Tassiulas IFN Array v1.0
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE1740 | GEO | 2004/09/09
SECONDARY ACCESSION(S): PRJNA90359
REPOSITORIES: GEO
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Project description:IFN-gamma transcriptional responses in control and IFN-gamma primed primary human macrophages Keywords: repeat sample
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Project description:IFN-gamma transcriptional responses in control and IFN-gamma primed primary human macrophages
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Project description:Influenza A Virus (IAV) triggers an exuberant host response that promotes acute lung injury. However, the determinants of the pathological host response to IAV remain incompletely understood. In the current study, we identified interferon (IFN)-γ-regulated subset of monocytes, CCR2+ monocytes, as a driver of lung damage during IAV pathogenesis. IFN-γ regulated the recruitment and inflammatory phenotype of CCR2+ monocytes, and CCR2 (CCR2-/-) and IFN-γ (IFN-γ-/-) deficient mice exhibited reduced lung inflammation, pathology, and increased resistance against bacterial co-infection by Streptococcus pneumoniae (Spn). Adoptive transfer of WT (IFN-γR1+), but not IFN-γR1 deficient (IFN-γR1-) CCR2+ monocytes, restored the wild-type (WT)-like pathological phenotype of lung damage in IAV-infected CCR2-/- mice. The CD8+ T cells were the most significant source of IFN-γ in IAV-infected lungs. Collectively, our data highlight that IFN-γ regulates CCR2+ monocyte-mediated lung pathology during IAV pathogenesis.
2021-11-25 | GSE189407 | GEO
Project description:Timecourse experiment (0hr, 2hr,6hr and 21hr) where RNA was extracted from non-rested PBMCs which were exposed to 4 different conditions- nothing (mock), interferon (IFN)gamma, IFN gamma and a non-specific antibody and IFN gamma with purified patient antibody. The purified patient antibody is demonstrated to have a specific anti-interferon gamma effect over time, with the expression profile in the arrays with IFN gamma plus patient antibody most closely resembling the mock arrays. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Keywords: disease_state_design
2005-09-17 | GSE3319 | GEO
Project description:Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients’ intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-g) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, proteomics analysis of CAR T cells revealed that iNOS-expressing macrophages promote the upregulation of genes mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by the depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs), potentially by modulating IFN-g expression in CAR T cells, could improve outcomes for LBCL patients.
2026-05-31 | MTBLS14634 | MetaboLights
Project description:Macrophages are known to be polarized into inflammatory (M1) and immunoregulatory (M2) cells when they are stimulated by agonists such as IFN-gamma and IL-4, respectively. If circulating monocytes may be polarized in response to T cell signals is often misguidedly deduced from macrophage results. Here the transcriptional responses of human CD14+ monocytes to IFN-gamma and IL-4 were analyzed using whole genome microarrays. A principal component analysis and hierarchical clustering showed that monocyte and macrophage responses were distinct. Monocytes stimulated with IFN-gamma and IL-4 for 6 hours exhibited some features of macrophage polarization. Indeed, when 80 genes considered as M1 and M2 genes were analyzed, we found that M1 genes were modulated in response to IFN-gamma and that M2 genes were modulated in response to IL-4. The M1 polarization of monocytes was transient because only M2 genes were modulated when monocytes were stimulated with IFN-gamma and IL-4 for 18 hours. However, the activation of monocytes by IFN-gamma and IL-4 could not be reduced to M1/M2 polarization status. Indeed, monocytes exhibited early specific signatures composed of 46 and 39 up-regulated genes in response to IFN-gamma and IL-4, respectively, and a late signature common to both molecules that consisted of 57 up-regulated genes. Taken together, these results demonstrated the extreme plasticity of human monocytes and suggested the existence of a core transcriptional termination program. Using early and late signatures might be pertinent to investigate monocyte activation in inflammatory or infectious diseases. Monocytes were stimulated with IFN-gamma (20ng/mL) or IL-4 (20ng/mL) for 6 and 18 hours or culture for 6 and 18 hours without agonist (Unstimulated samples). Monocytes-derived-macrophages (MDM) stimulated with IFN-gamma and IL-4 for 18 hours were used as controls. Each microarray is derived from a single biological sample.
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Project description:Compared to primary human monocytes in whole blood cultures, few B cells activated STAT1 in response to stimulation of 2000 IU/ml IFN-beta for 45 minutes. Because activation of STAT1 leads to apoptosis induction, we tested the hypothesis that less pro-apoptotic genes are induced in B cells as compared to monocytes. Manuscript titled: Major differences in the responses of primary human leukocyte subsets to IFN-beta. Abstract: Treatment of cell lines with type I IFNs activates the formation of ISGF3 (STAT1/STAT2/ IRF9), which induces the expression of many genes. To study this response in primary cells, we treated fresh human blood with IFN-beta and used flow cytometry to analyze phosphorylated STATs1, 3 and 5 in CD4+ and CD8+ T cells, B cells, and monocytes. The activation of STAT1 was remarkably different among these leukocyte subsets. In contrast to monocytes, CD4+ and CD8+ T cells, few B cells activated STAT1 in response to IFN-beta, a finding that could not be explained by decreased levels of IFNAR2 or STAT1 or enhanced levels of SOCS1 or relevant protein tyrosine phosphatases in B cells. Micro-array and real-time PCR analyses revealed the induction of STAT1-dependent pro-apoptotic mRNAs in monocytes but not in B cells. These data show that ISGF3 or STAT1 homodimers are not the main activators of gene expression in primary B cells of healthy humans. Notably, in B cells and especially in CD4+ T cells, IFN-beta activated STAT5 in addition to STAT3, with biological effects often opposite from those driven by activated STAT1. These data help to explain why IFN-beta increases the survival of primary human B cells and CD4+ T cells, but enhances the apoptosis of monocytes, and also to understand how leukocyte subsets are differentially affected by endogenous type I IFNs during viral or bacterial infections, and by type I IFN treatment of patients with multiple sclerosis, hepatitis or cancer. Undiluted whole blood of 2 healthy individuals (HI) was used, and either stimulated with IFN-beta or left untreated (control) for 3 hrs. After 3 hrs, both B cells and monocytes were isolated from whole blood of the first healthy individual, and only B cells were isolated from whole blood of the second healthy individual.
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Project description:Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients’ intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-g) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, proteomics analysis of CAR T cells revealed that iNOS-expressing macrophages promote the upregulation of genes mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by the depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs), potentially by modulating IFN-gamma expression in CAR T cells, could improve outcomes for LBCL patients.
2026-05-31 | MTBLS14641 | MetaboLights
Project description:Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients’ intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-g) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, proteomics analysis of CAR T cells revealed that iNOS-expressing macrophages promote the upregulation of genes mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by the depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs), potentially by modulating IFN-g expression in CAR T cells, could improve outcomes for LBCL patients.
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