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 O. Wenzel, Oliver M. Steinmetz, Elion Hoxha, Jan-Eric Turner, Hans-Willi Mittrücker, Thorsten Wiech, Tobias B. Huber, Stefan Bonn (), Christian F. Krebs () and Ulf Panzer ()
Additional contact information
Jonas Engesser: University Medical Center Hamburg-Eppendorf
Robin Khatri: University Medical Center Hamburg-Eppendorf
Darius P. Schaub: University Medical Center Hamburg-Eppendorf
Yu Zhao: University Medical Center Hamburg-Eppendorf
Hans-Joachim Paust: University Medical Center Hamburg-Eppendorf
Zeba Sultana: University Medical Center Hamburg-Eppendorf
Nariaki Asada: University Medical Center Hamburg-Eppendorf
Jan-Hendrik Riedel: University Medical Center Hamburg-Eppendorf
Varshi Sivayoganathan: University Medical Center Hamburg-Eppendorf
Anett Peters: University Medical Center Hamburg-Eppendorf
Anna Kaffke: University Medical Center Hamburg-Eppendorf
Saskia-Larissa Jauch-Speer: University Medical Center Hamburg-Eppendorf
Thiago Goldbeck-Strieder: University Medical Center Hamburg-Eppendorf
Victor G. Puelles: University Medical Center Hamburg-Eppendorf
Ulrich O. Wenzel: University Medical Center Hamburg-Eppendorf
Oliver M. Steinmetz: University Medical Center Hamburg-Eppendorf
Elion Hoxha: University Medical Center Hamburg-Eppendorf
Jan-Eric Turner: University Medical Center Hamburg-Eppendorf
Hans-Willi Mittrücker: University Medical Center Hamburg-Eppendorf
Thorsten Wiech: University Medical Center Hamburg-Eppendorf
Tobias B. Huber: University Medical Center Hamburg-Eppendorf
Stefan Bonn: University Medical Center Hamburg-Eppendorf
Christian F. Krebs: University Medical Center Hamburg-Eppendorf
Ulf Panzer: University Medical Center Hamburg-Eppendorf

Nature Communications, 2024, vol. 15, issue 1, 1-12

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.

Date: 2024
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DOI: 10.1038/s41467-024-52525-w

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