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

Jonas EngesserRobin KhatriDarius P SchaubYu ZhaoHans-Joachim PaustZeba SultanaNariaki AsadaJan-Hendrik RiedelVarshi SivayoganathanAnett PetersAnna KaffkeSaskia-Larissa Jauch-SpeerThiago Goldbeck-StriederVictor G PuellesUlrich O WenzelOliver M SteinmetzElion HoxhaJan-Eric TurnerHans-Willi MittrückerThorsten WiechTobias B HuberStefan BonnChristian F KrebsUlf Panzer
Published in: Nature communications (2024)
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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