Regulation of pulmonary graft-versus-host disease by IL-26+CD26+CD4 T lymphocytes.
Regulation of pulmonary graft-versus-host disease by IL-26+CD26+CD4 T lymphocytes.
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DOI：
10.4049/jimmunol.1402785
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发表时间：
2015-04-15
期刊：
影响因子：
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通讯作者：
Morimoto C
中科院分区：
文献类型：
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作者：
Ohnuma K;Hatano R;Aune TM;Otsuka H;Iwata S;Dang NH;Yamada T;Morimoto C
闭塞性细支气管炎是异基因造血干细胞移植后可能危及生命的非感染性肺部并发症，也是肺部慢性移植物抗宿主病（cGVHD）的唯一特征性表现。在目前的研究中，我们确定了IL-26对移植相关闭塞性细支气管炎的新作用。经亚致死剂量辐照的NOD/Shi-scidIL 2 r γ敲除小鼠（HuCB小鼠）移植人脐带血后逐渐出现移植物抗宿主病（GVHD）的临床体征，如体重减轻、皮毛起皱和脱发。在组织学上，HuCB小鼠的肺表现出闭塞性细支气管炎，胶原沉积增加，人IL-26+ CD 26 + CD 4 T细胞主要浸润。同时，皮肤表现出脂肪损失和硬化的网状真皮的基底角质细胞凋亡的存在下，而肝脏表现出门静脉纤维化和胆汁淤积。此外，尽管IL-26在啮齿类动物中不存在，但我们发现IL-26增加了成纤维细胞中的胶原合成，并在使用IL-26转基因小鼠的小鼠GVHD模型中促进了肺纤维化。体外分析表明，在CD 26共刺激后，HuCB CD 4 T细胞的IL-26产生显著增加，而与小窝蛋白-1（Cave-IG）（CD 26的配体）N-末端融合的IG Fc结构域有效抑制IL-26的产生。在GVHD发作之前或之后给予Cav-Ig阻碍了GVHD的临床和组织学特征的发展，而不中断供体来源的人细胞的植入，保留了移植物抗白血病效应。因此，这些结果提供了肺的cGVHD部分由IL-26+ CD 26 + CD 4 T细胞引起的原理证明，并且用Cav-Ig治疗可能有益于cGVHD预防和治疗。
Obliterative bronchiolitis is a potentially life-threatening noninfectious pulmonary complication after allogeneic hematopoietic stem cell transplantation and the only pathognomonic manifestation of pulmonary chronic graft-versus-host disease (cGVHD). In the current study, we identified a novel effect of IL-26 on transplant-related obliterative bronchiolitis. Sublethally irradiated NOD/Shi-scidIL2rγnull mice transplanted with human umbilical cord blood (HuCB mice) gradually developed clinical signs of graft-versus-host disease (GVHD) such as loss of weight, ruffled fur, and alopecia. Histologically, lung of HuCB mice exhibited obliterative bronchiolitis with increased collagen deposition and predominant infiltration with human IL-26+CD26+CD4 T cells. Concomitantly, skin manifested fat loss and sclerosis of the reticular dermis in the presence of apoptosis of the basilar keratinocytes, whereas the liver exhibited portal fibrosis and cholestasis. Moreover, although IL-26 is absent from rodents, we showed that IL-26 increased collagen synthesis in fibroblasts and promoted lung fibrosis in a murine GVHD model using IL-26 transgenic mice. In vitro analysis demonstrated a significant increase in IL-26 production by HuCB CD4 T cells following CD26 costimulation, whereas Ig Fc domain fused with the N-terminal of caveolin-1 (Cav-Ig), the ligand for CD26, effectively inhibited production of IL-26. Administration of Cav-Ig before or after onset of GVHD impeded the development of clinical and histologic features of GVHD without interrupting engraftment of donor-derived human cells, with preservation of the graft-versus-leukemia effect. These results therefore provide proof of principle that cGVHD of the lungs is caused in part by IL-26+CD26+CD4 T cells, and that treatment with Cav-Ig could be beneficial for cGVHD prevention and therapy.