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

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

PROVIDER: PRJNA1052093 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27201415_1.fastq.gz	Fastqsanger.gz
	SRR27201415_2.fastq.gz	Fastqsanger.gz
	SRR27201416_1.fastq.gz	Fastqsanger.gz
	SRR27201416_2.fastq.gz	Fastqsanger.gz
	SRR27201417_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

2024-06-28 | GSE250138 | GEO

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

Project description: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. By performing spatial and single-cell transcriptome analysis, we characterized inflammatory niches in the kidneys of 34 patients with ANCA-GN and identified pro-inflammatory, 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 in these T cells, 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. Ustekinumab was given subcutaneously (90 mg) at weeks 0, 4, 12, and 24 and clinical and renal responses were evaluated at week 26. This treatment was well-tolerated and induced clinical response in all ANCA-GN patients, including an improved kidney function and Birmingham Vasculitis Activity Score. Our findings suggest that the pathogenesis-based treatment of ANCA-GN patients with ustekinumab is efficacious and warrants further investigation in clinical trials.

2024-07-01 | GSE253633 | GEO

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

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

| PRJNA1066376 | ENA

CC chemokine ligand 18 (CCL18) is associated with disease activity and relapse in ANCA-associated crescentic glomerulonephritis

Project description:Anti neutrophil cytoplasmic antibody (ANCA) associated vasculitis is the most frequent cause of crescentic glomerulonephritis. Histopathologic features and clinical course of the disease are diverse and judgment of disease activity is often limited due to the lack of reliable activity markers. In order to define potentially new molecular or cellular markers in the kidney which may predict clinical outcome, we performed microarray analyses of renal biopsies from patients with ANCA-associated crescentic glomerulonephritis. We correlated expression profiles with clinical data from our prospective study of patients with renal ANCA disease. The CC chemokine ligand 18 (CCL18) was one of the most up-regulated proteins in kidneys of patients with ANCA-associated crescentic glomerulonephritis. CCL18 producing cells in the kidneys were identified as CD68 and CD209 positive myeloid dendritic cells. The density of CCL18 positive cells correlated with the severity of acute tubular injury and with the impairment of renal function. CCL18 protein levels were elevated in serum samples of patients with renal ANCA disease when compared with patients with non- ANCA-associated crescentic glomerulonephritis. Persistence of high CCL18 serum levels correlated with impairment of renal function and the risk of relapsing disease. Therefore, CCL18 might serve as a marker for persistent disease activity and renal relapses in ANCA-associated vasculitis.

2015-09-03 | E-MTAB-1944 | biostudies-arrayexpress

ANCA Glomerulonephritis: From Molecules to Man

Project description:ANCA Glomerulonephritis: From Molecules to Man

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Single-cell TCR-sequencing of T cells in crescentic glomerulonephritis

Project description:Single-cell TCR sequencing of T cells from ANCA-associated glomerulonephritis patients and experimental crescentic glomerulonephritis mouse model.

2023-03-31 | GSE223107 | GEO

Digital spatial profiling revealed the mechanism involved in the progression of affected glomeruli in ANCA associated glomerulonephritis [GEOmx]

Project description:We previously showed that the rupture of Bowman’s capsule (BC) promotes the progression of crescent glomerulonephritis by enhancing CD8+ T cell entry into the glomeruli. In the present study, we utilized digital spatial profiling to simultaneously profile the altered mRNA transcript and protein abundances in the glomerular and periglomerular areas of biopsy samples of ANCA-associated glomerulonephritis. The paraffin-embedded biopsy samples were stained with Collagen IV, CD45, and Syto13 to distinguish the glomeruli with crescent formation but intact BC, with focal BC rupture, and with extensive rupture of BC and glomeruli without crescent formation and leukocytes infiltration in ANCA-GN. By assessing multiple discrete glomerular areas, we found that the transcript expression level of secreted phosphoprotein 1and its receptor CD44 were upregulated significantly in the glomeruli with more severe ruptures of BC, and their expression levels correlated positively with the fibrotic markers. We also found that 1) both alternative and classic complement pathways were activated in the glomeruli from patients with ANCA-GN; 2) M1 macrophages involved mostly in the early stage of BC rupture while M2 macrophages were involved in the late stage and may contribute to the fibrosis process of the crescents, and 3) apoptosis is likely the mechanism mediating the loss of glomerular cells in ANCA-GN. Our results demonstrate that digital spatial profiling allows the comparative analysis of mRNA and protein profiles in the individual glomeruli affected differently by the disease processes and to identify potential novel mechanisms in patients with ANCA-GN.

2022-02-01 | GSE192995 | GEO

Digital spatial profiling revealed the mechanism involved in the progression of affected glomeruli in ANCA associated glomerulonephritis [RNA-Seq]

2022-02-01 | GSE192994 | GEO

ScRNA-seq of human kidney immune cells of patients with ANCA-associated glomerulonephritis, Lupus Nephritis against a healthy nephrectomy control

Project description:ANCA-associated glomerulonephritis (AGN) associates with a high risk of end-stage kidneydisease. The role of kidney immune cells in local inflammation remains unclear. Herewe investigate kidney immune cell diversity and function. Kidney tissue from AGN patients (n=5) and a lupus nephritis (LN) patient (n=1) were aquired during a biopsy procedure for a clinical indication. Needle-core biopsies were obtained for histopathological examination, and an additional pass was performed to retrieve kidney tissue for scRNA-seq. Healthy kidney tissue (n=1) was obtained from a kidney that was surgically removed do tue due to a (non-invasive) papillary urothelial carcinoma. Immediately after collection, kidney tissue was processed into a single-cell suspension and sorted using a 4-color flow cytometry panel to isolate living, CD45+immune cells. To aid in the multi-omic characterization, surface markers and T and B cell repertoires were sequenced in 2 samples (1 AGN patient and the nephrectomy control). These samples were incubated with an oligo-antibody TotalSeq-C cocktail containing 130 unique cell surface antigens.

2024-06-28 | E-MTAB-13596 | biostudies-arrayexpress

Intrarenal single cell sequencing of MPO-ANCA associated glomerulonephritis patients reveal novel targetable treatment options

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