Clinical Studies of Inflammatory Bowel Diseases

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在各种环境下确定IBD的免疫和遗传机制。今年的研究成果包括： 1.完成了一项针对IL-12p40的新型口服制剂在影响部分常见变量免疫缺陷患者的炎症性肠病中的安全性和有效性的初步研究(我们在2006年的胃肠病学杂志131：748-756上报道了这种IBD)。我们招募了四名患者，并观察到至少一名患者的症状显著逆转，包括脂溢症、d-木糖吸收、体重增加和红细胞减少的改善。 2.与Biogen-IDEC合作进行一项使用Avonex(干扰素β1a)治疗溃疡性结肠炎的II期研究。利用我们在UC中基于NIH的开放标签试验的结果，我们正在推进一项多中心概念验证安慰剂对照试验的计划，以进一步测试这种I型干扰素在UC中的安全性和有效性。 3.启动一项方案，研究患有特发性结肠炎的Hermansky-Pudlak综合征患者的免疫异常和对常规IBD治疗的反应。Hermansky-Pudlak综合征(HPS)是一种研究IBD病因学的模型遗传病，它是由不同染色体上的单基因突变引起的相互作用蛋白缺陷引起的。HPS患者皮肤和眼睛中的色素丢失(眼皮肤白化病)，视力下降，血小板紊乱导致容易出血，并可能发展为肺纤维化。患有HPS的患者患IBD的风险也是普通人群的十倍以上；结肠炎可能是肉芽肿性的，我们已经证明它只与两种已知的HPS基因缺陷有关。 本计划在过去一年中包括的有效NIH方案(曼农博士担任PI)： 特发性炎症性肠病的免疫调节研究：克罗恩病、溃疡性结肠炎和不明原因的肠炎(包括 02-I-0153常见变异型免疫缺陷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：一项评估免疫和临床疗效的初步研究 03-I-0019-I型干扰素治疗溃疡性结肠炎的开放性先导性研究 04-I-0231炎症性肠病免疫学或遗传学研究临床标本采购 06-I-0021A随机、双盲、口服IL-12/23抑制剂STA-5326甲磺酸对克罗恩病患者外周血和粘膜单个核细胞表型及细胞因子反应的初步研究 口服IL-12/23抑制剂甲磺酸STA-5326治疗常见变量免疫缺陷相关症状性胃肠炎的安全性和有效性的初步研究 加强炎症性肠病治疗Hermansky-Pudlak综合征相关性结肠炎的免疫发病机制及疗效观察

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. Completing a pilot study of the safety and efficacy of a novel oral agent targeting IL-12p40 in the inflammatory enteropathy affecting a subset of common variable immunodeficiency patients (we reported on this IBD in Gastroenterology 131:748-756, 2006). We enrolled four patients and observed at least one subject who had significant reversal of symptoms including steatorrhea, d-xylose absorption, weight gain, and improvement in cytopenias. 2. Collaborating with Biogen-Idec on a Phase II study using Avonex (Interferon beta 1a) in ulcerative colitis. Using the results of our NIH-based open-label trial in UC, we are moving forward with plans for a multi-center proof-of-concept placebo-controlled trial to further test the safety and efficacy of this type-I interferon in UC. 3. Initiating a protocol to study the immune abnormalities and response to conventional IBD therapy for Hermansky-Pudlak syndrome patients who develop idiopathic colitis. 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 have shown that it is associated with only two of the known HPS gene defects. Active NIH protocols included in this program during this past year (Dr. Mannon as PI): 82-I-0183 Studies of the Immune Regulation of Idiopathic Inflammatory Bowel Diseases: Crohns Disease, Ulcerative Colitis, and Undefined Inflammatory Conditions of the Gut (including 02-I-0153 The Immune Basis for the Gastrointestinal Complications of Common Variable Immunodeficiency 02-I-0019 Granulocyte-Colony Stimulatiing Factor Treatment for Crohns 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 04-I-0231 Procurement of Clinical Specimens for Immunologic or Genetic Studies in Inflammatory Bowel Diseases 06-I-0021 A Randomized, Double-blind, Pilot Study of the Oral IL-12/23 Inhibitor, STA-5326 mesylate, to Investigate Peripheral Blood and Mucosal Mononuclear Cell Phenotype and Cytokine Responses in Patients with Crohns Disease 06-I-0037 A Pilot Study of Safety and Efficacy of the Oral IL-12/23 Inhibitor, STA-5326 Mesylate, for Symptomatic Gastrointestinal Inflammation Associated with Common Variable Immunodeficiency 07-I-0205 An Observational Study of the Immunopathogenesis of and Response to Step-Up Inflammatory Bowel Disease Therapy for Hermansky-Pudlak Syndrome-Associated Colitis