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

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<sup>+</sup> and CD8<sup>+</sup> 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.

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Publication Details

Journal
Nature Communications
Published
2024-09-19
DOI
https://doi.org/10.1038/s41467-024-52525-w
Citations
34
Primary Topic
Vasculitis and related conditions
Type
article
Field-Weighted Citation Impact
14.24

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article

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

Hans‐Joachim Paust, Jan‐Eric Turner, Thorsten Wiech, Stefan Bonn et al.
34 citations
Nature Communications
Vasculitis and related conditions
14.24
article

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

Hans‐Joachim Paust, Jan‐Eric Turner, Thorsten Wiech, Stefan Bonn, Hans‐Willi Mittrücker, Varshi Sivayoganathan, Saskia-Larissa Jauch-Speer, Christian F. Krebs, Anett Peters, Victor G. Puelles, Anna Kaffke, Ulrich Otto Wenzel, Ulf Panzer, Yu Zhao, Oliver M. Steinmetz, Jan-Hendrik Riedel, Nariaki Asada, Tobias B. Huber, Robin Khatri, Jonas Engeßer, Thiago Goldbeck-Strieder, Darius P. Schaub, Zeba Sultana, Elion Hoxha
article en
34 citations

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<sup>+</sup> and CD8<sup>+</sup> 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.

Nature CommunicationsVol. 15(1)
Universität Hamburg (DE), MSH Medical School Hamburg – University of Applied Sciences and Medical University (DE), University Medical Center Hamburg-Eppendorf (DE)
Deutsche Forschungsgemeinschaft
Good health and well-being
Openalex Percentile: Top 1%
Vasculitis and related conditions
14.24
DOIOpen Access PDFOpenAlex
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