High-mobility group box 1 promotes early acute allograft rejection by enhancing IL-6-dependent Th17 alloreactive response
High-mobility group box 1 promotes early acute allograft rejection by enhancing IL-6-dependent Th17 alloreactive response
复制标题
高迁移率组盒 1 通过增强 IL-6 依赖性 Th17 同种反应反应促进早期急性同种异体移植排斥
DOI：
10.1038/labinvest.2010.141
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发表时间：
2011-01-01
影响因子：
5
通讯作者：
Fang, Min
中科院分区：
文献类型：
--
作者：
Duan, Lihua;Wang, Cong-Yi;Fang, Min
以前，我们报道了细胞外高迁移率族蛋白1（HMGB 1）作为一种先天性alarmin参与心脏移植急性排斥反应。我们现在提出的证据表明，HMGB 1是通过刺激树突状细胞分泌IL-6来诱导产生白细胞介素-17（IL-17）的同种异体反应性T细胞的关键。这些IL-17+ T细胞可能是负责心脏移植排斥反应的早期阶段的主要效应细胞，通过介导中性粒细胞流入同种异体移植物，因此，阻断IL-17 A显着延长小鼠心脏移植物的存活。与经典模型中IFN-γ+-Th 1细胞在急性同种异体移植排斥反应中的主导作用相反，我们的数据表明，IFN-γ+-Th 1细胞通过在IL-17+ T细胞反应消退时诱导单核细胞浸润而导致移植物破坏的晚期。阻断HMGB 1可显著降低受者脾同种异体反应性Th 17细胞和产生IFN-γ的CD 8 + T细胞，导致移植物中中性粒细胞浸润减少沿着IL-6和IL-17表达水平降低，心脏移植物存活延长。总之，这些数据支持了一种新的模型，其中HMGB 1诱导产生IL-17的同种异体反应性T细胞介导早期同种异体排斥反应，而产生IFN-γ的同种异体反应性Th 1细胞在Th 17反应消退后引起移植物破坏。
Previously, we reported that extracellular high-mobility group box 1 (HMGB1) functions as an innate alarmin implicated in cardiac allograft acute rejection. We now present evidence suggesting that HMGB1 is pivotal in inducing interleukin-17 (IL-17)-producing alloreactive T cells by stimulating dendritic cells secretion of IL-6. Those IL-17+ T cells are likely to be the major effector cells responsible for the early stage of cardiac allograft rejection through mediating an influx of neutrophils into allografts, and therefore, blockade of IL-17A significantly prolonged murine cardiac allograft survival. In contrast to the classical model for a dominant role of IFN-γ+-Th1 cells have in acute allograft rejection, our data suggest that IFN-γ+-Th1 cells are responsible for the late stage of graft destruction by inducing monocyte infiltration when IL-17+ T-cell response recedes. Blockade of HMGB1 significantly decreased splenic alloreactive Th17 cells and IFN-γ-producing CD8+ T cells in the recipients, leading to less infiltration of neutrophils along with lower IL-6 and IL-17 expression levels in the grafts as well as prolongation of cardiac allograft survival. Together, these data support a novel model in which HMGB1 induces IL-17-producing alloreactive T cells to mediate early stage of allograft rejection, whereas IFN-γ-producing alloreactive Th1 cells provoke graft destruction after Th17 response recedes.