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，粘膜免疫科参与了一些正在进行的和新的研究，涉及炎症性肠病和常见可变免疫缺陷患者。