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Immuno-genomic effects of JAK blockade in vivo

ABSTRACT: Small molecule inhibitors of JAK kinases have shown clinical effcacy in the treatment of certain autoimmune diseases. While these are known to block upstream JAK signalling events, their broader impact on the transcriptional footprint in immunocytes are unknown. Here we explore the effects of pan- and isoform-specific JAK blockade on the immuno-genomic network by genomic profiling.

ORGANISM(S): Mus musculus

PROVIDER: GSE84853 | GEO | 2016/07/27

SECONDARY ACCESSION(S): PRJNA335370

REPOSITORIES: GEO

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Immuno-genomic effects of JAK blockade in vivo

Project description:Small molecule inhibitors of JAK kinases have shown clinical effcacy in the treatment of certain autoimmune diseases. While these are known to block upstream JAK signalling events, their broader impact on the transcriptional footprint in immunocytes are unknown. Here we explore the effects of pan- and isoform-specific JAK blockade on the immuno-genomic network by genomic profiling. 6week old male C57BL/6 mice were gavaged with JAK inhibitor or vehicle for indicated treatment periods. Spleens were harvested and mechanically disrupted to prepare single cell suspensions. These were then stained in multiple surface marker panels to differentiate distinct immunocyte populations. Cells were sorted directly into TriZol. RNA was prepared in Trizol for gene expression profiling by Affymetrix Mouse Gene 1.0 ST Arrays.

2016-07-27 | E-GEOD-84853 | biostudies-arrayexpress

Immuno-genomic effects of JAK blockade

Project description:Immuno-genomic effects of JAK blockade

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JAK/STAT blockade in cHL

Project description:Here we investigated the effects of JAK/STAT pharmacological inhibition on cHL cell models using ruxolitinib, a JAK 1/2 inhibitor. We use five classical Hodgkin lymphoma cell lines: L428, L1236, L540, KMH2, L591

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Immuno-genomic effects of JAK blockade

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-07-20 | GSE84568 | GEO

Effect of JAK blockade on IFNa response in B cells in vitro

Project description:B cells respond robustly to type 1 interferons which signal through JAK1 and TYK2. Here we analyzed the effects of a panel of JAK inhibitors on the IFNa transcriptional response in activated B cells in vitro. Splenic B cells were isolated by negative selection from 6wk old male C57BL/6 mice. These were activated with LPS(10ug/ml) for 48hrs and thereafter cultured with IFNa (100U/ml) in the presence or absence of JAK inhibitors at IC80 for 2hrs or 8hrs in vitro. Cells were then transferred directly into TriZol. RNA was prepared in Trizol for gene expression profiling by Affymetrix Mouse Gene 1.0 ST Arrays.

2016-07-20 | E-GEOD-84560 | biostudies-arrayexpress

Effect of JAK blockade on IFNa response in CD4+ T cells in vitro

Project description:CD4+ T cells respond robustly to type 1 interferons which signal through JAK1 and TYK2. Here we analyzed the effects of a panel of JAK inhibitors on the IFNa transcriptional response in activated CD4+ T cells in vitro. Splenic CD4+ T cells were isolated by negative selection from 6wk old male C57BL/6 mice. These were activated with CD3/28 beads for 48hrs and thereafter cultured with IFNa (100U/ml) in the presence or absence of JAK inhibitors at IC80 for 2hrs or 8hrs in vitro. Cells were then transferred directly into TriZol. RNA was prepared in Trizol for gene expression profiling by Affymetrix Mouse Gene 1.0 ST Arrays.

2016-07-20 | E-GEOD-84565 | biostudies-arrayexpress

Mus musculus

Project description:Immuno-genomic effects of JAK blockade in vivo

| PRJNA335370 | ENA

Metabolic profiling of rheumatoid arthritis neutrophils reveals altered energy metabolism that is not affected by JAK inhibition

Project description:Neutrophils play a key role in the pathophysiology of rheumatoid arthritis (RA) where release of ROS and proteases directly causes damage to joints and tissues. Neutrophil function is directly affected by Janus Kinase (JAK) inhibitor drugs, including tofacitinib and baricitinib, which are clinically effective treatments for RA. However clinical trials have reported increased infection rates and transient neutropenia during therapy. The subtle differences in the mode of action, efficacy and safety of JAK inhibitors has been the primary research topic of many clinical trials and systematic reviews, to provide a more precise and targeted treatment to patients. The aim of this study was to determine both the differences in the metabolome of neutrophils from healthy controls and people with RA, and the effect of different JAK inhibitors on the metabolome of healthy and RA neutrophils. Isolated neutrophils from healthy controls (HC) (n=6) and people with RA (n=7) were incubated with baricitinib, tofacitinib or a pan-JAK inhibitor (all 200ng/mL) for 2h. Metabolites were extracted and 1H nuclear magnetic resonance (NMR) was applied to study the metabolic changes. Multivariate analyses and machine learning models show a divergent metabolic pattern in RA neutrophils compared to HC at baseline (F1 score = 86.7%) driven by energy metabolites (ATP, ADP, GTP and glucose). No difference was observed in the neutrophil metabolome when treated with JAK inhibitors. However, JAK inhibitors significantly inhibited ROS production and baricitinib decreased NET production (p-value<0.05). Bacterial killing was not inhibited by JAK inhibitors, indicating their effect on neutrophils is beneficial to inhibit joint damage in RA without impairing host defence. This study highlights altered energy metabolism in RA neutrophils which may explain the cause of their dysregulation in inflammatory disease.

2023-07-11 | MTBLS4766 | MetaboLights

Effect of JAK blockade on IFNa response in B cells in vitro

2016-07-20 | GSE84560 | GEO

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