An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition
An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition
复制标题
DOI：
10.1172/jci.insight.92111
复制
发表时间：
2017-06-15
期刊：
影响因子：
8
通讯作者：
Blazar, Bruce R.
中科院分区：
文献类型：
--
作者：
Forcade, Edouard;Paz, Katelyn;Blazar, Bruce R.
慢性移植物抗宿主病（cGvHD）仍然是需要新疗法的异基因干细胞移植的主要并发症。CD 146和CCR 5由活化的T细胞表达，并与增加的T细胞迁移能力和Th 17极化相关。我们在40例HSCT患者的队列中进行了多参数流式细胞术分析，并建立了cGvHD小鼠模型，以了解CD 146表达亚群的作用。我们观察到20例ROR γ t表达增强的活动性cGvHD患者中CD 146（+）CD 4 T细胞频率增加。该Th 17倾向亚群富集共表达CD 146和CCR 5的细胞，其具有混合的Th 1/Th 17特征，并且在cGvHD患者中更常见。利用具有闭塞性细支气管炎（BO）的鼠cGvHD模型，我们观察到来自CD 146缺陷小鼠的供体T细胞与来自WT小鼠的供体T细胞相比引起肺cGvHD显著降低。cGvHD减少不是生殖中心B细胞或T滤泡辅助细胞生成失败的结果。相反，CD 146缺陷型T细胞的肺巨噬细胞浸润和T细胞CCR 5、IL-17和IFN-γ共表达显著降低，表明肺终末器官效应机制缺陷。因此，我们评估了小分子ROR γ t活性抑制剂TMP 778的作用。与靶向Th 17通路的药物（如STAT 3抑制剂或IL-17阻断抗体）类似，TMP 778显著缓解了鼠模型中的cGvHD。我们的数据表明，表达CD 146的T细胞作为cGvHD生物标志物，并表明靶向Th 17通路可能代表cGvHD的有希望的治疗。
Chronic graft-versus-host disease (cGvHD) remains a major complication of allogeneic stem cell transplantation requiring novel therapies. CD146 and CCR5 are expressed by activated T cells and associated with increased T cell migration capacity and Th17 polarization. We performed a multiparametric flow cytometry analysis in a cohort of 40 HSCT patients together with a cGvHD murine model to understand the role of CD146-expressing subsets. We observed an increased frequency of CD146(+) CD4 T cells in the 20 patients with active cGvHD with enhanced ROR gamma t expression. This Th17-prone subset was enriched for cells coexpressing CD146 and CCR5 that harbor mixed Th1/Th17 features and were more frequent in cGvHD patients. Utilizing a murine cGvHD model with bronchiolitis obliterans (BO), we observed that donor T cells from CD146-deficient mice versus those from WT mice caused significantly reduced pulmonary cGvHD. Reduced cGvHD was not the result of failed germinal center B cell or T follicular helper cell generation. Instead, CD146-deficient T cells had significantly lower pulmonary macrophage infiltration and T cell CCR5, IL-17, and IFN-gamma coexpression, suggesting defective pulmonary end-organ effector mechanisms. We, thus, evaluated the effect of TMP778, a small-molecule ROR gamma t activity inhibitor. TMP778 markedly alleviated cGvHD in murine models similarly to agents targeting the Th17 pathway, such as STAT3 inhibitor or IL-17-blocking antibody. Our data suggest CD146-expressing T cells as a cGvHD biomarker and suggest that targeting the Th17 pathway may represent a promising therapy for cGvHD.