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Immune Profiling-Based Treatment for ANCA-Associated Glomerulonephritis with Ustekinumab

ABSTRACT: Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is a life-threatening systemic autoimmune disease that frequently presents as crescentic glomerulonephritis (GN) leading to kidney failure1. Despite recent advances2, treatment for most patients with ANCA-associated GN relies on unspecific immunosuppressive agents that are hazardous and only partially efficacious. To develop an anti-T-cell cytokine treatment strategy based on the immunopathogenesis of the individual patient, we established the combination of rapid single-cell immune profiling with standard histopathological analyses of renal biopsies. We report two patients with biopsy-proven ANCA-associated GN who presented with renal failure and active urinary sediment despite immunosuppressive therapy. Our data suggest that the integration of single-cell immune profiling with clinical and histopathological information facilitates personalized anti-cytokine therapies, such as ustekinumab in ANCA-GN, and warrants further investigation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207438 | GEO | 2025/10/01

REPOSITORIES: GEO

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Project description:We investigated a glomerulonephritis (GN) model in rats induced by nephrotoxic serum (NTS) which contains antibodies against the glomerular basement membrane (GBM). The anti-GBM GN model in rats is widely used since its biochemical and histopathological characteristics are similar to crescentic nephritis and Goodpasture's disease in humans. Male Wistar Kyoto (WKY) and Sprague Dawley (SD) rats were dosed once with 1, 2.5 and 5 ml/kg nephrotoxic serum (NTS) or 1.5 and 5 ml/kg NTS, respectively. GN and tubular damage were observed histopathologically in all treated rats after 14 days. To obtain insight into molecular processes during GN pathogenesis, mRNA expression was investigated in WKY and SD kidneys. The immunopathological processes during GN are still not fully understood and likely involve both innate and adaptive immunity. In the present study, several hundred mRNAs were found deregulated, which functionally were mostly associated with inflammation and regeneration. The ?-chain of the major histocompatibility complex class II RT1.B (Rt1-Bb) and complement component 6 (C6) were identified as two mRNAs differentially expressed between WKY and SD rat strains which could be related to known different susceptibilities to NTS of different rat strains; both were increased in WKY and decreased in SD rats. Increased Rt1-Bb expression in WKY rats could indicate a stronger and more persistent cellular reaction of the adaptive immune system in this strain, in line with findings indicating adaptive immune reactions during GN. The complement cascade is also known to be essential for GN development, especially terminal cascade products like C6. Two different rat strains (WKY and SD) were dosed with different doses of NTS and after 14 days rats were euthanized and kidneys were removed for RNA extraction and hybridization on Affymetrix microarrays. We sought to analyze the deregulation of gene expression during NTS-induced glomerulonephritis and to compare the effect in the two rat strains.

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Immune Profiling-Based Treatment for ANCA-Associated Glomerulonephritis with Ustekinumab

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