Expanded double negative T cells in SLE

描述（由申请人提供）：系统性红斑狼疮折磨着100万至200万美国人，并与显著的发病率和死亡率相关。虽然在过去的30年里，类固醇和细胞毒药物的明智使用以及抗生素的有效使用使总体生存率和生活质量显著提高，但我们仍然缺乏具体的治疗方法，其中，缺乏对相关致病机制和适当的疾病生物标志物的充分了解是造成这种情况的原因。系统性红斑狼疮（SLE）患者的免疫细胞和细胞因子异常是多种多样的，包括细胞毒性反应下降、活化诱导细胞死亡减少、T调节功能下降、树突状细胞功能增加、IFNa、IL-6增加和IL-2、IFN？和TNFa的生产。不同的分子和生化异常可以解释一些细胞和细胞因子异常。在外周T细胞中，存在大量缺乏表面CD4和CD8的T细胞（双阴性（DN） T细胞），当与自体B细胞共培养时，它们促进了免疫球蛋白和抗dsdna的产生。我们最近发现SLE患者的这种DN T细胞群可以在体外扩增，它产生IL-17，更重要的是，产生IL-17的DN T细胞浸润到狼疮肾炎患者的肾组织中。因此，我们提出，SLE患者中扩大的DN T细胞群产生IL-17并参与靶器官损伤。我们将在本申请中概述的实验中测试我们的论文，并分为四个具体目标：在第一个目标中，我们将在sle患者中建立CD4+和扩增的DN T细胞产生IL-17的存在-确定临床相关性。在第二篇文章中，我们将确定SLE患者DN T细胞的起源、扩增的需求、它们的早期和晚期信号特征以及它们对细胞控制机制的易感性。第三，我们将确定SLE中TH17生成的要求。最后，我们研究SLE中浸润靶组织的T细胞的性质，并探索导致不适当归巢的机制。这些研究旨在提出IL-17作为SLE患者的新治疗靶点，并将产生将Th17细胞作为疾病活性生物标志物的信息。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus afflicts 1 to 2 million Americans and is associated with significant morbidity and mortality. While wise use of steroids and cytotoxics drugs along with effective use of antibiotics overall survival and quality of life have increased significantly over the last 30 years, we still lack specific treatment, and among others, the lack of full understanding of involved pathogenic mechanisms and of proper disease biomarkers are to be blamed for this. Immune cell and cytokine abnormalities in patients with systemic lupus erythematosus (SLE) are diverse and involve among others decreased cytotoxic responses, decreased activation induced cell death, decreased T regulatory function, increased dendritic cell function, increased IFNa, IL-6 and decreased IL-2, IFN? and TNFa production. Distinct molecular and biochemical abnormalities may account for several cell and cytokine abnormalities. Among peripheral T cells an expanded population of T cells missing CD4 and CD8 from the surface (double negative (DN) T cells exists which when placed in coculture with autologous B cells promoted the production of immunoglobulin and anti-dsDNA. We have recently found that this DN T cell population in SLE patients can be expanded in vitro and that it produces IL- 17 and more importantly, IL-17 producing DN T cells infiltrated kidney tissue of patients with lupus nephritis. We propose, accordingly, that an expanded DN T cell population in patients with SLE produces IL-17 and participates in target organ damage. We will test our thesis in experiments outlined in this application and grouped in four specific aims: In the first aim we will establish the presence of CD4+ and expanded DN T cells producing IL-17 in patients with SLE-determine clinical correlations. In the second we will determine the origin of DN T cells is SLE patients, the requirements for expansion, their early and late signaling profile and their susceptibility to cellular control mechanisms. In the third we will determine the requirements for the generation of TH17 in SLE. In the last aim we study the nature of T cells that infiltrate target tissues in SLE and explore mechanisms which are responsible for the inappropriate homing. These studies intend to propose IL-17 as a novel treatment target in SLE patients and will generate information which will propose Th17 cells as a biomarker of disease activity.