The Cell Type Specific Immune Regulatory Functions of Amphiregulin in Glomerulonephritis

双调蛋白在肾小球肾炎中的细胞类型特异性免疫调节功能

• 批准号: 421050765
• 负责人: Professor Dr. Oliver Michael Steinmetz
• 金额: --
• 依托单位: III. Medizinische Klinik und Poliklinik (Nephrologie, Rheumatologie - Nierentransplantation - Sektion Endokrinologie/Diabetologie)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/421050765?language=en
• 关键词: Cell; Type; Specific; Immune; Regulatory

Glomerulonephritis (GN) remains a leading cause of end stage renal disease worldwide. Autoimmune diseases like anti neutrophil cytoplasmic antibody (ANCA) associated vasculitis and systemic lupus erythematosus (SLE) are typical underlying pathologies. Since currently available therapies are rather non-specific and relatively toxic, the search for new and innovative therapeutic options is highly rewarding. A novel and promising therapeutic target is the multi-functional cytokine Amphiregulin (AREG). AREG belongs to the epidermal growth factor (EGF) family and mediates its effects via binding to the promiscuous EGF-receptor (EGFR). Recent studies, including our own data from the past funding period, have identified AREG as an important mediator of inflammatory diseases. A better understanding of AREG´s immune functions is highly warranted, since EGFR blockers are already in use for tumor therapy and various AREG directed compounds are currently being developed, so that they could also be applied to treat immune mediated diseases. It is of note, however, that both, pro- as well as anti-inflammatory AREG effects have been reported. In this respect, data by us and others suggest, that the cellular source of AREG might be important for the resulting function. While resident tissue cell derived AREG seems to have pro-inflammatory and pro-fibrotic effects, leukocyte derived AREG was shown to be predominantly anti-inflammatory and reparative. One main goal of the current grant application is thus to clarify the cell type specific differential roles of AREG in acute GN and chronically developing lupus nephritis to lay the groundwork for AREG directed therapies. The second main goal will be characterization of the currently ill-defined immune-regulatory mechanisms initiated by AREG signaling. Previous studies, including our data from the past funding period have pointed towards strong immunosuppressive effects of AREG on CD4+ T cell responses. We thus aim to in depth analyze the clinical relevance of this observation, and to identify the cellular players and signaling pathways involved herein. Models used will include antigen specific immunization, nephrotoxic nephritis (NTN), which resembles human rapidly progressive GN, as well as one inducible (pristane) and one genetic (MRL/lpr) model of SLE. Finally, we will translate our findings to human GN and characterize AREG expression by its different cellular sources in lupus nephritis patients from French and German collectives, using RNAseq and multiplex immunofluorescence techniques. Our findings will be correlated with clinical and histopathological data and provide the basis for evaluation of AREG as a prognostic biomarker as well as for interventions against the AREG/EGFR axis as novel option for the treatment of GN.

肾小球肾炎（GN）仍然是全世界终末期肾病的主要原因。自身免疫性疾病，如抗中性粒细胞胞浆抗体（ANCA）相关血管炎和系统性红斑狼疮（SLE）是典型的潜在病理。由于目前可用的疗法相当非特异性且毒性相对较大，因此寻找新的和创新的治疗选择是非常有价值的。多功能细胞因子双调蛋白（AREG）是一个新颖且有前途的治疗靶点。 AREG 属于表皮生长因子 (EGF) 家族，通过与混杂的 EGF 受体 (EGFR) 结合来介导其作用。最近的研究，包括我们自己在过去资助期间的数据，已确定 AREG 是炎症性疾病的重要介质。更好地了解 AREG 的免疫功能是非常有必要的，因为 EGFR 阻滞剂已经用于肿瘤治疗，并且目前正在开发各种 AREG 定向化合物，因此它们也可以用于治疗免疫介导的疾病。然而，值得注意的是，AREG 的促炎作用和抗炎作用均已被报道。在这方面，我们和其他人的数据表明，AREG 的细胞来源可能对最终的功能很重要。虽然驻留组织细胞来源的 AREG 似乎具有促炎和促纤维化作用，但白细胞来源的 AREG 主要具有抗炎和修复作用。因此，当前拨款申请的一个主要目标是阐明 AREG 在急性肾小球肾炎和慢性狼疮肾炎中的细胞类型特异性差异作用，为 AREG 定向治疗奠定基础。第二个主要目标是描述目前由 AREG 信号传导启动的不明确的免疫调节机制。之前的研究，包括我们过去资助期的数据，都表明 AREG 对 CD4+ T 细胞反应具有强烈的免疫抑制作用。因此，我们的目标是深入分析这一观察结果的临床相关性，并确定其中涉及的细胞参与者和信号通路。使用的模型将包括抗原特异性免疫、肾毒性肾炎（NTN）（类似于人类快速进展的肾小球肾炎），以及一种诱导型（降植烷）和一种遗传型（MRL/lpr）SLE模型。最后，我们将把我们的研究结果转化为人类 GN，并使用 RNAseq 和多重免疫荧光技术，表征法国和德国狼疮肾炎患者中不同细胞来源的 AREG 表达。我们的研究结果将与临床和组织病理学数据相关，并为评估 AREG 作为预后生物标志物以及针对 AREG/EGFR 轴的干预措施作为治疗 GN 的新选择提供基础。