Modeling SLE Nephritis Through Urine MCP-1

描述(由申请人提供)：人类系统性红斑狼疮的肾脏受累很常见，通常很严重。虽然目前的免疫抑制药物可以控制肾性SLE，但如果能够预测狼疮肾红斑狼疮的发生、严重程度或反应，并相应地改进治疗，那么治疗将更有效，毒性更小。目前还没有经过临床验证的生物标志物可以用来可靠地监测整个红斑狼疮周期中的SLE肾脏活动。然而，来自该实验室的最新数据显示，肾炎患者尿液中趋化因子单核细胞趋化蛋白-1(MCP-1)水平显著升高，似乎反映了疾病的活动性和严重性。因此，尿单核细胞趋化蛋白-1(UMCP-1)是反映狼疮性肾炎肾脏炎症程度的生物标志物，可用来预测即将发生的红斑、红斑的严重程度和红斑的预后。本研究的目的是验证UMCP-1作为SLE肾炎、红斑周期和肾炎的生物标志物。研究目标将通过利用俄亥俄SLE研究(OSS)数据库和由俄亥俄州立大学开发的标本库的两个具体目标来实现。OSS包含临床信息和一组特征良好的SLE患者的系列尿样，这些患者在几年内每两个月进行一次前瞻性跟踪。目的1采用双抗体夹心法测定SLE患者肾功能不全前、中、后UMCP-1水平，并与临床病程进行相关性分析。将计算UMCP-1作为红斑发作、严重程度和治疗反应的预测因子的敏感性和特异性，并将评估UMCP-1与SLE的传统临床标志物的相互作用。在目标2中，肾活检时测量的UMCP-1将与浸润性肾白细胞、肾小球新月体、肾小球硬化、间质纤维化和肾小管萎缩相关，以确定UMCP-1水平是否反映了SLE肾炎中发现的影响肾脏存活率的特定肾脏损害。为了测试UMCP-1与肾脏炎症或纤维化的相关性是否更好，将UMCP-1与肾脏炎症的关联强度与UMCP-1与肾脏纤维化的关联强度进行比较。综上所述，本项目有望证明UMCP-1是狼疮性肾炎及其病情的有效生物标志物，并可用于辅助治疗决策。

DESCRIPTION (provided by applicant): Kidney involvement in human SLE is common and usually severe. Although current immunosuppressive drugs can control renal SLE, therapy would be more effective with less toxicity if the onset, severity, or responsiveness of lupus renal flares could be predicted, and treatment modified accordingly. Presently there are no clinically validated biomarkers that can be used to reliably monitor SLE renal activity throughout the flare cycle. However, recent data from this laboratory show that levels of the chemokine monocyte chemoattractant protein-1 (MCP-1) increase significantly in the urine of patients having a renal flare, and appear to reflect disease activity and severity. It was thus postulated that urine MCP-1 (uMCP-1) is a lupus nephritis biomarker that reflects the level of kidney inflammation, and that can be used to predict impending flare, flare severity, and flare prognosis. The purpose of this investigation is to validate uMCP-1 as a biomarker of SLE nephritis flare cycles and renal inflammation. The study goals will be addressed through two Specific Aims that utilize the Ohio SLE Study (OSS) database and specimen bank, developed at Ohio State University. The OSS contains clinical information and serial urine samples from a cohort of well-characterized SLE patients followed prospectively every 2 months over several years. In Aim 1, uMCP-1 levels will be measured by ELISA in samples obtained before, during, and after SLE renal flares, and correlated to clinical course. The sensitivity and specificity of uMCP-1 as a predictor of flare onset, severity, and response to therapy will be calculated, and the interaction of uMCP-1 with traditional clinical markers of SLE will be assessed. In Aim 2, uMCP-1 measured at kidney biopsy will be correlated with infiltrating renal leukocytes, glomerular crescents, glomerulosclerosis, interstitial fibrosis, and tubular atrophy, to determine whether uMCP-1 levels reflect specific renal lesions found in SLE nephritis that can affect kidney survival. To test whether uMCP-1 correlates better with renal inflammation or fibrosis, the strength of the association of uMCP-1 and renal inflammation will be compared to the strength of the association of uMCP-1 and renal fibrosis. In summary, this project is expected to demonstrate that uMCP-1 is a valid biomarker of lupus nephritis and its flare, and can be used to facilitate treatment decisions.