Clinical Studies of Inflammatory Bowel Diseases

炎症性肠病的临床研究

• 批准号: 7196691
• 负责人: Peter Mannon
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7196691
• 关键词: Crohn' s disease; T lymphocyte; cellular pathology; cytokine; diarrhea; drug screening /evaluation; endoscopy; flow cytometry; gastrointestinal absorption /transport; gene expression; human genetic material tag; human subject; human therapy evaluation; immunogenetics; immunoregulation; immunotherapy; inflammation; inflammatory bowel diseases; interleukin 12; malabsorption; mucosal immunity; outcomes research; patient oriented research; ulcerative colitis

This program is dedicated to the translation of basic research findings into clinical trials of novel therapies for inflammatory bowel diseases (IBD) AND to using basic research methods to define the immune and genetic mechanisms underlying IBD in a variety of settings. This year's research accomplishments include: 1. Publishing results of a multi-center Phase II study of an anti-IL-12 antibody for active Crohn's disease (NEJM 351:2069-79,2004). Anti-IL-12 treatment caused significant improvement in symptoms vs placebo (3mg/kg sc q week for 7 weeks) and induced remissions in many patients. Beneficial responses were accompanied by significant decreases in Th1 inflammatory cytokines (measured in subjects enrolled at the NIH). These results are particularly relevant because they established the effectiveness of targeting IL-12 in Crohn's disease, showed that IL-12 is an important inflammatory cytokine driving disease even in chronic stages, and they demonstrate the advantage of targeting therapies at proximal points in an inflammatory cascade. 2. Reporting new findings that another Th1 cytokine, IL-23, plays a role in the inflammation of Crohn's disease (Gastroenterology128:A-118,2005). This is important because it presents the possibility that other Th1 cytokines may play a significant role in ongoing inflammation and that therapies targeting IL-23 specifically (e.g. the p19 subunit) should be tested for safety and effectiveness in Th1 diseases like Crohn's. 3. Reporting new findings that the often-devastating intestinal inflammation that can complicate Common Variable Immunodeficiency (Gastroenterology 128:A505,2005) is a Th1-mediated process that appears different from Crohn?s disease in its lack of a role for IL-23. This finding is important because there is no treatment for this form of IBD (it does not respond to the chronic replacement of immunoglobulin that controls the frequent infections) and I am currently putting in place a new treatment protocol for these patients based on anti-IL-12 strategies. 4. Publishing results of the NIH experience with gastrointestinal disease in Hermansky-Pudlak syndrome (Clin. Gastroenterol. Hepatol.,2005 in press). Hermansky-Pudlak syndrome (HPS) is a model inherited disease for study of IBD etiology because it is caused by a defect in interacting proteins due to single gene mutations on different chromosomes. Patients with HPS have loss of pigment in the skin and eye (oculocutaneous albinism) with reduced vision, a platelet disorder leading to easy bleeding, and may develop pulmonary fibrosis. Patients with HPS also have a risk of IBD over ten-fold greater than the general population; the colitis may be granulomatous and we show that it is associated with only two of the known HPS gene defects. These findings are important because they summarize such data on the largest group of HPS subjects so studied, and the data suggest a genetic animal model to test susceptibility to IBD and measure individual function of the various parts of the mucosal immune system (from colonic biodiversity to molecular and cellular aspects of the innate and adaptive mucosal immune system) that may be affected by these defects. Current active NIH protocols included in this program (Dr. Mannon as PI): 82-I-0183 Studies of the Immune Regulation of Idiopathic Inflammatory Bowel Diseases: Crohn?s Disease, Ulcerative Colitis, and Undefined Inflammatory Conditions of the Gut 02-I-0153 The Immune Basis for the Gastrointestinal Complications of Common Variable Immunodeficiency 02-I-0019 Granulocyte-Colony Stimulating Factor Treatment for Crohn?s Disease: A Pilot Study Assessing Immune and Clinical Response 03-I-0019 An Open-label, Pilot Study of Type I Interferon Treatment of Ulcerative Colitis 03-I-0177 A Single Arm Study of Extracorporeal Photoimmune Therapy with UVADEX for Corticosteroid Sparing in Patients with Corticosteroid-dependent Crohn's Disease Refractory or Intolerant to Immunosuppressants and/or Anti-TNF Agent 04-I-0231 Procurement of Clinical Specimens for Immunologic or Genetic Studies in Inflammatory Bowel Diseases 05-I-0108 A Multicenter, Open-label, Study of Extracorporeal Photoimmune Therapy with UVADEX in the Treatment of Patients with Moderately Active Crohn's Disease Who Are Refractory or Intolerant to Immunosuppressants and/or Anti-TNF Agent

该计划致力于将基础研究成果转化为炎症性肠病（IBD）新疗法的临床试验，并使用基础研究方法来定义各种环境中IBD的免疫和遗传机制。今年的研究成果包括： 1.发表了抗IL-12抗体治疗活动性克罗恩病的多中心II期研究结果（NEJM 351：2069- 79，2004）。与安慰剂相比，抗IL-12治疗导致症状显著改善（3 mg/kg sc q周，持续7周），并在许多患者中诱导缓解。有益的反应伴随着Th 1炎性细胞因子的显著降低（在NIH招募的受试者中测量）。这些结果是特别相关的，因为它们确立了靶向IL-12在克罗恩病中的有效性，表明IL-12即使在慢性阶段也是驱动疾病的重要炎性细胞因子，并且它们证明了在炎性级联中的近端点处靶向治疗的优势。 2.报道了另一种Th 1细胞因子IL-23在克罗恩病的炎症中起作用的新发现（Gastroenterology 128：A-118，2005）。这一点很重要，因为它提出了其他Th 1细胞因子可能在持续炎症中发挥重要作用的可能性，并且应该测试特异性靶向IL-23（例如p19亚基）的治疗在Th 1疾病（如克罗恩病）中的安全性和有效性。 3.报告新的发现，往往破坏性肠道炎症，可以复杂的常见可变免疫缺陷（胃肠病学128：A505，2005）是一个Th 1介导的过程，似乎不同于克罗恩病？s的疾病在其缺乏的作用，IL-23。这一发现很重要，因为这种形式的IBD没有治疗方法（它对控制频繁感染的免疫球蛋白的慢性替代没有反应），我目前正在为这些患者制定一种基于抗IL-12策略的新治疗方案。 4.发表了NIH在Hermansky-Pudlak综合征中胃肠道疾病经验的结果（Clin. Gastroenterol.肝醇、2005年出版）。Hermansky-Pudlak综合征（HPS）是IBD病因学研究的模型遗传性疾病，因为它是由不同染色体上的单基因突变引起的相互作用蛋白质缺陷引起的。患有HPS的患者皮肤和眼睛中的色素丧失（眼皮肤白化病），视力下降，血小板紊乱导致容易出血，并且可能发展为肺纤维化。HPS患者患IBD的风险也比一般人群高10倍以上;结肠炎可能是肉芽肿性的，我们发现它只与两种已知的HPS基因缺陷有关。这些发现很重要，因为它们总结了最大一组HPS受试者的数据，这些数据表明遗传动物模型可以测试对IBD的易感性，并测量可能受这些缺陷影响的粘膜免疫系统各部分的个体功能（从结肠生物多样性到先天性和适应性粘膜免疫系统的分子和细胞方面）。 本项目中包含的当前有效NIH方案（Dr. Mannon作为PI）： 82-I-0183特发性炎症性肠病的免疫调节研究：克罗恩病？疾病、溃疡性结肠炎和不明原因的肠道炎症 02-I-0153常见变异型免疫缺陷病胃肠道并发症的免疫基础 02-I-0019粒细胞集落刺激因子治疗克罗恩病？s病：一项评估免疫和临床应答的初步研究 03-I-0019一项I型干扰素治疗溃疡性结肠炎的开放标签、初探性研究 03-I-0177一项在免疫抑制剂和/或抗TNF药物难治性或不耐受的皮质类固醇依赖性克罗恩病患者中使用UVADEX进行体外光免疫治疗以节省皮质类固醇的单臂研究 04-I-0231炎症性肠病免疫学或遗传学研究的临床标本采购 05-I-0108一项UVADEX体外光免疫疗法治疗免疫抑制剂和/或抗TNF药物难治性或不耐受的中度活动性克罗恩病患者的多中心、开放标签研究