Characterization and function of regulatory T cells in glomerulonephritis

肾小球肾炎中调节性 T 细胞的特征和功能

• 批准号: 138669447
• 负责人: Professorin Dr. Gisa Tiegs
• 金额: --
• 依托单位: Institut für Experimentelle Immunologie und Hepatologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/138669447?language=en
• 关键词: Characterization; function; regulatory; cells; glomerulonephritis

CD4+CD25+Foxp3+ regulatory T cells (Tregs) are of critical importance for the maintenance of peripheral tolerance and prevention of autoimmunity. If autoimmune responses target the kidney, glomerulonephritis (GN) may develop. To analyse the role of endogenous Tregs for regulation of GN, we used “depletion of regulatory T cell” (DEREG) mice which express the diphtheria toxin (DTx) receptor under control of the Foxp3 promoter. In a murine model of crescentic glomerulonephritis, Treg depletion upon DTx injection exacerbated the Th1 response and resulted in an aggravated course of GN. Interestingly, Treg depletion in nephritic DEREG mice resulted in an increased renal IL-10 and PD-1 expression. In the first part of the project, IL-10-producing cell populations in renal tissue, in particular following Treg depletion, will be identified by using different transgenic mouse strains. Candidate cells are CD4+Foxp3- T cells, dendritic cells, macrophages, or regulatory B cells. In the second part, the therapeutic potential of these putative suppressor cells will be analysed by adoptive cell transfer experiments. Finally, co-inhibitory molecules such as PD-1/PD-L1 will be analysed with respect to their cellular expression and protective function in nephrotoxic serum nephritis. The aim will be the characterization of the regulatory cell subpopulation which is most efficient for treatment of GN.

CD4+CD25+Foxp3+调节性T细胞(Tregs)对于维持外周免疫耐受和预防自身免疫具有重要作用。如果自身免疫反应针对肾脏，则可能发展为肾小球肾炎(GN)。为了分析内源性Tregs对GN的调节作用，我们使用了在Foxp3启动子控制下表达白喉毒素(DTX)受体的“调节性T细胞耗竭”(DEREG)小鼠。在新月体肾炎的小鼠模型中，DTX注射后Treg的耗尽加剧了Th1反应，并导致了GN的加重。有趣的是，肾炎性DEREG小鼠的Treg缺失导致肾脏IL-10和PD-1表达增加。在该项目的第一部分，将通过使用不同的转基因小鼠品系来鉴定肾组织中产生IL-10的细胞群，特别是在Treg耗尽后。候选细胞包括CD4+Foxp3-T细胞、树突状细胞、巨噬细胞或调节性B细胞。在第二部分中，将通过过继细胞转移实验来分析这些假定的抑制细胞的治疗潜力。最后，将分析PD-1/PD-L1等共抑制分子在肾毒性血清性肾炎中的细胞表达和保护作用。其目的将是确定对治疗肾炎最有效的调节细胞亚群的特征。