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

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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]
Copyright of Nature Communications is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Nature Communications; 9/19/2024, Vol. 15 Issue 1, p1-12, 12p
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  Data: <searchLink fieldCode="DE" term="%22ANTINEUTROPHIL+cytoplasmic+antibodies%22">ANTINEUTROPHIL cytoplasmic antibodies</searchLink><br /><searchLink fieldCode="DE" term="%22KIDNEY+failure%22">KIDNEY failure</searchLink><br /><searchLink fieldCode="DE" term="%22KIDNEY+physiology%22">KIDNEY physiology</searchLink><br /><searchLink fieldCode="DE" term="%22DISEASE+relapse%22">DISEASE relapse</searchLink><br /><searchLink fieldCode="DE" term="%22IMMUNOSUPPRESSIVE+agents%22">IMMUNOSUPPRESSIVE agents</searchLink><br /><searchLink fieldCode="DE" term="%22T+cells%22">T cells</searchLink>
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  Data: 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<superscript>+</superscript> and CD8<superscript>+</superscript> 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]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Nature Communications is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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