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Immune profiling-based targeting of pathogenic T cells with ustekinumab in ANCA-associated glomerulonephritis

Authors :
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
Ulf Panzer
Source :
Nature Communications, Vol 15, Iss 1, Pp 1-12 (2024)
Publication Year :
2024
Publisher :
Nature Portfolio, 2024.

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.

Subjects

Subjects :
Science

Details

Language :
English
ISSN :
20411723
Volume :
15
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
edsdoj.287d8b69dd7e4d95bc28f18d29e2859c
Document Type :
article
Full Text :
https://doi.org/10.1038/s41467-024-52525-w