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Research of the roles of PD-1/PD-Ligand in human lupus nephritis and murine lupus-like nephritis

PD-1/PD-Ligand在人狼疮性肾炎和小鼠狼疮样肾炎中的作用研究

基本信息

批准号：
17591042
负责人：
KAWANO Seiji
金额：
$ 2.24万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591042/
关键词：
PD-1 Periferal tolerance Lupus nephritis NZB W PDリガンドマウスモデルシェーグレン症候群

项目摘要

Autoimmune diseases develop as a result of the breakage of tolerance in a combination of genetic backgrounds and various exogenous factors. In lupus nephritis, it is supposed that some unknown factors may trigger and lead to the breakage of peripheral tolerance, resulting in the activation and survival of self-reactive T cells that promote autoimmune process. Recently, B7-CD28 family molecules have revealed their crucial roles in activation and post-activation regulation of T cells. PD-1, one of B7 family receptor and transmitting immunosuppressive signals to lymphocytes, is supposed to be very important in the maintenance of peripheral tolerance, since the murine knockout models have been reported to cause autoimmune-disease-like symptoms. Interestingly, PD-L1 is distributed in epithelia of various peripheral tissues.We analyzed whether there was abnormality of PD-1/PD-L system in a lupus nephritis model, NZB/W F1 mouse, and examined whether lupus-like nephritis develop when you modify the PD-1/PD-L system. We confirmed the expression of PD-1/PD-L1 in the kidney of NZB/W F1 mouse. PD-1 was expressed on infiltrating lymphocytes, and PD-L1 was on infiltrating lymphocytes, glomerular cells, and tubular cells. Next, we performed intraperitoneal injection of anti-PD-L1 antibody to NZB/W F1 mice for three months. Urine protein appeared in the anti-PD-L1 antibody-treated group earlier than in non-treated group, and about half of mice died early in anti-PD-L1 treated group. Therefore, we concluded that the anti-PD-L1 antibody treatment exacerbated nephritis. In addition, serum interferon γ level was markedly increased in antibody-treated group.In conclusion, PD-1/PD-L system is closely related to the development of lupus-like nephrits, and we expect that future studies will help to develop a therapeutic method to cure lupus nephritis, or other autoimmune diseases.

自身免疫性疾病的发展是由于遗传背景和各种外源性因素组合的耐受性破坏的结果。在狼疮性肾炎中，一些未知因素可能触发并导致外周免疫耐受的破坏，导致自身反应性T细胞的激活和存活，从而促进自身免疫过程。最近，B7-CD 28家族分子在T细胞活化和活化后调节中的关键作用被揭示。PD-1是B7家族的受体之一，能将免疫抑制信号传递给淋巴细胞，在维持外周免疫耐受中起着重要作用。有趣的是，PD-L1分布在各种外周组织的上皮细胞中，我们分析了在狼疮肾炎模型NZB/W F1小鼠中PD-1/PD-L系统是否存在异常，并检查了当你改变PD-1/PD-L系统时是否会发生狼疮样肾炎。我们证实了PD-1/PD-L1在NZB/WF 1小鼠肾脏中的表达。PD-1在浸润淋巴细胞上表达，PD-L1在浸润淋巴细胞、肾小球细胞和肾小管细胞上表达。接下来，我们对NZB/W F1小鼠进行抗PD-L1抗体腹膜内注射三个月。抗PD-L1抗体治疗组小鼠尿蛋白出现时间早于未治疗组，抗PD-L1抗体治疗组约半数小鼠早期死亡。因此，我们得出结论，抗PD-L1抗体治疗加重了肾炎。结论：PD-1/PD-L系统与狼疮样肾炎的发生发展密切相关，未来的研究将有助于开发治疗狼疮性肾炎或其他自身免疫性疾病的方法。