| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 15, Iss 1, Pp 1-12 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-024-52525-w |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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