Th17 lymphocytes in human autoimmune diseases

一种新的T细胞谱系(称为Thl7细胞)的特征是这些淋巴细胞能够分泌高水平的 促炎症细胞因子白介素17(IL-17)水平。小鼠Thl7细胞在许多疾病中发挥关键作用 不同的自身免疫模型以及导致其产生的分化途径 广泛存在于小鼠身上。与之形成鲜明对比的是，Thl7细胞在人类自身免疫性疾病中的作用 很大程度上是未知的，直到最近我们和其他人才确定了驱动Thl7的可溶因素 来自健康人的细胞的分化。在这项提案中，我们将确定小鼠Thl7是否 范例转化为人类自身免疫力。我们将测试Th17细胞数量缺陷的假设， 功能和分化是人类自身免疫性疾病的一个子集，针对这些细胞类型 使用抗IL-17单抗和其他淋巴细胞靶向干预将对 诊所。我们将应用斯坦福大学开发的三个技术平台(自身抗原微阵列、磷光 细胞术、HIT、高通量转录免疫表型)，以及多重 细胞因子/趋化因子分析、荧光激活细胞分选(FACS)和免疫组织化学 描述这些细胞系的特征。这项建议有四个具体目标：(一)来检验这一假设 白介素21(IL-21)是人Thl7分化所必需的；为了识别新的细胞表面标记， 进一步定义Thl7细胞，以提纯活性细胞进行功能研究；来描述数字的特征 血液和炎症组织中Thl7和Th1细胞以及调节性T细胞(Tregs)的功能 来自各种系统性自身免疫性疾病的患者；以及(Iv)在…中进行机械研究 参加ACE资助的多发性自身免疫性疾病临床试验的患者 新兴的生物制剂。拟议中的研究将为人类提供新的机械论见解。 自身免疫，并将开发和传播新的试剂和多重分析平台，供其他 王牌调查员。

A new T cell lineage (termed Thl7 cells) is characterized by the ability of these lymphocytes to secrete high levels of the proinflammatory cytokine interleukin-17 (IL-17). Murine Thl7 cells play critical roles in many different models of autoimmunity, and the differentiation pathways leading to their production have been characterized extensively in mice. In stark contrast, the role of Thl7 cells in human autoimmune diseases is largely unknown, and only recently have we and others identified the soluble factors that drive Thl7 differentiation in cells derived from healthy humans. In this proposal we will determine if the murine Thl7 paradigm translates into human autoimmunity. We will test the hypothesis that defects in Thl7 cell number, function and differentiation underly a subset of human autoimmune diseases, and that targeting these cell types with anti-IL-17 monoclonal antibodies (mAbs) and other lymphocyte-targeted interventions will be effective in the clinic. We will apply three technology platforms developed at Stanford (autoantigen microarrays, phosphoflow cytometry, and HIT, High Throughput Immunophenotyping using Transcription), as well as multiplexed cytokine/chemokine assays, fluorescence activated cell sorting (FACS), and immunohistochemistry to characterize these cell lineages. There are 4 specific aims of this proposal: (i.) to test the hypothesis that interleukin-21 (IL-21) is required for human Thl7 differentiation; (ii.) to identify novel cell surface markers that further define Thl7 cells in order to purify viable cells for functional studies; (iii.) to characterize the number and function of effector Thl7 and Thl cells, and regulatory T cells (Tregs), in blood and inflamed tissue derived from patients with a variety of systemic autoimmune diseases; and (iv.) to perform mechanistic studies in human patients enrolled in ACE-funded clinical trials of multiple autoimmune diseases treated with existing or emerging biologic agents. The proposed studies will provide new mechanistic insights into human autoimmunity, and will develop and disseminate new reagents and multiplexed assay platforms for use by other ACE investigators.