Significance of Intrarenal T Cells in SLE Nephritis

 描述（由申请人提供）：本研究的目的是促进对T细胞在慢性狼疮肾炎（LN）发生和进展中的作用的理解。它解决了临床问题，为什么在近一半的情况下，LN不响应治疗和进展为慢性肾小球肾炎。初步数据显示LN肾活检具有可变的克隆扩增的CD 4和/或CD 8 T细胞浸润，其特征表明这些细胞驱动炎症过程。某些肾活检显示具有CD 28无效记忆效应表型的克隆扩增的CD 8 T细胞，其以类似于细胞毒性细胞突触的方式粘附于鲍曼氏囊或肾小管上皮。对肾功能减退的患者重复活检，这些相同的克隆型持续多年，广泛分布于肾小球周围和小管内，并在外周血中发现。CD 4 T细胞以两种不同的模式存在：大的弥漫性肾小球周围和肾小管间聚集体，其中一些表现为多克隆或作为记忆效应表型T细胞粘附于鲍曼氏囊或肾小管，类似于CD 8 T细胞。克隆扩增的记忆效应CD 8 T细胞的适应性免疫反应的功能的发现不适合目前的LN的范例，我们提出的假设，而急性肾小球炎是由免疫复合物驱动，慢性LN是由CD 4，特别是CD 8 T细胞克隆识别自身肽的发展，导致肾小球和肾小管细胞损伤。在第一个目标中，我们将描述肾内浸润性CD 4或CD 8+细胞的程度和详细特征。 CD 8 T细胞在新发肾炎中的作用及其在肾损伤中的作用我们将区分可能驱动肾损伤的克隆扩增的CD 4或CD 8 T细胞和炎症继发招募的多克隆T细胞。我们将这些发现与结果相关联，以确定T细胞浸润的特征，这些特征预测对治疗的不良反应和进行性肾脏疾病。在第二个目标中，我们将类似地确定T细胞特征的情况下， 慢性LN伴肾脏受累恶化，需要重复活检，比较当前和既往活检肾内T细胞的特征，可能预测进展。

 DESCRIPTION (provided by applicant): The goal of this study is to advance understanding of the role of T cells in the development and progression of chronic lupus nephritis (LN). It addresses the clinical problem of why in nearly half of cases, LN does not respond to therapy and progress to chronic glomerulonephritis. Preliminary data show LN kidney biopsies have a variable infiltrate of clonally expanded CD4 and/or CD8 T cells with features suggesting these cells drive the inflammatory process. Certain kidney biopsies exhibit clonally expanded CD8 T cells with a CD28null memory effector phenotype that adhere to Bowman's capsule or to tubular epithelium in a manner resembling a cytotoxic cell synapse. On repeat biopsies of patients with diminishing renal function, these same clonotypes persisted for many years, became widely distributed in periglomerular and intratubular sites, and were found in the peripheral blood. CD4 T cells exist in two different patterns: large diffuse periglomerular and intertubular aggregates, some of which appear either polyclonal or as a memory effector phenotype T cell adhering to Bowman's capsule or tubules, similar to the CD8 T cells. The finding of clonally expanded memory-effector CD8 T cells with features of an adaptive immune response does not fit the current paradigms of LN, and we advance the hypothesis that while acute glomerulitis is driven by immune complexes, chronic LN is driven by the development of CD4 and especially CD8 T cell clonal recognition of self-peptides, resulting in glomerular and tubular cell injury. In the frst aim we will delineate the extent and detailed characteristics of the infiltrating intrarenal CD4 or CD8 T cells in new onset nephritis and define their role in renal injury. We will discriminate between clonally expanded CD4 or CD8 T cells that potentially drive renal injury and polyclonal T cells secondarily recruited by inflammation. We will correlate these findings with outcomes to identify features in the T cell infiltrate that predict poor response to therapy and progressive renal disease. In the second aim we will similarly determine the T cell characteristics of cases of chronic LN with worsening renal involvement requiring repeat biopsy, comparing current and prior biopsies for the features of intrarenal T cells that might predict progression.