Successful treatment of murine autoimmune cholangitis by parabiosis: Implications for hematopoietic therapy.
Successful treatment of murine autoimmune cholangitis by parabiosis: Implications for hematopoietic therapy.
复制标题
通过联体共生成功治疗小鼠自身免疫性胆管炎：对造血治疗的影响
DOI：
10.1016/j.jaut.2015.09.002
复制
发表时间：
2016-01
影响因子：
12.8
通讯作者：
Lian ZX
中科院分区：
文献类型：
--
作者：
Yang JB;Wang YH;Yang W;Lu FT;Ma HD;Zhao ZB;Jia YJ;Tang W;Tsuneyama K;Ridgway WM;Gershwin ME;Lian ZX
尽管有关于导致胆管损伤的效应子途径的重要数据，但原发性胆汁性肝硬化（PBC）的治疗仍存在显著未满足的需求。我们将注意力集中在PBC的小鼠模型，显性负性转化生长因子β受体II（Tg）小鼠。为了进一步确定导致这些小鼠胆道病理学的途径，我们开发了CD4细胞缺失的Tg小鼠（CD4 −/− Tg）。有趣的是，这些小鼠比对照Tg小鼠发生更严重的胆管炎。这些缺乏CD4细胞的小鼠表现出效应CD8细胞产生的IFN-γ水平增加。胆管炎的增加似乎是由于缺乏CD4 Treg细胞。基于这些数据，我们将8 - 9周龄的已确诊疾病的CD4 −/− Tg小鼠与C57 BL/6对照小鼠进行了parabiosis。这种联体"双胞胎"的自身免疫性胆管炎有显着减少，即使他们在手术时已建立病理。我们制备了由CD4 −/− Tg和CD8 −/−小鼠构建的混合骨髓嵌合体小鼠，不仅胆管炎得到改善，而且在野生型CD4细胞存在下，终末分化的CD8 + T效应细胞减少。总之，即使在存在致病性CD8 T细胞的情况下，"纠正" CD4 T细胞亚群在治疗自身免疫性胆管炎中也是有效的。
There is a significant unmet need in the treatment of primary biliary cirrhosis (PBC) despite significant data on the effector pathways that lead to biliary duct damage. We focused attention on a murine model of PBC, the dominant negative transforming growth factor β receptor II (Tg) mice. To further define the pathways that lead to biliary pathology in these mice, we developed Tg mice deleted of CD4 cells (CD4−/−Tg). Interestingly, these mice developed more severe cholangitis than control Tg mice. These mice, which lack CD4 cells, manifested increased levels of IFN-γ produced by effector CD8 cells. It appears that increased cholangitis is due to the absence of CD4 Treg cells. Based on these data, we parabiosed CD4−/−Tg mice with established disease at 8–9 weeks of age with C57BL/6 control mice. Such parabiotic “twins” had a significant reduction in autoimmune cholangitis, even though they had established pathology at the time of surgery. We prepared mixed bone marrow chimera mice constructed from CD4−/−Tg and CD8−/− mice and not only was cholangitis improved, but a decrease in terminally differentiated CD8+ T effector cells in the presence of wild type CD4 cells was noted. In conclusion, “correcting” the CD4 T cell subset, even in the presence of pathogenic CD8 T cells, is effective in treating autoimmune cholangitis.