Humanized anti-IL-26 monoclonal antibody as a novel targeted therapy for chronic graft-versus-host disease
Humanized anti-IL-26 monoclonal antibody as a novel targeted therapy for chronic graft-versus-host disease
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DOI：
10.1111/ajt.17178
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发表时间：
2022-09-09
影响因子：
8.8
通讯作者：
Ohnuma, Kei
中科院分区：
文献类型：
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作者：
Hatano, Ryo;Itoh, Takumi;Ohnuma, Kei
IL-26 是一种 Th17 细胞因子，啮齿类动物中不存在该基因。为了表征IL-26在慢性全身炎症中的体内免疫学作用，我们分别在小鼠同种异体移植物抗宿主病（GVHD）和慢性异种GVHD模型中使用人IL26转基因（hIL-26Tg）小鼠和人脐带血单核细胞（hCBMC）。将 hIL-26Tg 小鼠的骨髓和脾 T 细胞转移至 B10。 BR 小鼠导致 GVHD 进展，并出现多个器官组织损伤的临床症状。 IL-26 显着增加 GVHD 靶组织和外周血中的中性粒细胞水平。 hIL-26Tg小鼠来源的供体CD4 T细胞中Th17细胞因子的表达水平显着增加，而IL-26不影响供体CD8 T细胞的细胞毒功能。此外，hIL-26Tg 小鼠中粒细胞集落刺激因子、IL-1β 和 IL-6 水平尤其增强。我们还开发了一种用于治疗用途的人源化中和抗 IL-26 单克隆抗体 (mAb)，在慢性异种 GVHD 发作后施用该抗体可减轻体重减轻并延长生存期，同时保留移植物抗白血病效应。综上所述，我们的数据阐明了 IL-26 在慢性 GVHD 模型中的体内免疫学作用，并表明人源化抗 IL-26 mAb 可能是治疗慢性 GVHD 的潜在治疗剂。
IL-26 is a Th17 cytokine, with its gene being absent in rodents. To characterize the in vivo immunological effects of IL-26 in chronic systemic inflammation, we used human IL26 transgenic (hIL-26Tg) mice and human umbilical cord blood mononuclear cells (hCBMC) in mouse allogeneic-graft-versus-host disease (GVHD) and chronic xenogeneic-GVHD model, respectively. Transfer of bone marrow and spleen T cells from hIL-26Tg mice into B10. BR mice resulted in GVHD progression, with clinical signs of tissue damage in multiple organs. IL-26 markedly increased neutrophil levels both in the GVHD-target tissues and peripheral blood. Expression levels of Th17 cytokines in hIL-26Tg mice-derived donor CD4 T cells were significantly increased, whereas IL-26 did not affect cytotoxic function of donor CD8 T cells. In addition, granulocyte-colony stimulating factor, IL-1 beta, and IL-6 levels were particularly enhanced in hIL-26Tg mice. We also developed a humanized neutralizing anti-IL-26 monoclonal antibody (mAb) for therapeutic use, and its administration after onset of chronic xenogeneic-GVHD mitigated weight loss and prolonged survival, with preservation of graft-versus-leukemia effect. Taken together, our data elucidate the in vivo immunological effects of IL-26 in chronic GVHD models and suggest that a humanized anti-IL-26 mAb may be a potential therapeutic agent for the treatment of chronic GVHD.