Cytokine receptor populations in human autoimmune diabetes

人类自身免疫性糖尿病中的细胞因子受体群体

• 批准号: 9096009
• 负责人: Nora E Sarvetnick
• 金额: $ 48.64万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096009
• 关键词: Affect; Animals; Antigens; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding Proteins; Blood; CD8 receptor; CD8B1 gene; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cytokine Receptors; Data; Development; Diabetes Mellitus; Disease; Disease susceptibility; Environment; Flow Cytometry; Goals; Health; Human; Immune; Immune system; Individual; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-18; Investigation; Islet Cell; Knowledge; Leukocytes; Licensing; Ligands; Maintenance; Measures; Modeling; Onset of illness; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Population; Prevention; Quality of life; Reaction; Recording of previous events; Research; Rheumatoid Arthritis; Risk Factors; Role; Sampling; Stimulus; Surrogate Markers; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Intervention; Tissues; Viral; Work; base; cytokine; data access; diabetes control; diabetic; expectation; interleukin-18 receptor; islet; mouse model; non-diabetic; novel; pathogen; receptor; response; type I diabetic

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D), which results from autoimmunity directed against insulin-producing islet cells, has devastating effects on health and quality of life. In this application we propose to investigate the role of an important new subpopulation of CD8 T cells in new-onset diabetes patients. This population is defined by expression of the IL-18 receptor (IL-18R) and contains cells with both innate and effector features. The goal of this application is to understand the role of this IL-18R-positive CD8 T cell subpopulation in human T1D. This work is important for several reasons. First, this expanded and unique T cell subpopulation has never been described in circulating leukocytes of new-onset human Type 1 diabetics. Second, IL-18 and its receptor are risk factors for autoimmune diseases, indicating that these factors may induce autoimmune reactions related to type 1 diabetes. Third, the IL-18 binding protein has been evaluated for its use in clinical trials for rheumatoid arthritis, and the work described here could provide the basis for clinical trials with the binding protein in diabetes patients. Fourth, the presence of this specific cell population could be developed as a surrogate marker for disease susceptibility and identify patients who would respond positively to treatment with the binding protein. Fifth, our results will provide critical "proof of concept" data on the activation and pathogenicity of this cell population in human diabetes. Sixth, these investigations will uncover the role of circulating factors that stimulate or inhibit the pathogenic potential of this cell population. Therefore, our approach will provide novel findings facilitating clinical trials blocking the IL-18R pathway in new-onset diabetes patients.

描述（由申请人提供）：1型糖尿病（T1 D）是由针对产生胰岛素的胰岛细胞的自身免疫引起的，对健康和生活质量具有破坏性影响。在本申请中，我们提出研究一个重要的新的CD 8 T细胞亚群在新发糖尿病患者中的作用。该群体由IL-18受体（IL-18 R）的表达定义，并且包含具有先天和效应子特征的细胞。本申请的目的是了解这种IL-18 R阳性CD 8 T细胞在免疫调节中的作用。 人类T1 D亚群。这项工作之所以重要，有几个原因。首先，这种扩增和独特的T细胞亚群从未在新发人类1型糖尿病患者的循环白细胞中描述过。其次，IL-18及其受体是自身免疫性疾病的危险因素，表明这些因素可能诱发与1型糖尿病相关的自身免疫反应。第三，IL-18结合蛋白已被评估用于类风湿性关节炎的临床试验，这里描述的工作可以为糖尿病患者的结合蛋白的临床试验提供基础。第四，这种特异性细胞群的存在可以被开发为疾病易感性的替代标志物，并识别对结合蛋白治疗有积极反应的患者。第五，我们的研究结果将提供关键的“概念验证”数据，该细胞群在人类糖尿病中的激活和致病性。第六，这些研究将揭示刺激或抑制该细胞群致病潜力的循环因子的作用。因此，我们的方法将 提供了新的发现，促进了在新发糖尿病患者中阻断IL-18 R通路的临床试验。