2Rγ(null) mice, immediately cleared HLA-A02:01-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.
移植物抗宿主病（GVHD）由供体来源的同种异体反应性T细胞介导，是异基因造血干细胞移植中非复发死亡率的主要原因。其治疗方法尚不明确。我们制备了等位基因特异性抗人白细胞抗原（HLA）单克隆抗体（ASHmAbs），该抗体特异性靶向HLA分子，可使表达靶标的细胞稳定死亡。在异种GVHD小鼠模型中检测了其中一种针对HLA - A02:01的ASHmAb（A2 - kASHmAb）。为诱导致命性GVHD，给未接受照射的NOD/Shi - scid/IL - 2Rγ(null)小鼠注射健康供体的人外周血单个核细胞，其中一些表达HLA - A02:01，一些不表达。给予A2 - kASHmAb可提高注射了表达HLA - A02:01外周血单个核细胞小鼠的生存率（p < 0.0001），并且在人源化NOD/Shi - scid/IL - 2Rγ(null)小鼠中，可立即从小鼠外周血中清除表达HLA - A02:01的人血细胞。给予A2 - kASHmAb后2至4周，小鼠血液中可再次检测到人类外周血单个核细胞，这表明kASHmAb可以安全地给予GVHD患者，而不会永久性地消除移植物。这种方法不同于现有的GVHD药物治疗方法，可能为HLA不匹配的异基因造血干细胞移植中GVHD的治疗打开一扇新的大门。
