Bibliographic Details
| Title: |
Immune profiling-based targeting of pathogenic T cells with ustekinumab in ANCA-associated glomerulonephritis. |
| Authors: |
Engesser, Jonas, Khatri, Robin, Schaub, Darius P., Zhao, Yu, Paust, Hans-Joachim, Sultana, Zeba, Asada, Nariaki, Riedel, Jan-Hendrik, Sivayoganathan, Varshi, Peters, Anett, Kaffke, Anna, Jauch-Speer, Saskia-Larissa, Goldbeck-Strieder, Thiago, Puelles, Victor G., Wenzel, Ulrich O., Steinmetz, Oliver M., Hoxha, Elion, Turner, Jan-Eric, Mittrücker, Hans-Willi, Wiech, Thorsten |
| Source: |
Nature Communications; 9/19/2024, Vol. 15 Issue 1, p1-12, 12p |
| Subject Terms: |
ANTINEUTROPHIL cytoplasmic antibodies, KIDNEY failure, KIDNEY physiology, DISEASE relapse, IMMUNOSUPPRESSIVE agents, T cells |
| 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. Antineutrophil cytoplasmic antibody (ANCA) is currently treated with broad-spectrum immune suppressive drugs. Here the authors decipher inflammatory niches in the kidney of patients with ANCA-GN by combining spatial and single-cell transcriptomics to identify ustekinumab as a promising treatment option and successfully treat four ANCA-GN patients. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
