Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by downregulating Th1 and Th17
Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by downregulating Th1 and Th17
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DOI：
10.4044/joma.124.197
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
H. Nishimori;Y. Maeda;M. Tanimoto
中科院分区：
文献类型：
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作者：
H. Nishimori;Y. Maeda;M. Tanimoto
慢性移植物抗宿主病（cGVHD）是异基因造血细胞移植后晚期死亡和发病的主要原因，但其发病机制仍不清楚。我们利用一种明确的cGVHD小鼠模型研究了辅助性T细胞（Th）亚群在cGVHD中的作用。在该模型中，cGVHD的发生与Th1、Th2和Th17反应上调有关。骨髓移植后早期Th1和Th2反应上调，随后Th17细胞上调。同种异体受者的肺和肝脏中浸润的Th17细胞数量明显多于同基因受者。然后我们利用干扰素 - γ缺陷和白细胞介素 - 17缺陷小鼠作为供体来评估Th1和Th17在cGVHD中的作用。输注干扰素 - γ - / - 或白细胞介素 - 17 - / - T细胞可减轻皮肤和唾液腺的cGVHD。Am80是一种有效的合成类视黄醇，可调节皮肤中的Th1和Th17反应以及转化生长因子 - β的表达，从而减轻皮肤cGVHD。这些结果表明Th1和Th17有助于cGVHD的发生，因此靶向Th1和Th17可能是预防和治疗cGVHD的一种有前景的治疗策略。
引言
移植物抗宿主病（GVHD）是移植中供体T细胞对宿主组织（如皮肤、肠道、肝脏和肺）进行免疫攻击的结果。1,2根据临床表现和组织病理学的差异，GVHD可分为急性和慢性两种类型。慢性移植物抗宿主病（cGVHD）是异基因造血干细胞移植后晚期死亡和发病的主要原因。3 - 5 cGVHD的临床表现通常类似于自身免疫性疾病，如系统性红斑狼疮、干燥综合征、扁平苔藓和硬皮病。传统上认为急性GVHD期间产生的主要细胞因子是Th1细胞因子，而cGVHD期间产生的是Th2细胞因子。尽管最近的研究表明cGVHD可能是由Th1细胞、7 Th17细胞、8或自身抗体分泌的细胞因子引起的，或者是由两者共同引起的，但导致cGVHD发生的免疫机制尚未完全清楚。Th17细胞是极化效应T细胞的第三个亚群，其特征是表达促炎细胞因子白细胞介素 - 17和其他细胞因子。9白细胞介素 - 17属于一个由6个成员组成的家族：白细胞介素 - 17A、白细胞介素 - 17B、白细胞介素 - 17C、白细胞介素 - 17D、白细胞介素 - 17E（也称为白细胞介素 - 25）和白细胞介素 - 17F。其中，白细胞介素 - 17A和白细胞介素 - 17F是特征最明确的细胞因子，并形成异二聚体。白细胞介素 - 17起……
Chronic GVHD (cGVHD) is a main cause of late death and morbidity after alloge-neic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplanta-tion, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-␥– deficient and IL-17–deficient mice as donors. Infusion of IFN-␥ ؊/؊ or IL-17 ؊/؊ T cells attenuated cGVHD in the skin and salivary glands. Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses as well as TGF- expression in the skin, resulting in an attenuation of cutaneous cGVHD. These results suggest that Th1 and Th17 contribute to the development of cGVHD and that targeting Th1 and Th17 may therefore represent a promising therapeutic strategy for preventing and treating cGVHD. Introduction GVHD is a result of immune attack of host tissues, such as the skin, gut, liver, and lung, by donor T cells in transplants. 1,2 On the basis of the differences in clinical manifestations and histopathology, GVHD can be divided into acute and chronic types. Chronic GVHD (cGVHD) is the main cause of late death and morbidity after allogeneic hematopoietic stem cell transplantation. 3-5 cGVHD often presents with clinical manifestations that resemble those observed in autoimmune diseases, such as systemic lupus erythe-matosus, Sjögren syndrome, lichen planus, and scleroderma. It has traditionally been assumed that the predominant cytokines produced during acute GVHD are Th1 cytokines, whereas those produced during cGVHD are Th2 cytokines. Although recent studies have suggested that cGVHD could be caused by cytokines secreted by Th1 cells, 6 Th17 cells, 7 or autoantibodies, 8 or both, the immune mechanisms leading to the development of cGVHD are not completely understood. Th17 cells are a third subset of polarized effector T cells characterized by their expression of proinflammatory cytokine IL-17 and other cytokines. 9 IL-17 belongs to a family of 6 members: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25), and IL-17F. Of these, IL-17A and IL-17F are the best characterized cytokines and form heterodimers. IL-17 plays an …