TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation
TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation
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TLR4失活可防止异基因造血干细胞移植后发生移植物抗宿主病
DOI：
10.1038/cmi.2012.58
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发表时间：
2013-03-01
影响因子：
24.1
通讯作者：
Cai, Zhen
中科院分区：
文献类型：
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作者：
Zhao, Yi;Liu, Qiuyan;Cai, Zhen
移植物抗宿主病(GVHD)是造血干细胞移植后最常见的并发症。为了阐明细菌脂多糖的主要受体Toll样受体4(TLR4)在急性移植物抗宿主病(−/−)发病中的作用，我们建立了TLR4基因敲除的小鼠GVHD模型，并对其免疫学机制进行了分析。与野生型(TLR4+/+)小鼠相比，TLR4型−/−小鼠作为骨髓和脾细胞移植供体或受体时，移植物抗宿主病症状的发生和死亡率均有所延迟。此外，组织病理学分析显示，在TLR4BALB/c嵌合体中，肝和小肠组织损伤减轻，淋巴细胞浸润最少。与TLR4+/+相比，TLR4−/−小鼠树突状细胞在脂多糖诱导过程中不表达CD80、CD86、CD40、MHC-II和IL-12，仍处于未成熟状态。此外，与TLR4+/+小鼠树突状细胞相比，TLR4BALB/c鼠脾树突状细胞促进同种异体T细胞增殖尤其是辅助性T细胞1(TH1)的能力明显减弱，而TLR4BALB/c嵌合小鼠血清中Th2细胞特异性细胞因子干扰素-γ和IL-10水平显著高于TLR4+/+嵌合小鼠。总体而言，我们的数据显示TLR4可能在GVHD的发病机制中发挥作用，靶向TLR4基因治疗可能提供一种新的治疗方法来降低GVHD的风险。
Graft-versus-host disease (GVHD) is the most common complication after hematopoietic stem cell transplantation. To clarify the role of Toll-like receptor 4 (TLR4), which is a major receptor for bacterial lipopolysaccharides (LPS), in the development of acute GVHD, we used a TLR4-knockout (TLR4−/−) mouse GVHD model and analyzed the underlying immunological mechanisms. When TLR4−/− mice were used as bone marrow and splenocyte cell graft donors or recipients, GVHD symptom occurrence and mortality were delayed compared to wild-type (TLR4+/+) mice. In addition, histopathological analyses revealed that in TLR4−/−→ BALB/c chimeras, liver and small intestine tissue damage was reduced with minimal lymphocytic infiltration. In contrast to TLR4+/+, TLR4−/− mice dendritic cells did not express CD80, CD86, CD40, MHC-II or IL-12 during LPS induction and remained in an immature state. Furthermore, the ability of TLR4−/− mice spleen dendritic cells to promote allogeneic T-cell proliferation and, in particular, T-helper cell 1 (Th1) development was obviously attenuated compared with TLR4+/+ mice dendritic cells, and the levels of interferon-γ (IFN-γ) and IL-10, Th2-cell specific cytokines, were significantly higher in the serum of TLR4−/−→ BALB/c than in TLR4+/+→ BALB/c chimeric mice. Overall, our data revealed that TLR4 may play a role in the pathogenesis of GVHD and that targeted TLR4 gene therapy might provide a new treatment approach to reduce the risk of GVHD.