T cell costimulatory blockade ameliorates induction of experimental membranous nephropathy potentially through T-helper 17 cell suppression in the kidney.
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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引用次数: 0
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 (CFA) 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 to untreated HN rats. Glomerular IgG deposition was reduced in CTLA4-Ig-treated and CTLA4-Ig plus bortezomib-treated rats compared to 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 (IL)-6, IL-17, IL-21) and regulatory T cell (Foxp3, TGF-β) expression in the kidney but not the spleen. Immunohistochemical staining of CD4+ and intracellular STAT3+ cells were reduced in CTLA4-Ig plus bortezomib-treated and CTLA4-Ig-treated compared to untreated HN rats. On flow cytometry, CTLA4-Ig reduced B cells and plasma cells but not T cell subsets.
Conclusion: 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.
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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