Dr Edmund Chung1, Dr Yuan Wang1, Ms Karli Shaw1, Ms Emily Ronning1, Dr Geoff Zhang1, Dr Min Hu2, Dr Karen Keung3, Dr Hugh McCarthy1, Prof David Harris2, Prof Stephen Alexander1
1The Centre For Kidney Research, The Children’s Hospital At Westmead, Westmead, Australia, 2Centre for Transplantation and Renal Research, Westmead Institute for Medical Research, Westmead, Australia, 3Department of Nephrology, Prince of Wales Hospital, Randwick, Australia
Aim: To assess the efficacy of T cell costimulatory blockade with or without proteasome inhibition in Heymann nephritis (HN), an experimental model of membranous nephropathy.
Background: Recent advances in membranous nephropathy treatment have focused on B cell depletion, which is incompletely effective, potentially due to persistent autoantibody-producing plasma cells. Short-course proteasome inhibition (bortezomib) to deplete plasma cells and T cell costimulatory blockade (CTLA4-Ig) to prevent T cell-dependent B cell activation may represent an effective alternative treatment.
Methods: Lewis rats were immunised with Fx1A/complete Freund’s adjuvant (CFA) to induce HN and received short-course bortezomib with CTLA4-Ig or CTLA4-Ig alone. Control rats were immunised with CFA alone. Serum creatinine, proteinuria, kidney histology, serum anti-Fx1A levels on enzyme-linked immunosorbent assay, kidney/splenic messenger RNA expression and flow cytometry on splenocytes were evaluated at 12 weeks.
Results: Bortezomib/CTLA4-Ig-treated and CTLA4-Ig-treated rats had significant and similar reductions in serum creatinine and proteinuria, and less glomerulosclerosis, tubular injury, and interstitial infiltrate compared to untreated HN rats. Glomerular IgG deposition was observed in bortezomib/CTLA4-Ig-treated, CTLA4-Ig-treated, and untreated HN rats with no differences in serum anti-Fx1A levels, which were all significantly higher than in control rats. Bortezomib/CTLA4-Ig-treated and CTLA4-Ig-treated rats exhibited significantly reduced Th17 cytokine (IL6, IL17) and regulatory T cell (Foxp3, TGF-β) expression in the kidney but not the spleen. There were no between-group differences in kidney/splenic expression of Th1 markers (interferon-γ, Tbet), splenic expression of plasma cell markers (Blimp1, XBP1, IRF4) or T follicular helper cell markers (Bcl6, IL21), nor B cells or T cell subsets on flow cytometry.
Conclusions: CTLA4-Ig alone ameliorated HN via kidney Th17 suppression independent of autoantibody production and may represent an effective adjunct treatment in membranous nephropathy.
Biography:
Dr Edmund Chung is an adult nephrologist with a strong interest in glomerulonephritis and identifying strategies to limit the progression of chronic kidney disease. He completed his BMed/MD at UNSW in 2013, MMed (Clin Epi) at The University of Sydney in 2015 and FRACP in 2021. He joined the editorial board of the Cochrane Kidney and Transplant Group in 2022 to help establish best evidence-based practice. He is currently undertaking a PhD on immunotherapies to deplete autoantibodies or expand regulatory T cells in experimental membranous nephropathy with the goal of translating novel efficacious and less toxic treatments into clinical care.