T cell costimulatory blockade ameliorates induction of experimental membranous nephropathy potentially through T-helper 17 cell suppression in the kidney.

IF 5.6 2区医学 Q1 TRANSPLANTATION Nephrology Dialysis Transplantation Pub Date : 2025-10-30 DOI:10.1093/ndt/gfaf030

Edmund Y M Chung, Yuan Min Wang, Karli Shaw, Emily Ronning, Ya Wang, Geoff Yu Zhang, Min Hu, Karen Keung, Hugh J McCarthy, David C H Harris, Stephen I Alexander

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Abstract

Background and hypothesis: Recent advances in membranous nephropathy treatment have focused on B cell depletion, which is incompletely effective, potentially due to persistent autoantibody-producing plasma cells or alternative pathways of injury. T cell costimulatory blockade [cytotoxic-T-lymphocyte-associated antigen 4 (CTLA4)-Ig] to prevent T cell-dependent B cell activation and short-course proteasome inhibition (bortezomib) to deplete plasma cells may represent a complementary form of treatment.

Methods: Lewis rats were immunized with Fx1A and complete Freund's adjuvant to induce experimental membranous nephropathy (Heymann nephritis or HN) and treated with CTLA4-Ig alone or CTLA4-Ig plus a short-course of bortezomib. Serum creatinine, proteinuria, kidney histology, serum anti-Fx1A levels, kidney and spleen messenger RNA expression, and flow cytometry on splenocytes were evaluated at 12 weeks.

Results: CTLA4-Ig-treated and CTLA4-Ig plus bortezomib-treated rats had significant and similar reductions in serum creatinine and proteinuria, with less histological kidney injury compared with untreated HN rats. Glomerular IgG deposition was reduced in CTLA4-Ig-treated and CTLA4-Ig plus bortezomib-treated rats compared with untreated HN rats but there were no significant differences in serum anti-Fx1A levels. CTLA4-Ig-treated and CTLA4-Ig plus bortezomib-treated rats exhibited significantly reduced T helper (Th)-17 cell cytokines (interleukin-6, -17, -21) and regulatory T cell (Foxp3, TGF-β) expression in the kidney but not the spleen. Immunohistochemical staining of CD4+ and intracellular STAT3+ cells was reduced in CTLA4-Ig plus bortezomib-treated and CTLA4-Ig-treated compared with untreated HN rats. On flow cytometry, CTLA4-Ig reduced B cells and plasma cells but not T cell subsets.

Conclusions: CTLA4-Ig ameliorated induction of experimental membranous nephropathy, potentially through suppression of Th17 cells in the kidney, and may represent an effective adjunct treatment in membranous nephropathy.

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T细胞共刺激阻断可能通过抑制肾中的T-辅助性17细胞改善实验性膜性肾病的诱导。

背景和假设：最近膜性肾病的治疗进展主要集中在B细胞耗竭上，但这种方法并不完全有效，可能是由于持续产生自身抗体的浆细胞或其他损伤途径。T细胞共刺激阻断（细胞毒性T淋巴细胞相关抗原4 (CTLA4)-Ig）防止T细胞依赖性B细胞活化和短期蛋白酶体抑制（硼替佐米）消耗浆细胞可能是一种补充治疗形式。方法：用Fx1A和完全弗氏佐剂（CFA）免疫Lewis大鼠诱导实验性膜性肾病（Heymann肾炎或HN），并单独或联合短疗程硼替佐米治疗。12周时测定血清肌酐、蛋白尿、肾脏组织学、血清抗fx1a水平、肾脏和脾脏信使RNA表达以及脾细胞流式细胞术。结果：CTLA4-Ig处理和CTLA4-Ig +硼替佐米处理的大鼠血清肌酐和蛋白尿显著降低，与未处理的HN大鼠相比，组织学肾损伤较小。与未治疗的HN大鼠相比，CTLA4-Ig处理和CTLA4-Ig加硼替佐米处理的大鼠肾小球IgG沉积减少，但血清抗fx1a水平无显著差异。CTLA4-Ig处理和CTLA4-Ig +硼替佐米处理的大鼠肾脏中T辅助细胞(Th)-17细胞因子（白细胞介素(IL)-6、IL-17、IL-21）和调节性T细胞（Foxp3、TGF-β）表达显著降低，但脾脏中没有。与未处理的HN大鼠相比，CTLA4-Ig +硼替佐米处理和CTLA4-Ig处理的CD4+和细胞内STAT3+细胞的免疫组化染色降低。流式细胞术显示，CTLA4-Ig减少了B细胞和浆细胞，但没有减少T细胞亚群。结论：CTLA4-Ig可能通过抑制肾中Th17细胞改善实验性膜性肾病的诱导，可能是膜性肾病的有效辅助治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nephrology Dialysis Transplantation 医学-泌尿学与肾脏学

CiteScore

10.10

自引率

4.90%

发文量

1431

审稿时长

1.7 months

期刊介绍： Nephrology Dialysis Transplantation (ndt) is the leading nephrology journal in Europe and renowned worldwide, devoted to original clinical and laboratory research in nephrology, dialysis and transplantation. ndt is an official journal of the [ERA-EDTA](http://www.era-edta.org/) (European Renal Association-European Dialysis and Transplant Association). Published monthly, the journal provides an essential resource for researchers and clinicians throughout the world. All research articles in this journal have undergone peer review. Print ISSN: 0931-0509.

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