Th17 lymphocytes in human autoimmune diseases

一种新的T细胞谱系（称为Thl 7细胞）的特征在于这些淋巴细胞分泌高表达的T细胞的能力。 促炎细胞因子白细胞介素-17（IL-17）水平。鼠Thl 7细胞在许多免疫系统中起关键作用。 不同的自身免疫模型，以及导致其产生的分化途径， 在小鼠中广泛表现。与此形成鲜明对比的是，Thl 7细胞在人类自身免疫性疾病中的作用被忽视。 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Thl 7的可溶性因子 来自健康人的细胞的分化。在该提议中，我们将确定鼠Thl 7是否在小鼠体内表达。 这种模式转化为人类自身免疫。我们将检验Th 17细胞数量缺陷， 功能和分化是人类自身免疫性疾病的一个子集的基础， 抗IL-17单克隆抗体（mAb）和其他淋巴细胞靶向干预将有效地 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，磷酸流 流式细胞术，和HIT，使用转录的高重复免疫表型分析），以及多重 细胞因子/趋化因子测定、荧光激活细胞分选（FACS）和免疫组织化学， 描述这些细胞谱系。该提案有四个具体目标：（一）来验证一个假设 白细胞介素-21（IL-21）是人Thl 7分化所需的;（ii.）以鉴定新的细胞表面标记物， 进一步定义Thl 7细胞以纯化活细胞用于功能研究;（iii.）来描述这个数字 以及效应子Th 17和Th 1细胞以及调节性T细胞（T细胞）在血液和炎性组织中的功能 来自患有多种系统性自身免疫疾病的患者;和（iv.）进行机械研究， 参与ACE资助的多种自身免疫性疾病临床试验的人类患者， 新兴生物制剂。这些研究将为人类的行为提供新的机制见解。 自身免疫，并将开发和传播新的试剂和多重检测平台，供其他 ACE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.