CD8(+) T cells modulate autosomal dominant polycystic kidney disease progression.
CD8(+) T cells modulate autosomal dominant polycystic kidney disease progression.
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DOI：
10.1016/j.kint.2018.06.025
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发表时间：
2018-12
影响因子：
19.6
通讯作者：
Hopp K
中科院分区：
文献类型：
--
作者：
Kleczko EK;Marsh KH;Tyler LC;Furgeson SB;Bullock BL;Altmann CJ;Miyazaki M;Gitomer BY;Harris PC;Weiser-Evans MCM;Chonchol MB;Clambey ET;Nemenoff RA;Hopp K
常染色体显性遗传性多囊肾病（ADPKD）是最常见的遗传性肾病。迄今为止，缓解该疾病的疗法主要集中在靶向肾上皮细胞信号传导的异常。ADPKD具有许多癌症特征，靶向T细胞带来了新的治疗干预措施。然而，对T细胞在ADPKD中的作用和治疗潜力知之甚少。在这里，我们使用了一个orthopathic ADPKD模型，Pkd 1 p.R3277 C（RC），开始定义T细胞在疾病进展中的作用。使用流式细胞术，我们发现肾脏CD 8+和CD 4 + T细胞进行性增加，与疾病的严重程度相关，但与CD 8 + T细胞的选择性激活。通过免疫荧光，在小鼠、患者和ADPKD上皮细胞系的肾脏中，通过qPCR/原位杂交检测到特异性定位于囊性病变的T细胞和增加水平的T细胞募集趋化因子（CXCL 9/CXCL 10）。重要的是，与IgG对照组相比，C57 Bl/6 Pkd 1 RC/RC小鼠中1至3个月的CD 8 + T细胞免疫耗竭导致ADPKD病理学恶化，细胞凋亡减少，增殖增加，与CD 8 + T细胞的肾脏保护作用一致。因此，我们的研究表明T细胞，特别是CD 8 + T细胞在ADPKD进展中的功能作用。因此，使用免疫肿瘤学药物靶向该途径可能代表ADPKD的新治疗方法。
Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent inherited nephropathy. To date, therapies alleviating the disease have largely focused on targeting abnormalities in renal epithelial cell signaling. ADPKD has many hallmarks of cancer, where targeting T cells has brought novel therapeutic interventions. However, little is known about the role and therapeutic potential of T cells in ADPKD. Here, we used an orthologous ADPKD model, Pkd1 p.R3277C (RC), to begin to define the role of T cells in disease progression. Using flow cytometry, we found progressive increases in renal CD8+ and CD4+ T cells, correlative with disease severity, but with selective activation of CD8+ T cells. By immunofluorescence, T cells specifically localized to cystic lesions and increased levels of T-cell recruiting chemokines (CXCL9/CXCL10) were detected by qPCR/in situ hybridization in the kidneys of mice, patients, and ADPKD epithelial cell lines. Importantly, immunodepletion of CD8+ T cells from one to three months in C57Bl/6 Pkd1RC/RC mice resulted in worsening of ADPKD pathology, decreased apoptosis, and increased proliferation compared to IgG-control, consistent with a reno-protective role of CD8+ T cells. Thus, our studies suggest a functional role for T cells, specifically CD8+ T cells, in ADPKD progression. Hence, targeting this pathway using immune-oncology agents may represent a novel therapeutic approach for ADPKD.
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