Immune profiling-based targeting of pathogenic T cells with ustekinumab in ANCA-associated glomerulonephritis
Jonas Engeßer, Robin Khatri, Darius P. Schaub, Yu Zhao, Hans‐Joachim Paust, Zeba Sultana, Nariaki Asada, Jan-Hendrik Riedel, Varshi Sivayoganathan, Anett Peters, Anna Kaffke, Saskia-Larissa Jauch-Speer, Thiago Goldbeck-Strieder, Victor G. Puelles, Ulrich Wenzel, Oliver M. Steinmetz, Elion Hoxha, Jan‐Eric Turner, Hans‐Willi Mittrücker, Thorsten Wiech, Tobias B. Huber, Stefan Bonn, Christian F. Krebs, Ulf Panzer
Abstract
Abstract Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a life-threatening autoimmune disease that often results in kidney failure caused by crescentic glomerulonephritis (GN). To date, treatment of most patients with ANCA-GN relies on non-specific immunosuppressive agents, which may have serious adverse effects and be only partially effective. Here, using spatial and single-cell transcriptome analysis, we characterize inflammatory niches in kidney samples from 34 patients with ANCA-GN and identify proinflammatory, cytokine-producing CD4 + and CD8 + T cells as a pathogenic signature. We then utilize these transcriptomic profiles for digital pharmacology and identify ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, as the strongest therapeutic drug to use. Moreover, four patients with relapsing ANCA-GN are treated with ustekinumab in combination with low-dose cyclophosphamide and steroids, with ustekinumab given subcutaneously (90 mg) at weeks 0, 4, 12, and 24. Patients are followed up for 26 weeks to find this treatment well-tolerated and inducing clinical responses, including improved kidney function and Birmingham Vasculitis Activity Score, in all ANCA-GN patients. Our findings thus suggest that targeting of pathogenic T cells in ANCA-GN patients with ustekinumab might represent a potential approach and warrants further investigation in clinical trials.