Protective Role of T-bet and Th1 Cytokines in Pulmonary Graft-versus-Host Disease and Peribronchiolar Fibrosis
Protective Role of T-bet and Th1 Cytokines in Pulmonary Graft-versus-Host Disease and Peribronchiolar Fibrosis
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DOI：
10.1165/rcmb.2011-0131oc
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发表时间：
2012-02-01
影响因子：
6.4
通讯作者：
Palmer, Scott M.
中科院分区：
文献类型：
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作者：
Gowdy, Kymberly M.;Nugent, Julia L.;Palmer, Scott M.
T细胞中表达的T-box （T-bet）是Thelper (Th) 1应答的关键转录因子。虽然Th1细胞被认为有助于某些同种免疫反应，但它们在肺移植物抗宿主病（GVHD）中的作用尚不确定。我们建立了小鼠造血细胞移植（HCT）和吸入LPS暴露后急性肺性GVHD模型。我们使用t- bet缺陷供体测试了肺GVHD可以独立于Th1细胞发生的假设。B10。BR（H2(k)）小鼠与C57BI/6J（H2(b)）小鼠（Allo野生型[WT]或SynWT）或缺乏T-bet的C57BI/6J小鼠（allobet（-/-）或SynTbet(-/-)）的细胞进行同种异体（Allo）或同基因（Syn） HCT。HCT后，小鼠每天暴露于雾化LPS，随后进行支气管肺泡灌洗，并分析肺组织的细胞因子、淋巴细胞炎症、病理和纤维化。独立于LPS暴露，allobet（-/-）小鼠发生肺部GVHD，表现为淋巴细胞炎症。此外，allobet（-/-）小鼠表现出慢性肺GVHD的特征，包括细支气管周围纤维化和胶原含量增加。与LPS暴露的AlloWT小鼠或LPS暴露的SynTbet（-/-）小鼠相比，LPS暴露增加了allobet（-/-）小鼠的中性粒细胞募集，降低了静态顺应性。此外，与其他组相比，lps暴露的allobet（-/-）小鼠肺部IL-17、IL-13和Th17细胞增加，调节性T细胞减少。我们的结果表明Th1细胞因子在肺GVHD中是不可缺少的。在缺乏T-bet的情况下，与细支气管周围纤维化相关的Th17和Th2细胞因子的产生增加，并被LPS进一步增强。这些结果表明，局部先天免疫和非th1 T细胞亚群之间的相互作用有助于慢性肺GVHD。
T-box expressed in T cells (T-bet) is a critical transcription factor for Thelper (Th) 1 responses. Although Th1 cells are thought to contribute to certain alloimmune responses, their role in pulmonary graft-versus-host disease(GVHD) is uncertain. We have established a murine model of acute pulmonary GVHD after hematopoietic cell transplant (HCT) and inhaled LPS exposure. We tested the hypothesis that pulmonary GVHD can occur independent of Th1 cells using T-bet-deficient donors. B10.BR(H2(k)) mice underwent allogeneic (Allo) or syngeneic (Syn) HCT with cells from either C57BI/6J(H2(b)) mice (Allo wild-type [WT] or SynWT) or C57BI/6J mice lacking T-bet (AlloTbet(-/-) or SynTbet(-/-)). After HCT, mice were exposed daily to aerosolized LPS and subsequently bronchoalveolar lavage and lung tissue were analyzed for cytokines, lymphocytic inflammation, pathology, and fibrosis. Independent of LPS exposure, AlloTbet(-/-) mice developed pulmonary GVHD manifested by lymphocytic inflammation. Furthermore, AlloTbet(-/-) mice developed features of chronic pulmonary GVHD, including increased peribronchiolar fibrosis and collagen content. LPS exposure increased neutrophil recruitment and decreased static compliance in AlloTbet(-/-) mice as compared with LPS-exposed AlloWT mice or LPS-exposed SynTbet(-/-) mice. In addition, LPS-exposed AlloTbet(-/-) mice had increased pulmonary IL-17, IL-13, and Th17 cells, and diminished regulatory T cells compared with the other groups. Our results demonstrate that Th1 cytokines are dispensable in pulmonary GVHD. In the absence of T-bet, there is increased production of Th17 and Th2 cytokines that is associated with peribronchiolar fibrosis and is further enhanced by LPS. These results suggest that the interplay between local innate immunity and non-Th1 T cell subsets contribute to chronic pulmonary GVHD.