Chronic murine colitis is dependent on the CD154/CD40 pathway and can be attenuated by anti-CD154 administration
Chronic murine colitis is dependent on the CD154/CD40 pathway and can be attenuated by anti-CD154 administration
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DOI：
10.1053/gast.2000.16485
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发表时间：
2000-09-01
期刊：
影响因子：
29.4
通讯作者：
Terhorst, C
中科院分区：
文献类型：
--
作者：
De Jong, YP;Comiskey, M;Terhorst, C
背景和目标：在大多数动物模型中，实验性结肠炎是由显示辅助性T细胞1（Th 1）表型的T淋巴细胞的失调引起的，肿瘤坏死因子（TNF）家族的成员CD 154（CD 40 L/gp 39）在T细胞活化时上调，并且已显示在诱导Th 1应答中起关键作用。我们研究了慢性实验性结肠炎是否依赖于CD 154/CD 40途径以及是否可以通过抗CD 154抗体治疗来预防疾病。CD 45 Rb（hi）细胞转移到重组激活基因缺陷（Rag（-/-））小鼠和tg ≥ 26动物的骨髓移植中，在两种模型中，用来自CD 154缺陷动物的细胞重建小鼠。在另一系列实验中，野生型CD 45 Rb（hi）T细胞重建的受体从实验开始或在疾病发作后用抗CD 154治疗。结果：与野生型细胞相比，CD 154缺陷的T细胞诱导更温和的临床疾病、更少的体重减轻和更少的结肠炎组织学体征。CD 154缺陷型T细胞受体血清中白细胞介素12的水平比野生型细胞受体低5倍。然而，没有观察到偏离Th 1表型的迹象。即使在结肠炎发作后开始，抗CD 154抗体治疗也显著损害了疾病发展。CD 154/CD 40通路在Th 1诱导的慢性实验性结肠炎中起着关键作用，即使在疾病发作后，改善结肠炎但不诱导辅助性T细胞2（Th 2）表型。
Background & Aims: Experimental colitis in most animal models is caused by dysregulation of T lymphocytes that display a T helper 1 (Th1) phenotype, CD154 (CD40L/gp39), a member of the tumor necrosis factor (TNF) family, is up-regulated on T cells on activation and has been shown to play a key role in the induction of a Th1 response. We investigated whether chronic experimental colitis is dependent on the CD154/CD40 pathway and whether disease can be prevented by anti-CD154 antibody treatment, Methods: Two models of chronic colitis were used: CD45Rb(hi) cell transfer into recombination activation gene-deficient (Rag(-/-)) mice and bone marrow transplant of tg epsilon 26 animals, In both models, mice were reconstituted with cells from CD154-deficient animals. In another series of experiments, wildtype CD45Rb(hi) T cell-reconstituted recipients were treated with anti-CD154, either from the start of the experiment or after onset of disease, Results: T cells deficient in CD154 induced a milder clinical disease, less weight loss, and fewer histologic signs of colitis than wild-type cells. The level of interleukin 12 in the serum of CD154-deficient T-cell recipients was 5-fold less than that of wild-type cell recipients. Nevertheless, no signs of deviation from a Th1 phenotype were observed, Treatment with anti-CD154 antibodies substantially impaired disease development, even when started after the onset of colitis, Conclusions: The CD154/CD40 pathway plays a critical role in Th1-induced chronic experimental colitis, Blocking CD154, even after the onset of disease, ameliorates colitis but does not induce a T helper 2 (Th2) phenotype.