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  (ANCA-GN).  To date, treatment of most patients with ANCA-GN relies on unspecific immunosuppressive agents that harbor serious adverse effects and limited efficiency. Using spatial and single-cell transcriptome analysis we characterized inflammatory niches in the kidneys of 34 patients with ANCA-GN and idenjpgied proinflammatory cytokine  producing  CD4+ and CD8+ T cells as a key pathogenic tissue signature. By employing digital pharmacology we then idenjpgied ustekinumab, a monoclonal antibody targeting IL-12 and IL-23 in these T cells, as promising therapeutic avenue. Based on these findings, four patients with relapsing ANCA-GN were treated with ustekinumab in combination with low-dose cyclophosphamide. Ustekinumab was given subcutaneously (90 mg) at weeks 0, 4, 12, and 24 and clinical and renal response were evaluated at week 26. Treatment induced substantial clinical response in all ANCA-GN patients, with improvements in kidney function, and Birmingham Vasculitis Activity Score, and was well tolerated.  Our findings suggest that the pathogenesis-based treatment of ANCA-GN patients with ustekinumab is efficacious and warrants further investigation in clinical trials. Overall design: For spatial transcriptomics, formalin-fixed paraffin-embedded (FFPE) kidney tissue sections from patients with ANCA-associated glomerulenephritis (biopsies) and controls (healthy tissue from tumornephrectomies) were transferred on Visium (10x Genomics) slides (spatial for FFPE gene expression human transcriptome) and processed according to the manufacturer's instructions.