Prevention of acute graft-versus-host disease by humanized anti-CD26 monoclonal antibody
Prevention of acute graft-versus-host disease by humanized anti-CD26 monoclonal antibody
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DOI：
10.1111/bjh.12378
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发表时间：
2013-07-01
影响因子：
6.5
通讯作者：
Morimoto, Chikao
中科院分区：
文献类型：
--
作者：
Hatano, Ryo;Ohnuma, Kei;Morimoto, Chikao
CD 26（DPP 4）是T细胞共刺激分子以及T细胞活化标志物，并且CD 26（+）T细胞在发炎组织中积累，例如类风湿性滑膜炎和自身免疫性甲状腺炎。在本研究中，我们发现了CD 26（+）T细胞在移植物抗宿主病（GVHD）靶器官中的积聚。为了将我们的体外研究结果扩展到体内系统，我们研究了异种GVHD（x-GVHD）小鼠模型中的CD 26依赖性器官损伤。将人外周血单核细胞腹膜内注射到非肥胖糖尿病重度联合免疫缺陷/（-/-）（c）小鼠（hu-PBL-NOG小鼠）中后，小鼠表现出与外周血和GVHD靶组织中存在CD 26（高）人淋巴细胞相关的GVHD症状的发作。人源化抗人CD 26单克隆抗体（mAb）的施用降低了hu-PBL-NOG小鼠中的x-GVHD严重程度并延长了存活，而没有人T细胞的植入损失，而增加剂量的CTLA 4-免疫球蛋白融合蛋白减少了人淋巴细胞的植入。重要的是，在使用P815小鼠白血病细胞共移植的研究中，抗CD 26 mAb治疗保留了移植物抗白血病效应。此外，GVHD患者的靶组织中有CD 26（+）淋巴细胞浸润。总而言之，我们的数据表明CD 26在GVHD的调节中的作用，并指出CD 26作为这种疾病的治疗干预的新靶点。
CD26 (DPP4) is a T cell costimulatory molecule as well as T cell activation marker, and CD26(+) T cells are accumulated in inflamed tissues, such as rheumatoid synovitis and autoimmune thyroiditis. In the present study, we found accumulation of CD26(+) T cells in graft-versus-host disease (GVHD) target organs. To expand our in vitro findings to an in vivo system, we examined CD26-dependent organ injury in a xenogeneic GVHD (x-GVHD) murine model. Following intraperitoneal injection of human peripheral blood mononuclear cells into non-obese diabetic severe combined immunodeficiency/(-/-)(c) mice (hu-PBL-NOG mice), the mice exhibited the onset of GVHD symptoms associated with the presence of CD26(high) human lymphocytes in the peripheral blood and GVHD target tissues. Administration of humanized anti-human CD26 monoclonal antibody (mAb) decreased x-GVHD severity and prolonged survival in hu-PBL-NOG mice without loss of engraftment of human T cells, while increasing doses of CTLA4- immunoglobulin fusion protein diminished engraftment of human lymphocytes. Importantly, anti-CD26 mAb treatment preserved the graft-versus-leukaemia effects in studies using cotransplantation of P815 murine leukaemic cells. In addition, CD26(+) lymphocytes infiltrated the GVHD patients' target tissues. Altogether, our data indicate a role for CD26 in the regulation of GVHD and point to CD26 as a novel target for therapeutic intervention in this disease.