Cytokine receptor populations in human autoimmune diabetes

描述(申请人提供)：1型糖尿病(T1D)，是针对产生胰岛素的胰岛细胞的自身免疫导致的，对健康和生活质量有毁灭性的影响。在这项应用中，我们建议研究CD8T细胞的一个重要新亚群在新发糖尿病患者中的作用。这一群体由IL-18受体(IL-18R)的表达所定义，并包含具有先天和效应特征的细胞。这项应用的目标是了解IL-18R阳性的CD8 T细胞的作用 人类T1D亚群。这项工作之所以重要，有几个原因。首先，这种扩大的和独特的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被描述过。第二，IL-18及其受体是自身免疫性疾病的危险因素，提示这些因素可能诱导与1型糖尿病相关的自身免疫反应。第三，IL-18结合蛋白已经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进行结合蛋白的临床试验提供基础。第四，这种特定细胞群的存在可以作为疾病易感性的替代标记，并识别对结合蛋白治疗有阳性反应的患者。第五，我们的结果将为人类糖尿病中这种细胞群的激活和致病性提供关键的“概念证据”数据。第六，这些研究将揭示刺激或抑制这一细胞群体致病潜力的循环因子的作用。因此，我们的方法将 为新发糖尿病患者阻断IL-18R途径的临床试验提供新的发现。

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.