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

Abstract

Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a life-threatening autoimmune disease that often results in kidney failure caused by crescentic glomerulonephritis (ANCA-GN). To date, treatment of most patients with ANCA-GN relies on unspecific immunosuppressive agents that harbor serious adverse effects and are sometimes only partially effective. By performing spatial and single cell transcriptome analysis, we characterized inflammatory niches in the kidneys of 34 patients with ANCA-GN and identified proinflammatory, cytokine producing CD4+ (Th1 and Th17 subsets) and CD8+ T cells (Tc1 and Tc17-like subsets) as a key pathogenic signature. Digital pharmacology identified ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, as the most promising therapeutic drug to target. Based on these findings, four patients with relapsing ANCA-GN were treated with ustekinumab in combination with low-dose cyclophosphamide and steroids. Ustekinumab was given subcutaneously (90 mg) at weeks 0, 4, 12, and 24. Patients were followed up for 26 weeks. This treatment was well-tolerated and induced clinical response in all ANCA-GN patients, including improved kidney function and Birmingham Vasculitis Activity Score. Our findings suggest that immune-profiling-based targeting of pathogenic T cells in ANCA-GN patients with ustekinumab is a promising approach and warrants further investigation in clinical trials.