CD4+CD25hiFoxp3+ Cells Exacerbate Bleomycin-Induced Pulmonary Fibrosis
CD4+CD25hiFoxp3+ Cells Exacerbate Bleomycin-Induced Pulmonary Fibrosis
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DOI：
10.1016/j.ajpath.2016.03.020
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发表时间：
2016-08-01
影响因子：
6
通讯作者：
BeLperio, John A.
中科院分区：
文献类型：
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作者：
Birjandi, Shirin Z.;Palchevskiy, Vyacheslav;BeLperio, John A.
特发性肺纤维化是一种致命的肺部疾病，中位生存期为2至5年。十年的研究淡化了炎症对其发病机制的影响。然而，这些研究早于调节性T细胞(Tregs)及其所有功能的发现。在人类研究表明Tregs可以减少移植物抗宿主疾病和血管炎症的基础上，有人考虑将其用于治疗特发性肺纤维化。我们假设Treg治疗将减轻临床前肺纤维化小鼠模型中涉及的纤维增生。在气管内注射博莱霉素时，体内使用IL-2复合体扩增肺内CD4(+)CD25(Hi)Foxp3(+)细胞；然而，这出人意料地导致肺纤维化的增加。更重要的是，纤维化的增加是一个淋巴细胞依赖的过程。我们用一种基于CD4(+)CD25(Hi)Foxp3(+)细胞的疗法证实了这些结果。从机制上讲，我们证明了在博莱霉素攻击期间，CD4(+)CD25(Hi)Foxp3(+)细胞发生了改变，IL-2复合体对促纤维化(如转化生长因子-β或17型免疫反应细胞因子)没有影响，但肺组织中1型免疫反应细胞因子明显下调，2型免疫反应细胞因子明显增强。总而言之，我们的动物研究表明，特定的肺损伤可以诱导Treg改变，这可能会加剧肺纤维化。
Idiopathic pulmonary fibrosis is a fatal lung disease with a median survival of 2 to 5 years. A decade of studies has downplayed inflammation contributing to its pathogenesis. However, these studies preceded the discovery of regulatory T cells (Tregs) and all of their functions. On the basis of human studies demonstrating Tregs can decrease graft-versus-host disease and vasculitides, there is consideration of their use to treat idiopathic pulmonary fibrosis. We hypothesized that Treg therapy would attenuate the fibroplasia involved in a preclinical murine model of pulmonary fibrosis. IL-2 complex was used in vivo to expand CD4(+)CD25(hi)Foxp3(+) cells in the lung during intratracheal bleomycin challenge; however, this unexpectedly led to an increase in lung fibrosis. More important, this increase in fibrosis was a lymphocyte dependent process. We corroborated these results using a CD4(+)CD25(hi)Foxp3(+) cellular -based therapy. Mechanistically, we demonstrated that CD4(+)CD25(hi)Foxp3(+) cells undergo alterations during bleomycin challenge and the IL-2 complex had no effect on profibrotic (eg, transforming growth factor-beta or type 17 immune response cytokines; however, there was a marked down-regulation of the type 1 and augmentation of the type 2 immune response cytokines from the lungs. Collectively, our animal studies show that a specific lung injury can induce Treg alterations, which can augment pulmonary fibrosis.