Derkow Katja, Loddenkemper Christoph, Mintern Justine, Kruse Nils, Klugewitz Katja, Berg Thomas, Wiedenmann Bertram, Ploegh Hidde L, Schott Eckart
Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, CVK, Berlin, Germany.
Hepatology. 2007 Oct;46(4):1155-65. doi: 10.1002/hep.21796.
UNLABELLED: The pathogenesis of autoimmune liver diseases is poorly understood. Animal models are necessary to investigate antigen presentation and priming of T-cells in the context of autoimmunity in the liver. Transgenic mouse models were generated in which the model antigen ovalbumin is expressed in hepatocytes (TF-OVA) or cholangiocytes (ASBT-OVA). Transgenic OT-I (CD8) or OT-II (CD4) T-cells specific for ovalbumin were adoptively transferred into TF-OVA and ASBT-OVA mice to induce in vivo priming of antigen-specific T-cells. T-cell migration and activation, as well as induction of liver inflammation, were studied. OT-I T-cells preferentially located to the liver of both mouse strains whereas no migration of OT-II T-cells to the liver was observed. OT-I T-cells proliferated in the liver of TF-OVA mice and the liver and liver draining lymph nodes of ASBT-OVA mice. OT-II CD4 T-cells were activated in spleen and liver draining lymph node of TF-OVA mice but not in ASBT-OVA mice. Transfer of OT-I T-cells led to histologically distinct inflammatory conditions in the liver of ASBT-OVA and TF-OVA mice and caused liver injury as determined by the elevation of serum alanine aminotransferase. CONCLUSION: An antigen expressed in hepatocytes is presented to CD8 and CD4 T-cells, whereas the same antigen expressed in cholangiocytes is presented to CD8 but not CD4 T-cells. In both models, activation of CD8 T-cells occurs within the liver and causes liver inflammation. The models presented here are valuable to investigate the priming of T-cells in the liver and their role in the development of autoimmune disease of the liver.
未标记:自身免疫性肝病的发病机制尚不清楚。动物模型对于研究肝脏自身免疫背景下的抗原呈递和T细胞致敏是必要的。构建了转基因小鼠模型,其中模型抗原卵清蛋白在肝细胞(TF-OVA)或胆管细胞(ASBT-OVA)中表达。将对卵清蛋白特异的转基因OT-I(CD8)或OT-II(CD4)T细胞过继转移到TF-OVA和ASBT-OVA小鼠中,以诱导体内抗原特异性T细胞的致敏。研究了T细胞迁移和活化以及肝脏炎症的诱导情况。OT-I T细胞优先定位于两种小鼠品系的肝脏,而未观察到OT-II T细胞向肝脏的迁移。OT-I T细胞在TF-OVA小鼠的肝脏以及ASBT-OVA小鼠的肝脏和肝引流淋巴结中增殖。OT-II CD4 T细胞在TF-OVA小鼠的脾脏和肝引流淋巴结中被激活,但在ASBT-OVA小鼠中未被激活。OT-I T细胞的转移导致ASBT-OVA和TF-OVA小鼠肝脏出现组织学上不同的炎症情况,并通过血清丙氨酸转氨酶升高确定引起了肝损伤。 结论:在肝细胞中表达的抗原呈递给CD8和CD4 T细胞,而在胆管细胞中表达的相同抗原呈递给CD8但不呈递给CD4 T细胞。在两种模型中,CD8 T细胞的激活均发生在肝脏内并引起肝脏炎症。本文介绍的模型对于研究肝脏中T细胞的致敏及其在自身免疫性肝病发展中的作用具有重要价值。
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