Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12
Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12
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DOI：
10.1002/eji.1830260432
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发表时间：
1996-04-01
影响因子：
5.4
通讯作者：
Neurath, M
中科院分区：
文献类型：
--
作者：
Duchmann, R;Schmitt, E;Neurath, M
越来越多的证据表明，对肠道植物群的高反应性是炎症性肠病（IBD）发病机制中的一个关键事件。为了支持这一假设，我们最近描述了人类对固有肠道植物群存在耐受性，但在活动性IBD病变中被破坏。在本研究中，我们尝试将该模型转移到来自不同遗传背景的小鼠（BALB/c，SJL/J，C3 H/HeJ）中。我们发现，来自小鼠脾、小肠和大肠的单核细胞不增殖，即当暴露于来自自体肠（BsA）的细菌超声处理物时是耐受的，但确实增殖，即当暴露于来自自体肠（BsA）的细菌超声处理物时是耐受的。e.当暴露于来自同系同窝小鼠（BsH）的异源肠的细菌超声处理物时具有免疫力。此外，我们表明，局部和全身耐受BsA被打破的半抗原试剂2.4.6-三硝基苯磺酸（TNBS），模仿克罗恩病的几个重要特征诱导的慢性肠道炎症的小鼠模型。在全身接受白细胞介素（IL）-10或IL-12抗体治疗的小鼠中，对BsA的耐受性得到恢复，TNBS诱导的结肠炎得到消除。治疗特异性地恢复了对BsA的耐受性，但不抑制对BsH的增殖。总之，我们在这里报告了一种新的小鼠模型，用于研究对细菌产品的免疫和耐受性。我们的数据表明，对BsA的耐受性是一种重要的保护机制，通过IL-10和IL-12抗体恢复对肠道植物群的耐受性可能对炎症性肠病患者具有潜在的治疗效用。
There is now increasing evidence that hyperresponsiveness towards intestinal flora is a crucial event in the pathogenesis of inflammatory bowel disease (IBD). In support of this hypothesis, we recently described in humans that tolerance exists towards indigenous intestinal flora but is broken in active IBD lesions. In the present study, we have attempted to transfer this model into mice from different genetic backgrounds (BALB/c, SJL/J, C3H/HeJ). We found that mononuclear sells from spleen, small bowel and large bowel of mice do not proliferate, i.e. are tolerant when exposed to bacterial sonicates derived from autologous intestine (BsA) but do proliferate, i. e. are immune when exposed to bacterial sonicates derived from the heterologous intestine of syngenic littermates (BsH). Furthermore, we demonstrate that both local and systemic tolerance to BsA is broken in a murine model of chronic intestinal inflammation induced by the hapten reagent 2.4.6-trinitrobenzene sulfonic acid (TNBS), which mimics several important characteristics of Crohn's disease. Tolerance to BsA was restored and TNBS-induced colitis was abrogated in mice systemically treated with interleukin (IL)-10 or antibodies to IL-12. Treatment specifically restored tolerance to BsA, bur did not suppress proliferation to BsH. In summary, we here report a new mouse model for the study of immunity and tolerance towards bacterial products. Our data suggest that tolerance to BsA is an important protective mechanism and that restoration of tolerance to resident intestinal flora by IL-10 and antibodies to IL-12 may be of potential therapeutic utility in patients with inflammatory bowel disease.