Clinical Studies of Inflammatory Bowel Diseases

炎症性肠病的临床研究

• 批准号: 10272088
• 负责人: Warren Strober
• 金额: $ 37.54万
• 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/10272088
• 关键词: Abdomen; Abdominal Cramps; Abdominal Pain; Abnormal Cell; Adult; Affect; Aftercare; Agammaglobulinaemia tyrosine kinase; Annual Reports; Antibodies; Antigen-Presenting Cells; Area; B-Lymphocytes; Biological Response Modifier Therapy; Biopsy; Body Weight decreased; Cell physiology; Cells; Cellular Immunology; Chronic; Clinical; Clinical Protocols; Clinical Research; Code; Colitis; Common Variable Immunodeficiency; Crohn' s disease; Data Analyses; Development; Diarrhea; Disease; Disease remission; Dose; Eligibility Determination; Enhancers; Enrollment; Environmental Risk Factor; Excision; Exhibits; Exposure to; FOXP3 gene; Feces; Follow-Up Studies; Frequencies; Functional disorder; Future; Gene Expression Regulation; Generations; Genetic Polymorphism; Goals; Hepatic; High Prevalence; Histone Deacetylase Inhibitor; Immune; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; Immunologic Deficiency Syndromes; Immunologics; Immunomodulators; Impairment; In Vitro; Individual; Inflammasome; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response Pathway; Institutional Review Boards; Interferon Type II; Interferons; Interleukin-12; Intestinal Obstruction; Intestines; LRRK2 gene; Laboratories; Laboratory Research; Lamina Propria; Lead; Leukocyte L1 Antigen Complex; Maintenance; Malabsorption Syndromes; Medical center; Microarray Analysis; Modeling; Molecular; Molecular Abnormality; Molecular Immunology; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; NF-kappa B; National Institute of Allergy and Infectious Disease; Natural History; New York; Outcome; Pathogenesis; Patients; Pattern; Phase; Process; Production; Proteins; Protocols documentation; Publishing; Refractory; Regulatory T-Lymphocyte; Relapse; Reporting; Research; Research Activity; Research Project Grants; Risk; Role; Sampling; Sampling Studies; Serum Albumin; Signal Transduction; Source; Specific qualifier value; Steroids; Symptoms; T-Lymphocyte; TNF gene; Testing; Therapeutic Effect; Tissues; Ulcerative Colitis; Up-Regulation; Villous Atrophy; Visit; Vorinostat; X-Linked Agammaglobulinemia; anakinra; clinical investigation; clinically significant; cohort; common treatment; cytokine; design; gastrointestinal; gastrointestinal symptom; hypogammaglobulinemia; improved; inflammatory disease of the intestine; inhibitor/antagonist; kinase inhibitor; macrophage; novel strategies; novel therapeutics; patient subsets; pediatric patients; peripheral blood; recurrent infection; research study; response; safety study; screening; side effect; trafficking; treatment response

In the past year the Mucosal Immunity Section has been engaged in a number of on-going and new research studies involving both patients with inflammatory bowel disease and common variable immunodeficiency. In the area of IBD, we have conducted studies of IBD associated with LRRK2 risk polymorphisms, as described in detail in a previous annual report. In these studies we have established that the polymorphism is associated with increased levels of LRRK2 and this elevation is accompanied by increased gut inflammation in an induced colitis model. Several observations derived from these studies have direct clinical significance. The first is that cells derived from patients who do not bear the LRRK2 risk polymorphism exhibit reduced pro-inflammatory cytokine responses in vitro when their cells are exposed to inhibitors of the kinase activity of LRRK2. The second is that induced colitis of normal mice or mice with elevated levels of LRRK2 is inhibited by administration of various LRRK2 inhibitors. These observations suggest that treatment of patients with inhibitors of LRRK2 can have a therapeutic effect in all patients with IBD regardless of their LRRK2 status. Currently, we are collaborating with Dr. Inga Peter and her colleagues at the Mt. Sinai Medical Center in New York focused on the development and testing of new LRRK2 inhibitors. In addition, we conducting in vitro studies of LRRK2 function with respect to its possible role as an enhancer of inflammasome and NF-kappaB activity. These studies will inform the design of studies of patients with LRRK2 polymorphisms we will conduct with Dr. Peter. In this period, we have continued a study of the safety and and immunologic effects of the administration of vorinostat, an HDAC inhibitor. The Clinical Protocol guiding the execution of this study (Protocol # 17-I-0101) has now obtained NIAID IRB and FDA approval. The study will ultimately enroll 20 patients who have failed other forms of Crohn's disease therapy; these patients will undergo a wide array of studies to evaluate the immunologic effects of HDAC inhibitor therapy including effects on regulatory T cells. During this period, we have treated an initial Crohns disease patient with verinostst. This patient had previously undergone multiple bowel resections due to intestinal obstruction and had. failed to achieve persistent remission despite treatment with steroids, immunomodulators and biologic therapies, the latter consisting of various anti-TNF-a agents. Following vorinostat therapy the patient reported significant improvement in abdominal pain and cramping as well as improvement in diarrhea symptoms. Administration of vorinostat resulted in decreased CDAI and fecal calprotectin levels during and after the treatment phase. Finally, these changes correlated with a 10-fold increase in FoxP3 cells co-expressing RORgammat. These results suggest that vorinostat may indeed be a new avenue of treatment for IBD patients and we are now actively screening additional patients for enrollment in the study. In the previous Annual Report we discussed extensive studies (now published) showing that Bruton Tyrosine Kinase (BTK) negatively regulates the NLRP3 inflammasome. As a consequence, mice with genetically-determined BTK dysfunction exhibited enhanced DSS-colitis due to increased lamina propria IL-1beta production that is responsive to agents that inhibit IL-1beta signaling. This correlated with the fact that Crohn's disease occurs with increased frequency in patients with BTK deficiency (patients with X-linked agammaglobulinemia). On the basis of these findings we initiated a study of treatment of Crohn's disease occurring in patients with X-linked agammaglobulinemia to determine if this form of Crohn's disease is uniquely susceptible to treatment with a IL-1beta signaling inhibitor (anakinra). So far, two patients (one adult and one pediatric patient) with X-linked agammaglobulinemia and colitis have been entered into study. Both patients had previously undergone bowel resection due to refractory intestinal inflammation. The immune workup revealed increased IL-1beta generation by peripheral blood macrophages. Both patients were started on anakinra. One patient exhibited amelioration of colitis and the other patient exhibited a partial therapeutic response indicated by decreased steroid requirement. These results encourage similar studies of additional BTK deficient patients with colitis. In the area of CVID we have continued to focus on gastrointestinal manifestations of this heterogeneous disease, i.e., patients with a CVID-entropathy characterized by diarrhea, malabsorption and villous atrophy. In prior studies of CVID we established that the CVID enteropathy is driven by cells producing IFN-gamma. In addition, we collaborated with Drs. Andriy Morgan and Natalia Stulzhenko in the Laboratory of Cellular and Molecular Immunology in studies of CVID that included microarray analyses of biopsy tissue of CVID patients with enteropathy showing that CVID enteropathy is characterized by up-regulation of genes related to various interferons. A major outcome of this collaborative study is the finding that those patients with enteropathy have little or no expression of IgA in intestinal biopsies whereas those patients without enteropathy have only moderately reduced levels of IgA. Moreover, this deficiency does not extend to mucosal IgG levels. This finding indicates that enteropathy occurs in the subset of CVID patients with severe mucosal B cell immunodeficiency affecting the mucosal immunoglobulin, IgA. Given the fact that a Th1 (IL-12-driven) process is a notable contributor to CVID enteropathy, it was reasonable to assume that IL-12 blockade by ustekinumab administration would lead to a decrease in gut inflammation and improvement of gastrointestinal symptoms. In an initial single dose study testing this possibility CVID enteropathy patients (n=3) received a single induction dose (270 mg 3.9 mg/kg for a typical 70 kg patient) of ustekinumab. All patients demonstrated significant improvement in stool pattern with a change from watery consistency to that of soft-formed consistency. All 3 patients have completed 6 months of follow-up study with two patients having an observed clinical response lasting for approximately 4-5 months duration. However, each of these patients have had a subsequent relapse of symptoms (diarrhea, weight loss and abdominal bloating complaints) within 6 months of their last dose. In the light of these results, we initiated a new, multi-dose study, wherein CVID enteropathy patients received an induction dose of 270 mg ustekinumab followed by a maintenance dose of 90 mg ustekinumab every 8 weeks through the week 40 study point. Re-enrollment of subjects previously treated on the single dose study was allowed and all three subjects met re-enrollment eligibility criteria. An additional two subjects who had not participated in the single dose study were also enrolled into the multi-dose study. All subjects have been observed to have improvements in consistency and frequency of stool, significant improvement in abdominal pain and bloating symptoms, and improved serum albumin and total protein levels. As of December 2019, the study was closed to accrual of new subjects, as specified in the Protocol. All subjects completed study visits/requirements in August 2019. Sample studies and data analysis was completed shortly thereafter. No research activity was performed after study expired on March 22, 2020. All remaining coded research samples have been stored for future use under the 89-I-0158 Protocol (Natural History Study of Humoral Immunodeficiencies). Taken together, these studies encourage the view that anti-IL-12p40 (ustekinumab)administration is a useful treatment of CVID enteropathy.

在过去的一年中，粘膜免疫部门参与了许多正在进行的研究和新研究，涉及炎症性肠病和常见可变免疫缺陷的患者。 在IBD领域，我们对与LRRK2风险多态性相关的IBD进行了研究，如先前的年度报告中详细描述。 在这些研究中，我们确定多态性与LRRK2水平升高有关，并且该升高伴随着诱导的结肠炎模型中肠炎的增加。 这些研究得出的几种观察结果具有直接的临床意义。 首先是，当不承受LRRK2风险多态性的患者中，当他们的细胞暴露于LRRK2激酶活性的抑制剂时，体外会降低促炎性细胞因子反应。 第二个是通过施用各种LRRK2抑制剂抑制了正常小鼠或LRRK2水平升高的诱导结肠炎。 这些观察结果表明，无论其LRRK2状态如何，对LRRK2抑制剂的患者对所有IBD患者都具有治疗作用。 目前，我们正在与Inga Peter博士及其同事在纽约西奈山医学中心合作，重点介绍了新的LRRK2抑制剂的开发和测试。 此外，我们对LRRK2功能进行了体外研究，以作为其作为炎症体和NF-kappab活性增强的作用。 这些研究将为我们将与Peter博士一起进行的LRRK2多态性患者的研究设计。 在此期间，我们继续研究了HDAC抑制剂Vorinostat的给药的安全性和免疫学影响。 指导这项研究执行的临床方案（协议＃17-I-0101）现已获得了NIAID IRB和FDA批准。 这项研究最终将招募20例未通过其他形式的克罗恩病疗法的患者。这些患者将接受广泛的研究，以评估HDAC抑制剂疗法的免疫学作用，包括对调节性T细胞的影响。 在此期间，我们用Verinostst治疗了一名最初的克罗恩斯疾病患者。该患者以前由于肠道阻塞而进行了多次肠切除术，并有。尽管对类固醇，免疫调节剂和生物疗法进行治疗，但未能实现持续缓解，后者由各种抗TNF-A剂组成。伏地治疗后，患者报告了腹痛和痉挛以及腹泻症状的改善。在治疗阶段和之后，伏地的给药导致CDAI和粪便钙蛋白钙蛋白钙斑蛋白水平降低。最后，这些变化与FOXP3细胞共表达的rorgammat的增长相关。这些结果表明，Vorinostat确实可能是IBD患者治疗的新途径，现在我们正在积极筛查更多患者参加研究。 在上一年的年度报告中，我们讨论了广泛的研究（现已发布），表明布鲁顿酪氨酸激酶（BTK）对NLRP3炎症组进行了负调节。结果，遗传确定的BTK功能障碍的小鼠由于固有层次IL-1BETA的产生增加而表现出增强的DSS-骨炎，这对抑制IL-1BETA信号传导的药物有反应。这与Crohn病的发生率增加的事实相关，BTK缺乏症患者（患有X连锁Agammagloblobloblobloinemia）的频率增加。 根据这些发现，我们开始了对X连锁Agammaglobloblobloblobloblobiamia患者的克罗恩病的治疗研究，以确定这种形式的克罗恩病是否完全容易受到IL-1BETA信号传导抑制剂（Anakinra）的治疗。到目前为止，已经介绍了两名患有X连锁Agammagloblobloblobloinemia和结肠炎的患者（一名成人和一名儿科患者）进行了研究。 两名患者先前由于难治性肠道炎症而进行了肠切除。免疫检查表明，外周血巨噬细胞增加了IL-1BETA的产生。两名患者都开始使用Anakinra。 一名患者表现出结肠炎的改善，另一名患者表现出部分治疗反应，表明类固醇的需求减少。这些结果鼓励对其他BTK缺乏结肠炎患者进行类似的研究。 在CVID领域，我们继续专注于这种异质疾病的胃肠道表现，即患有腹泻，不良疗法和绒毛性萎缩的CVID-肉眼患者。 在先前对CVID的研究中，我们确定CVID肠病是由产生IFN-GAMMA的细胞驱动的。 此外，我们与Drs合作。在CVID研究中，在细胞和分子免疫学实验室中，Andriy Morgan和Natalia Stulzhenko在内，其中包括对肠病的CVID患者的活检组织的微阵列分析，表明CVID肠病的表征是与各种干扰素相关的基因上的上调。 这项协作研究的一个主要结果是，那些肠病患者在肠活检中几乎没有或根本没有IgA表达，而那些没有肠病的患者只有中等降低了IgA水平。 此外，这种缺乏并不能扩展到粘膜IgG水平。 这一发现表明，肠病发生在影响粘膜免疫缺陷的严重粘膜B细胞免疫缺陷的子集中，影响了粘膜免疫球蛋白IGA。 鉴于TH1（IL-12驱动）过程是CVID肠病的显着贡献，因此可以合理地假设Ustekinumab给药的IL-12阻断会导致肠道炎症的减少和胃肠道症状的改善。在最初的单剂量研究中，对这种可能性CVID肠病患者（n = 3）接受了uStekinumab的单一诱导剂量（典型70 kg患者）。所有患者均表现出粪便模式的显着改善，从水性一致性变为柔软的一致性。所有3例患者均完成了6个月的随访研究，两名患者观察到持续约4-5个月的临床反应。但是，这些患者中的每一个都有随后的症状复发（腹泻，体重减轻和腹部肿胀的抱怨）。 鉴于这些结果，我们开始了一项新的多剂量研究，其中CVID肠病患者的诱导剂量为270 mg ustekinumab，然后每8周的维持剂量为90 mg Ustekinumab，直到40周40周研究点。 允许对先前在单剂量研究中治疗的受试者进行重新注册，并且所有三个受试者都符合重新注册资格标准。 多剂量研究还招募了另外两个未参加单剂量研究的受试者。 所有受试者均观察到粪便的一致性和频率有所改善，腹痛和腹胀症状的显着改善以及改善的血清白蛋白和总蛋白质水平。 截至2019年12月，该研究已关闭，以应计算中规定的新主题。 所有受试者在2019年8月完成了研究访问/要求。此后不久，完成了样本研究和数据分析。 研究在2020年3月22日到期后未进行研究活动。所有其余的编码研究样本均已存储在89-II-0158方案（自然史研究中的体液免疫缺陷研究）下，将来供将来使用。综上所述，这些研究鼓励人们认为抗IL-12P40（Ustekinumab）给药是对CVID肠病的有用治疗方法。