An antibiotic-responsive mouse model of fulminant ulcerative colitis.
An antibiotic-responsive mouse model of fulminant ulcerative colitis.
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DOI：
10.1371/journal.pmed.0050041
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发表时间：
2008-03-04
期刊：
影响因子：
15.8
通讯作者：
Allen, Paul M.
中科院分区：
文献类型：
--
作者：
Kang, Silvia S.;Bloom, Seth M.;Norian, Lyse A.;Geske, Michael J.;Flavell, Richard A.;Stappenbeck, Thaddeus S.;Allen, Paul M.
人类炎症性肠病（IBD）包括溃疡性结肠炎和克罗恩病，两者在病理严重程度上都表现出广泛的频谱。一种理论认为，对宿主免疫系统的多重遗传打击可能导致IBD的易感性和严重程度。然而，这一概念的实验证明仍然缺乏。几种基因小鼠模型，每个都概括了人类IBD的某些方面，利用单一基因缺陷诱导结肠炎。然而，它们都没有产生明显区分为溃疡性结肠炎或克罗恩病的病理，部分原因是它们都没有重现在人类患者中观察到的最严重的疾病形式。严重IBD模型的缺乏对致病机制的研究和新治疗方法的开发提出了挑战。我们假设，对通常抑制肠道免疫激活的调节机制的多重基因打击将产生更严重的、可重复的病理，类似于溃疡性结肠炎或克罗恩病。我们产生了一种新的小鼠系（dnKO），它具有TGFβRII和IL-10R2信号缺陷。这些小鼠迅速和可重复地发展出一种类似于暴发性人类溃疡性结肠炎的疾病，这与以前在仅具有单一缺陷的小鼠中观察到的更长更多变的病理过程截然不同。发病机制是由促炎细胞因子不受控制的产生驱动的，这在很大程度上是由T细胞激活引起的。使用IFNγ和TNFα抗体可显著改善疾病进程，广谱抗生素联合使用可完全抑制疾病进程。在这里，我们开发了我们所知的第一个暴发性溃疡性结肠炎小鼠模型，通过结合免疫调节中的多个基因命中，并证明了由此产生的疾病对抗细胞因子治疗和广谱抗生素都敏感。这些发现表明，IL-10和tgf - β途径协同抑制微生物诱导的促炎细胞因子的产生，包括IFNγ和TNFα，这两种细胞因子已知在人类溃疡性结肠炎的发病机制中发挥作用。我们的研究结果也提供了广谱抗生素可能在治疗溃疡性结肠炎患者中的应用的证据。该模型系统将有助于未来探索诱导免疫激活的微生物因素，并表征这些相互作用如何产生疾病。Paul Allen和他的同事描述了一种暴发性溃疡性结肠炎小鼠模型的发展，这种模型在免疫调节中具有多重基因突变，可以通过抗细胞因子治疗和广谱抗生素来调节。炎症性肠病（IBD）是一组以消化道（从口腔到肛门的管道）炎症（肿胀）为特征的疾病，在美国影响了大约140万人。IBD主要有两种类型。克罗恩病可以影响消化道的任何部位，但最常见的是涉及小肠的下部，所有的肠道层都会发炎。溃疡性结肠炎主要影响结肠（大肠）和直肠（最靠近肛门的肠道部分），只有肠道内壁发炎，内壁细胞死亡，形成溃疡或溃疡。这两种类型的IBD最常见于15至35岁之间，通常在家族中遗传，并且具有更高的癌症风险。症状-通常是腹泻和腹部痉挛-可轻可重，疾病可缓慢或突然发展。目前还没有治愈IBD的药物，但是调节免疫系统的药物（例如皮质类固醇）可以帮助一些人。一些人受益于药物治疗，这些药物专门抑制“促炎细胞因子”，即免疫系统产生的刺激炎症的蛋白质（例如TNFα和INFγ）。当药物治疗失败时，手术切除受影响的肠道部分可能是必要的。导致IBD的确切原因尚不清楚，但IBD患者似乎有一个过度活跃的免疫系统。免疫系统通常保护身体免受有害物质的侵害，但在IBD中，它错误地将通常存在于人体肠道中的食物物质和“好”细菌识别为外来物质，因此对它们产生反应。结果，免疫系统细胞在肠道内壁积聚，引起炎症。几种不同的途径通常会阻止不适当的免疫激活，那么IBD是由这些免疫调节途径中的一种或几种途径的改变引起的吗？在之前的研究中，只有一条通路存在缺陷的小鼠会出现轻微的肠道异常，但不会出现最严重形式的IBD所出现的问题。因此，在这项研究中，研究人员产生了一种新的小鼠系，在两种免疫调节途径中存在缺陷，并对其进行了表征，以观察这是否可能是一种更好的人类IBD动物模型。为了制造新的小鼠系，研究人员将T淋巴细胞中TGFβ信号通路有缺陷的小鼠与IL-10信号通路有缺陷的小鼠交配。这两种途径都具有抗炎作用，其中任何一种途径存在缺陷的小鼠在3-4个月大时出现轻度和可变的结肠炎症（结肠炎）。相比之下，双重缺陷小鼠（dnKO小鼠）未能茁壮成长，体重下降，并在4-6周龄时死亡。4- 5周龄dnKO小鼠的结肠出现炎症和溃疡（3周龄小鼠可见一些变化），并含有许多免疫系统细胞。具有单一缺陷信号通路的小鼠在这个年龄没有肠道异常。dnKO小鼠和IBD患者一样，血液中IFNγ、TNFα和其他促炎细胞因子的水平高于正常水平；这些升高的水平是淋巴细胞异常活化的结果。用中和IFNγ和TNFα（抗细胞因子治疗）的药物组合治疗dnKO小鼠，大大减少了这些小鼠的结肠炎；单独中和IFNγ有一定的有益作用，而单独中和TNFα没有作用。最后，早期用广谱抗生素治疗dnKO小鼠可完全抑制结肠炎。这些发现表明dnKO小鼠是暴发性（严重且进展迅速）溃疡性结肠炎的良好模型，并支持IBD涉及免疫调节中的多种遗传缺陷的观点。他们还表明，IL-10和tgf - β信号通路通常协同抑制IBD中对肠道细菌的不适当免疫反应。这种新的小鼠模型应该有助于研究人员揭示IBD的问题所在，也应该有助于他们开发溃疡性结肠炎的新疗法。更直接的是，这些发现表明联合抗细胞因子治疗可能比单一治疗更好地治疗溃疡性结肠炎。此外，他们建议应该开始临床研究，以测试广谱抗生素是否可以改善人们的溃疡性结肠炎。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0050041访问这些网站。Medline Plus百科全书有关于克罗恩病和溃疡性结肠炎的页面（英语和西班牙语）。有关克罗恩病和溃疡性结肠炎的信息可从英国国家卫生服务直接健康百科全书中获得。美国国家糖尿病、消化和肾脏疾病研究所提供关于克罗恩病和溃疡性结肠炎的信息和支持，炎症性肠病患者及其护理人员由克罗恩提供和美国结肠炎基金会以及英国结肠炎和克罗恩病国家协会
The constellation of human inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, which both display a wide spectrum in the severity of pathology. One theory is that multiple genetic hits to the host immune system may contribute to the susceptibility and severity of IBD. However, experimental proof of this concept is still lacking. Several genetic mouse models that each recapitulate some aspects of human IBD have utilized a single gene defect to induce colitis. However, none have produced pathology clearly distinguishable as either ulcerative colitis or Crohn's disease, in part because none of them reproduce the most severe forms of disease that are observed in human patients. This lack of severe IBD models has posed a challenge for research into pathogenic mechanisms and development of new treatments. We hypothesized that multiple genetic hits to the regulatory machinery that normally inhibits immune activation in the intestine would generate more severe, reproducible pathology that would mimic either ulcerative colitis or Crohn's disease. We generated a novel mouse line (dnKO) that possessed defects in both TGFβRII and IL-10R2 signaling. These mice rapidly and reproducibly developed a disease resembling fulminant human ulcerative colitis that was quite distinct from the much longer and more variable course of pathology observed previously in mice possessing only single defects. Pathogenesis was driven by uncontrolled production of proinflammatory cytokines resulting in large part from T cell activation. The disease process could be significantly ameliorated by administration of antibodies against IFNγ and TNFα and was completely inhibited by a combination of broad-spectrum antibiotics. Here, we develop to our knowledge the first mouse model of fulminant ulcerative colitis by combining multiple genetic hits in immune regulation and demonstrate that the resulting disease is sensitive to both anticytokine therapy and broad-spectrum antibiotics. These findings indicated the IL-10 and TGFβ pathways synergize to inhibit microbially induced production of proinflammatory cytokines, including IFNγ and TNFα, which are known to play a role in the pathogenesis of human ulcerative colitis. Our findings also provide evidence that broad-spectrum antibiotics may have an application in the treatment of patients with ulcerative colitis. This model system will be useful in the future to explore the microbial factors that induce immune activation and characterize how these interactions produce disease. Paul Allen and colleagues describe the development of a mouse model of fulminant ulcerative colitis with multiple genetic hits in immune regulation which can be moderated by anti-cytokine therapy and broad-spectrum antibiotics. Inflammatory bowel disease (IBD), a group of disorders characterized by inflammation (swelling) of the digestive tract (the tube that runs from the mouth to the anus), affects about 1.4 million people in the US. There are two main types of IBD. In Crohn's disease, which can affect any area of the digestive tract but most commonly involves the lower part of the small intestine (small bowel), all the layers of the intestine become inflamed. In ulcerative colitis, which primarily affects the colon (large bowel) and the rectum (the part of the bowel closest to the anus), only the lining of the bowel becomes inflamed, the cells in this lining die, and sores or ulcers form. Both types of IBD most commonly develop between the ages of 15 and 35 years, often run in families, and carry an increased risk of cancer. Symptoms—usually diarrhea and abdominal cramps—can be mild or severe and the disorder can develop slowly or suddenly. There is no medical cure for IBD, but drugs that modulate the immune system (for example, corticosteroids) can help some people. Some people benefit from treatment with drugs that specifically inhibit “proinflammatory cytokines,” proteins made by the immune system that stimulate inflammation (for example, TNFα and INFγ). When medical therapy fails, surgery to remove the affected part of the bowel may be necessary. Exactly what causes IBD is not clear, but people with IBD seem to have an overactive immune system. The immune system normally protects the body from harmful substances but in IBD it mistakenly recognizes the food substances and “good” bacteria that are normally present in the human gut as foreign and hence reacts against them. As a result, immune system cells accumulate in the lining of the bowel and cause inflammation. Several different pathways usually prevent inappropriate immune activation, so could IBD be caused by alterations in one or several of these immune regulatory pathways? In previous studies, mice with a defect in just one pathway have developed mild intestinal abnormalities but not the problems seen in the most severe forms of IBD. In this study, therefore, the researchers have generated and characterized a new mouse line with defects in two immune regulatory pathways to see whether this might be a better animal model of human IBD. To make their new mouse line, the researchers mated mice that had a defective TGFβ signaling pathway in their T lymphocytes with mice that had a defective IL-10 signaling pathway. Both these pathways are anti-inflammatory, and mice with defects in either pathway develop mild and variable inflammation of the colon (colitis) by age 3–4 months. By contrast, the doubly defective mice (dnKO mice) failed to thrive, lost weight, and died by 4–6 weeks of age. The colons of 4- to 5-week old dnKO mice were inflamed and ulcerated (some changes were visible in 3-week-old mice) and contained many immune system cells. Mice with a single defective signaling pathway had no gut abnormalities at this age. The dnKO mice, just like people with IBD, had higher than normal blood levels of IFNγ, TNFα, and other proinflammatory cytokines; these raised levels were the result of abnormal lymphocyte activation. Treatment of the dnKO mice with a combination of agents that neutralize IFNγ and TNFα (anti-cytokine therapy) greatly reduced the colitis seen in these mice; neutralization of IFNγ alone had some beneficial effects, but neutralization of TNFα alone had no effect. Finally, early treatment of the dnKO mice with broad-spectrum antibiotics completely inhibited colitis. These findings suggest that dnKO mice are a good model for fulminant (severe and rapidly progressing) ulcerative colitis and support the idea that IBD involves multiple genetic defects in immune regulation. They also indicate that the IL-10 and the TGFβ signaling pathways normally cooperate to inhibit the inappropriate immune responses to intestinal bacteria seen in IBD. This new mouse model should help researchers unravel what goes wrong in IBD and should also help them develop new treatments for ulcerative colitis. More immediately, these findings suggest that combined anti-cytokine therapy may be a better treatment for ulcerative colitis than single therapy. In addition, they suggest that clinical studies should be started to test whether broad-spectrum antibiotics can ameliorate ulcerative colitis in people. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050041. The Medline Plus Encyclopedia has pages on Crohn's disease and on ulcerative colitis (in English and Spanish) Information is available from the UK National Health Service Direct Health Encyclopedia about Crohn's disease and ulcerative colitis The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on Crohn's disease and ulcerative colitis Information and support for patients with inflammatory bowel disease and their caregivers is provided by the Crohn's and Colitis Foundation of America and by the UK National Association for Colitis and Crohn's Disease
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影响因子：
15.3
作者：
Fahlén, L;Read, S;Gorelik, L;Hurst, SD;Coffman, RL;Flavell, RA;Powrie, F
通讯作者：
Powrie, F
影响因子：
15.9
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
影响因子：
56.9
作者：
Duerr, Richard H.;Taylor, Kent D.;Cho, Judy H.
通讯作者：
Cho, Judy H.
影响因子：
32.4
作者：
Gorelik, L;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
--
作者：
Ahmed, AO;van Vianen, W;Bakker-Woudenberg, IAJM
通讯作者：
Bakker-Woudenberg, IAJM