CTLA-4Ig suppresses liver injury by inhibiting acquired immune responses in a mouse model of fulminant hepatitis
CTLA-4Ig suppresses liver injury by inhibiting acquired immune responses in a mouse model of fulminant hepatitis
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DOI：
10.1002/hep.20872
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发表时间：
2005-10-01
期刊：
影响因子：
13.5
通讯作者：
Sugiyama, T
中科院分区：
文献类型：
--
作者：
Nakayama, Y;Shimizu, Y;Sugiyama, T
在通过注射痤疮丙酸杆菌（P. acnes）和脂多糖（LPS）诱导的重型肝炎动物模型中，共刺激分子的表达在各种器官中显著上调。在本研究中，我们研究了CTLA-4 Ig阻断共刺激信号是否可以抑制该模型中的肝损伤。我们将编码CTLA-4 Ig的腺病毒（AACTLA-4 Ig）在痤疮丙酸杆菌致敏前7天、致敏当天或致敏后3天注射到小鼠中。发现病毒优先感染肝脏，并且早在病毒注射后2天就在血清中检测到CTILA-4 Ig。注射LPS后，检测肝损伤和存活率。大多数未注射AdCTLA-4 Ig的小鼠在注射LPS后12小时内死亡。相比之下，当在痤疮丙酸杆菌引发前7天或同一天注射病毒时，所有注射AdCTLA-4 Ig的小鼠均存活。重要的是，出血性肝损伤和血清丙氨酸氨基转移酶水平在LPS注射后显著降低，甚至当AdCTI-A-4 Ig在痤疮丙酸杆菌引发后3天注射时。免疫学分析表明，CTLA-4 Ig抑制肝淋巴结中痤疮丙酸杆菌特异性CD 4（+）T细胞的活化和扩增，导致细胞向肝脏的募集减少。干扰素-γ、白细胞介素-12和各种趋化因子在肝脏中的总量随后降低，导致不仅T细胞而且巨噬细胞的二次募集受到抑制。结论：CTLA-4 Ig可用于治疗严重肝损伤。
Expression of costimulatory molecules is significantly upregulated in various organs in an animal model of severe hepatitis induced by injection of Propionibacterium acnes (P. acnes) and lipopolysaccharide (LPS). In the present study, we examined whether blockade of costimulatory signals by CTLA-4Ig can suppress the liver injury in this model. We injected an adenovirus encoding CTLA-4Ig (AACTLA-4Ig) into mice 7 days before, on the same day, or 3 days after P. acnes priming. The virus was found to infect the liver preferentially, and CTILA-4Ig was detected in the serum as early as 2 days after viral injection. After injection of LPS, liver injury and survival rates were examined. Most of the mice not injected with AdCTLA-4Ig died within 12 hours after injection of LPS. In contrast, all the AdCTLA-4Ig-injected mice survived when the virus was injected 7 days before or on the same day as P. acnes priming. Importantly, hemorrhagic liver injury and serum alanine aminotransferase levels were significantly reduced after LPS injection even when AdCTI-A-4Ig was injected 3 days after P. acnes priming. Immunological analyses showed that CTLA-4Ig inhibited the activation and expansion of P. acnes-specific CD4(+) T cells in the hepatic lymph nodes, leading to a reduction in the recruitment of the cells to the liver. The total amounts of interferon-gamma, interleukin-12, and various chemokines in the liver were then decreased, resulting in inhibition of the secondary recruitment of not only T cells but also macrophages. In conclusion, CTLA-4Ig could be useful for treatment of severe liver injury.