ICOS and PD-1 Pathways: Regulators of Lupus Nephritis

ICOS 和 PD-1 通路：狼疮性肾炎的调节因子

• 批准号: 6821804
• 负责人: Vicki Rubin Kelley
• 金额: $ 34.85万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6821804
• 关键词: antigen presenting cell; biological signal transduction; flow cytometry; gene expression; genetically modified animals; immune response; laboratory mouse; leukocyte activation /transformation; ligands; lupus nephritis; podocyte; polymerase chain reaction; renal tubule; western blottings

DESCRIPTION (provided by applicant): Renal parenchymal cells, tubular epithelial cells (TEC) and/or antigen presenting cells (APC) interact with kidney infiltrating T cells and provide signals that drive, or halt T cell activation. The MRL-Faslpr model is appealing to dissect intrarenal signals that regulate lupus nephritis, and the systemic illness, since it shares features with human lupus. The CD28/CTLA4-B7 family of molecules provides positive and negative signals that regulate T cell activation. There are two newly identified members; 1) the inducible costimulator (ICOS), and its ligand ICOS-L that imparts positive and negative signals that regulate T cell activation, and 2) programmed death-1 (PD-1), and its ligands PD-L1 and PD-L2, that solely deliver negative signals that terminate immune responses. We hypothesize that the ICOS and PD-1 T cell pathways regulate immune responses and disease initiation/progression in lupus nephritis. The overall goal is to dissect the functions of these pathways, and investigate the mechanisms by which renal parenchymal cells, and APC regulate lupus nephritis. The specific aims are: 1) To determine the temporal expression, magnitude, and localization of the iCOS/ICOS-L and PD-1/PD-L1 molecules during lupus nephritis, and the systemic illness in mice. We will correlate ICOS and PD-1 expression patterns with MRL-Faslpr renal pathology and the systemic illness; determine their regulation on TEC; and compare the intrarenal ICOS and PD-1 pathway expression in several mouse strains with lupus nephritis. 2) To establish whether blocking the ICOS pathway regulates lupus nephritis in MRL (+/- Faslpr) mice. We will determine whether deleting ICOS, and blocking ICOS and ICOS-L in MRL mice alters the tempo and severity of lupus nephritis and the systemic illness; and establishes whether ICOS-L on TEC regulates T cell activation. 3) To establish whether blocking the PD-1 pathway regulates lupus nephritis in MRL mice. We will test the hypothesis that the PD-1 pathway provides a negative regulatory signal to block intrarenal T cell activation. We will determine whether deleting PD-L1, and blocking PD-1/PD-LI/PD-L2 during lupus nephritis in MRL mice, worsens disease. We will determine whether B7-1/B7-2 T cell activation signals over-ride the PD-1 pathway inhibitory signals; establish whether altered nephritis in PD-L1 deficient MRL mice is a result of deleting PD-L1 on leukocytes and/or on renal parenchymal cells; and determine whether TEC expressing PD-L1 inhibit T cell activation. Our ultimate goal is to determine whether ICOS and PD-1 pathways are potential therapeutic targets for lupus nephritis.

描述（由申请人提供）：肾实质细胞，管状上皮细胞（TEC）和/或抗原呈递细胞（APC）与肾脏浸润的T细胞相互作用，并提供驱动或停止T细胞激活的信号。 MRL-FASLPR模型吸引了剖析调节狼疮肾炎和全身性疾病的肾内信号，因为它与人类狼疮具有共同的特征。 CD28/CTLA4-B7分子家族提供了调节T细胞激活的正和负信号。有两个新确定的成员； 1）可诱导的共刺激剂（ICOS）及其配体ICOS-L赋予调节T细胞激活的正和负信号，以及2）编程死亡-1（PD-1）及其配体PD-L1和PD-L1 ，这仅提供终止免疫反应的负信号。我们假设ICOS和PD-1 T细胞途径调节狼疮肾炎中的免疫反应和疾病起步/进展。总体目标是剖析这些途径的功能，并研究肾实质细胞和APC调节狼疮肾炎的机制。具体目的是：1）确定狼疮肾炎期间ICOS/ICOS-L和PD-1/PD-L1分子的时间表达，大小和定位，以及小鼠的全身性疾病。我们将将ICO和PD-1表达模式与MRL-FASLPR肾脏病理和全身性疾病相关联；确定他们对TEC的调节；并比较狼疮性肾炎的几种小鼠菌株中肾内ICOS和PD-1途径的表达。 2）确定阻塞ICOS途径是否调节MRL（+/- FASLPR）小鼠中的狼疮肾炎。我们将确定在MRL小鼠中删除ICO，并阻止ICOS和ICOS-L会改变狼疮肾炎和全身性疾病的速度和严重程度。并确定ICOS-L对TEC是否调节T细胞激活。 3）确定阻塞PD-1途径是否调节MRL小鼠中的狼疮肾炎。我们将检验以下假设：PD-1途径提供了负调控信号以阻止肾内T细胞激活。我们将确定在MRL小鼠的狼疮肾炎期间删除PD-L1以及阻止PD-1/PD-1/PD-LI/PD-L2会使疾病恶化。我们将确定B7-1/B7-2 T细胞活化信号是否超过PD-1途径抑制信号；确定PD-L1缺乏的MRL小鼠中肾炎的改变是在白细胞上删除PD-L1和/或肾实质细胞上的PD-L1的结果。并确定表达PD-L1的TEC是否抑制T细胞活化。我们的最终目标是确定ICOS和PD-1途径是否是狼疮肾炎的潜在治疗靶标。