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Immune profiling-based targeting of pathogenic T cells with ustekinumab in ANCA-associated glomerulonephritis
Jonas Engesser1,2, Robin Khatri2,3, Darius P Schaub2,3
1Department of Medicine III, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Insights
Targeting specific T cells with ustekinumab shows promise for treating ANCA-associated vasculitis (AAV) and preventing kidney damage. This novel approach offers a potential new therapy for AAV patients.
Area of Science:
- Immunology
- Nephrology
- Rheumatology
Background:
- Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a severe autoimmune condition leading to kidney failure.
- Current treatments for ANCA-associated glomerulonephritis (ANCA-GN) use broad immunosuppressants with significant side effects and limited efficacy.
- Identifying specific cellular targets is crucial for developing more effective AAV therapies.
Purpose of the Study:
- To characterize the inflammatory landscape in ANCA-associated glomerulonephritis.
- To identify key cellular players and molecular targets for therapeutic intervention.
- To evaluate the efficacy and safety of ustekinumab in treating relapsing ANCA-GN.
Main Methods:
- Spatial and single-cell transcriptome analysis of kidney biopsies from 34 ANCA-GN patients.
- Digital pharmacology to identify potential therapeutic agents based on transcriptomic profiles.
- Clinical trial of ustekinumab in four patients with relapsing ANCA-GN, combined with standard therapy.
Main Results:
- Proinflammatory, cytokine-producing CD4+ and CD8+ T cells were identified as a pathogenic signature in ANCA-GN.
- Ustekinumab, targeting IL-12 and IL-23, emerged as a promising therapeutic candidate.
- Treatment with ustekinumab demonstrated tolerability and induced clinical responses, including improved kidney function and reduced disease activity, in all four treated patients.
Conclusions:
- Targeting pathogenic T cells with ustekinumab represents a potential novel therapeutic strategy for ANCA-associated vasculitis.
- Ustekinumab may offer a more targeted and effective treatment option for ANCA-GN, potentially reducing reliance on non-specific immunosuppressants.
- Further clinical trials are warranted to validate ustekinumab as a treatment for ANCA-GN.
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.
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