Clinical Studies of Inflammatory Bowel Diseases

炎症性肠病的临床研究

• 批准号: 7303893
• 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/7303893
• 关键词: Clinical; Studies; Inflammatory; Bowel; Diseases

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 natural history study of the life-threatening enteropathy complicating common variable immuodeficiency (CVID) (Gastroenterology 131:748-756, 2006) identifying IL-12 and interferon-gamma as key effector cytokines in the absence of IL-23 or IL-17. Compared to CVID patients without gut disease, CVID patients with enteropathy had longer duration of immunodeficiency, had measurable malabsorption, and had peripheral blood naive T cell and NK cell deficiencies. These results are important because they demonstrate a human Th1 inflammatory bowel disease not associated with IL-23 (very different from Crohn's disease. e.g.). Furthermore these data became the basis for a new protocol using a novel drug to target IL-12 in the treatment of this condition particularly for inferiority compared to therapies targeting IL-12 in some way. 2. Publishing new findings showing that another Th1 cytokine, IL-23, plays a role in the inflammation of Crohn's disease (Inflam. Bowel. Dis. 12:9-15, 2006). This is important because it presents the possibility that other Th1 cytokines may play a significant role in ongoing inflammation this 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 by targeting IL-13 in experimental ulcerative colitis treatment using interferon-beta (Clin. Immunol. 119: S33-34, 2006), we can induce clinical responses or remissions in a majority of patients; furthermore, more robust responses correlate with larger decreases in IL-13 production by lamin propria mononuclear cells. These findings have lead to discussions of expanded treatment protocols and development of new protocols using agents specifically targeting IL-13. 4. Publishing results of the NIH experience with gastrointestinal disease in Hermansky-Pudlak syndrome (Clin. Gastroenterol. Hepatol.,4: 73-80, 2006). 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. This retrospective study has lead to initiation of a prospective natural history study to define the cytokine and immune abnormalities associated with HPS inflammatory bowel disease.

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.发表了危及生命的肠病并发常见可变免疫缺陷（CVID）的自然史研究的结果（Gastroenterology 131：748-756，2006），其鉴定了在不存在IL-23或IL-17的情况下IL-12和干扰素-γ作为关键效应细胞因子。与无肠道疾病的CVID患者相比，有肠病的CVID患者免疫缺陷持续时间更长，有可测量的吸收不良，外周血幼稚T细胞和NK细胞缺乏。这些结果是重要的，因为它们证明了与IL-23无关的人Th 1炎性肠病（与克罗恩病非常不同）。例如）。此外，这些数据成为使用靶向IL-12的新药治疗这种疾病的新方案的基础，特别是在某种程度上与靶向IL-12的疗法相比具有劣效性。 2.发表的新发现显示另一种Th 1细胞因子IL-23在克罗恩病的炎症中起作用（Inflam.肠子12：9-15，2006）。这是重要的，因为它提出了其他Th 1细胞因子可能在持续的炎症中发挥重要作用的可能性，这种炎症和特异性靶向IL-23（例如p19亚基）的治疗应该在Th 1疾病如克罗恩病中测试安全性和有效性。 3.报告了新的发现，通过在使用干扰素-β的实验性溃疡性结肠炎治疗中靶向IL-13（Clin.Immunol.119：S33-34，2006），我们可以在大多数患者中诱导临床应答或缓解;此外，更稳健的应答与固有层单核细胞产生的IL-13的较大降低相关。这些发现导致了对扩展治疗方案的讨论和使用特异性靶向IL-13的试剂的新方案的开发。 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、4：73-80，2006）。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）。这项回顾性研究导致了一项前瞻性自然史研究的启动，以确定与HPS炎症性肠病相关的细胞因子和免疫异常。