Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2025
T cell costimulatory blockade ameliorates induction of experimental membranous nephropathy potentially through T-helper 17 cell suppression in the kidney.
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Chung Edmund Y M, Wang Yuan Min, Shaw Karli, Ronning Emily, Wang Ya, Yu Zhang Geoff, Hu Min, Keung Karen, McCarthy Hugh J, Harris David C H, Alexander Stephen I
Аннотация
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.
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.