Double-negative T cell therapy alone or in combination with oral UDCA alleviates primary biliary cholangitis in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE167116 | GEO | 2022/02/28
REPOSITORIES: GEO
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Project description:Primary biliary cholangitis (PBC) is a liver-specific autoimmune disease. Treatment of PBC with ursodeoxycholic acid (UDCA) is not sufficient to prevent disease progression, new and creative approaches to treating patients with PBC are urgently required. Double-negative T (DNT) cells, unique regulatory T cells, play crucial roles in maintaining immune system homeostasis. However, both the absolute number and proportion of liver DNT cells were reduced in PBC patients. Hence, it is worth pursuing that whether replenishment of DNT cells can improve the hepatic function and pathology of PBC. In this study, adoptive transfer of DNT cells significantly decreases plasma levels of ALT, AST, AMA-M2 and IgM in both dnTGFβ RII and 2OA-BSA-immunized PBC mouse models. In addition, DNT cells exhibit a strong suppression on liver T cells. While combination therapy with DNT cells and UDCA predominantly ameliorate liver inflammation and extensively inhibit hepatic T and B cells. In vitro study further reveals that UDCA promotes the proliferation of DNT cells, increased functional molecule perforin and reduced inhibitory molecule NKG2A and EPCR expression, resulting in augmenting the suppressive function of DNT cells via FXR/JNK signaling pathway in both mice and human DNT cells. In conclusion, UDCA augments the suppressive function of DNT cells via FXR/JNK. A single transfer of DNT cells in combination with UDCA strongly ameliorates PBC in mice. This study provides a potential application of DNT cell-based therapy for PBC. Methods: The DNT cells incubation with anti-CD3/CD28 antibodies were stimulated with UDCA (60uM) for 48 hours, then transcriptome sequencing studies were performed on DNT cells RNA.Transcriptome sequencing libraries were generated using NEBNext® Ultra™ RNA Library Prep Kit for Illumina® (NEB, USA) following manufacturer’s recommendations and sequenced on an Illumina Hiseq platform (Illumina, San Diego, CA). Sequences were aligned to the reference genome with TopHat and processed with Cufflinks, which quantifies each transcript in each sample using reference annotations produced by the University of California Santa Cruz UCSC. Differentially expressed genes with a fold change of >=1.41 and pvalue <= 0.05 between UDCA treated and control DNT cells were submitted to GO and KEGG enrichment analysis, which uses unbiased methods to assess pathway enrichment.
2023-10-31 | GSE215278 | GEO
Project description:Methods: To better understand the role of OX40 in the regulation of double-negative regulatory T cells (DNT), OX40 deficiency and wild-type DNT converted from naïve CD4 T cells were compared in a transcriptome sequencing study. Total RNA was isolated from FACS-separated DNT. Transcriptome sequencing libraries were generated using NEBNext® Ultra™ RNA Library Prep Kit for Illumina® (NEB, USA) following manufacturer’s recommendations and sequenced on an Illumina Hiseq platform (Illumina, San Diego, CA). Sequences were aligned to the reference genome with TopHat and processed with Cufflinks, which quantifies each transcript in each sample using reference annotations produced by the University of California Santa Cruz UCSC. Differentially expressed genes with a fold change of >=2.0 and padj < 0.05 between OX40 deficiency and control DNT were submitted to GO and KEGG enrichment analysis, which uses unbiased methods to assess pathway enrichment. Results: Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that OX40 knockout are involved in regulatory function of DNT; including suppressive function, apoptosis, proliferation, and so on. Compared to control DNT, OX40 knockout DNT exhibited up-regulation of 52 genes and down-regulated of 46 genes. The most enriched GO term were Signal Transduction, Protein Binding, and Banding.
2020-12-08 | GSE107908 | GEO
Project description:Primary biliary cholangitis (PBC) is an autoimmune liver disease of unknown pathogenesis. We find a decreased number and immunosupressive function of double nagative T (DNT) cells in PBC patients. To further unveil the mechanism by which suppressive function and quantity of DNT cells in PBC patients was impaired, we performed a whole-transcriptome analysis on DNT cells isolated from 13 PBC patients and 6 HCs. Total RNA of DNT cells from HCs and PBC patients were isolated and assessed. Transcriptome sequencing libraries were then generated using NEBNext® Ultra™ RNA Library Prep Kit for Illumina® (NEB, USA) following manufacturer’s recommendations and sequenced on an Illumina Hiseq platform (Illumina, San Diego, CA). Differentially expressed genes with a fold change of >=2.0 and p < 0.05 between HC and PBC patients were submitted to GO and KEGG enrichment analysis. Thie biologic processes of GO enrichment analysis showed that cell co-stimulations, cell migration, apoptotic process, cell activation and cell cytotoxicity were enriched, which helped to explain the alterations in number and suppressive function of DNT cells between HCs and patients from a mRNA level. Meanwhile, we observed that T cell receptor signaling pathway was enriched in DEGS and all identified genes with GSEA. Additionally the leading-edge genes of this pathway exhibited downregulation in PBC patients, subsequently supported by real-time PCR. PIK3R1 and MAP3K8 exhibited more significant reduction in DNT cells from PBC patients.
2024-11-30 | GSE138888 | GEO
Project description:Using outcome after long term follow-up to define risk at disease presentation high risk (n=9 who went on to require liver transplantation) and low risk (n=7 who responded fully to UDCA) patients were identified and their first liver biopsies retrieved. RNA was successfully extracted and analysed using nanostring® transcriptomics. Patients with progressive disease appear to have a distinct molecular signature. high risk (n=9 who went on to require liver transplantation) and low risk (n=7 who responded fully to UDCA) patient material was processed along with non-diseased control liver (n=8)
2016-04-02 | E-GEOD-79850 | biostudies-arrayexpress
Project description:Using outcome after long term follow-up to define risk at disease presentation high risk (n=9 who went on to require liver transplantation) and low risk (n=7 who responded fully to UDCA) patients were identified and their first liver biopsies retrieved. RNA was successfully extracted and analysed using nanostring® transcriptomics. Patients with progressive disease appear to have a distinct molecular signature.
2016-04-02 | GSE79850 | GEO
Project description:Methods: Methods: To better understand the role of resveratrol in the regulation of neutrophils activation and function, neutrophils with or without resveratrol in the expose of LPS were compared in a transcriptome sequencing study. Total RNA was isolated from bone marrow and FACS-separated neutrophils. Transcriptome sequencing libraries were generated using NEBNext® Ultra™ RNA Library Prep Kit for Illumina® (NEB, USA) following manufacturer’s recommendations and sequenced on an Illumina Hiseq platform (Illumina, San Diego, CA). Sequences were aligned to the reference genome with TopHat and processed with Cufflinks, which quantifies each transcript in each sample using reference annotations produced bythe University of California Santa Cruz UCSC. Differentially expressed genes with a fold change of >=2.0 and p value<0.01 between resveratrol treated and control neutrophils were submitted to GO and KEGG enrichment analysis, which uses unbiased methods to assess pathway enrichment. Results: Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that downregulated genes from resveratrol-stimulated neutrophils are involved in neutrophil migration, neutrophil chemotaxis, TNF signaling pathway and cytokine activity, among other. Compared to control neutrophils, neutrophils with resveratrol exhibited downregulated levels of cell survival related genes (Camkk1, Aqp1, Bcl2a1b, etc), cell cycle related genes (Ccnb1, Ccnb2, Cdc20, Cdk1, etc), adhesion and migration related genes (Cass4, Nectin4, Gp5, Gpr35, etc), and cytokines (Csf1, Csf3, Ccl2, Ccl7, Ccl12).
2023-02-09 | GSE215236 | GEO
Project description:Method: To better understand the mechanism of perforin in regulating liver CD8 T cell-mediated inflammation during NASH, we sorted CD8 T cells from the livers of WT or Prf1null mice fed the MCD diet for 4 weeks and performed mRNA sequencing of these hepatic CD8 T cells. Total RNA was isolated from FACS-separated hepatic CD8 T cells. Transcriptome sequencing libraries were generated using NEBNext® Ultra™ RNA Library Prep Kit for Illumina® (NEB, USA) following manufacturer’s recommendations and sequenced on an Illumina Hiseq platform (Illumina, San Diego, CA). Sequences were aligned to the reference genome with TopHat and processed with Cufflinks, which quantifies each transcript in each sample using reference annotations produced bythe University of California Santa Cruz UCSC. Differentially expressed genes with a fold change of >=2.0 and padj < 0.05 between CD8 T cells from perforin knockout mice or WT mice fed the MCD were submitted to GO and KEGG enrichment analysis, which uses unbiased methods to assess pathway enrichment. Result: Gene Ontology categories (biological processes) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed that the DEGs in hepatic CD8 T cells from MCD-fed Prf1null mice are involved in cell adhesion, apoptotic process, cell migration, T cell proliferation, regulation of cytokine secretion, complement and coagulation cascades, etc. Compared with CD8 T cells from the steatotic livers of WT mice, hepatic CD8 T cells from MCD-fed perforin knockout mice showed significantly upregulated levels of anti-apoptotic genes (Ei24, Tnfrsf22, Tnfrsf23, Maf and Siah2), chemokines (Cxcl3), chemokine receptor (Ccr5), genes linked to cell activation (Sfpq and P2rx7), proinflammatory cytokine secretion (C1qtnf1, C1qtnf6, CD36, and Tek) and proinflammatory signaling pathways (Tnfsf12, Tnfsf14, Ptgs2, Mapk3, Mapk7, Mapk12, Il12rb2 and Grb2), and downregulated levels of apoptosis-promoting genes (Dffb and Tnfrsf21).
2019-12-31 | GSE121328 | GEO
Project description:Background. Abcb4 (-/-) mice secrete phosphatidylcholine-deficient bile and develop sclerosing cholangitis (SC). The cholangitis involves differential hepatic transcription of genes whose products govern inflammation, activation of hepatic stellate cells and fibrosis. This study was undertaken to test the hypothesis that several genes involved in regulation of tissue inflammation and fibrosis display transcription rates that reflect SC disease activity. Methods. Abcb4 (-/-) mice fed cholic acid (CA) display high SC activity and ursodeoxycholic acid (UDCA) fed mice display low SC activity. Differential hepatic transcription of genes was accordingly measured in abcb4 (-/-) mice maintained on CA- and UDCA-supplemented diets using cDNA microarrays. Abcb4 (+/+) mice served as controls. The differential transcription of selected genes was verified by real time polymerase chain reaction. Liver tissue pathology was quantified by histopathology scoring and immunohistochemistry to visualize bile duct cells and activated hepatic stellate cells. Results. Differential transcription of Ccl2, Ccl20, Cxcl10, Nfκb1, Nfκb2, Tgfβ1, Tgfβ2, Sparc, Ctgf, Lgals3, Elf3, Spp1, Pdgfa, Pdgfrb, Col1a1, Col1a2 and Col4a1 genes paralleled the differing SC activities of cholic acid- and UDCA-fed abcb4 (-/-) mice. Histopathology scores and immunohistochemistry showed greatly enhanced activation of hepatic stellate cells during high SC activity due to CA feeding. Conclusion. Differential transcription of several genes relating to tissue inflammation and hepatic stellate cell activation parallels SC activity in abcb4 (-/-) mice. Data on their differential transcription may be used to gauge SC disease activity.
2008-08-20 | GSE11507 | GEO
Project description:Methods: To better understand the role of OX40 in the regulation of monocyte activation and polarization, OX40/Fc- or control IgG-treated liver monocytes were compared in a transcriptome sequencing study. Total RNA was isolated from FACS-separated hepatic monocytes. Transcriptome sequencing libraries were generated using NEBNext® Ultra™ RNA Library Prep Kit for Illumina® (NEB, USA) following manufacturer’s recommendations and sequenced on an Illumina Hiseq platform (Illumina, San Diego, CA). Sequences were aligned to the reference genome with TopHat and processed with Cufflinks, which quantifies each transcript in each sample using reference annotations produced bythe University of California Santa Cruz UCSC. Differentially expressed genes with a fold change of >=2.0 and padj < 0.05 between OX40 treated and control monocytes were submitted to GO and KEGG enrichment analysis, which uses unbiased methods to assess pathway enrichment. Results: Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that upregulated genes from OX40-stimulated monocytes are involved in inflammatory response; cytokine production regulation; lipid, cytokine and bacteria responses; innate immune response; enhanced cellular response to cytokines and the cytokine-cytokine receptor interaction; and the phagosome and chemokine signaling pathway, among others. Compared to control monocytes, OX40/Fc-treated monocytes exhibited upregulated levels of cytokines (Tnf, Il1a, Il1b, Il6 and Il12a), cytokine receptors (Il1rl1, Il2r, Il18r and Il23r), chemokines (Ccl3, Ccl4, Ccl22, Cxcl1, Cxcl2, Cxcl10 and Cx3cl1), chemokine receptors ( Ccrl2, Cxcr5 and Cxcr6) and antigen processing and presentation molecules (Cd40, Cd80, Cd86, Tlr1, Tlr2, and Ox40l). The coordinated action of various inflammatory modulators, signaling molecules, and transcription factors, including Nlrp3, Tank, Jak2, Stat5a, Hif1a, Nos2, Socs3, Mir155hg and Pparg, was determined to be involved in the OX40 regulation of monocyte M1 polarization. MyD88, Irf3, Irf5, Stat1, Nod1 and Nod2 may not be involved in OX40-triggered monocyte M1 polarization.
2019-12-31 | GSE105187 | GEO
Project description:UDCA regulated the proliferation and function of DNT cells via FXR
| PRJNA889525 | ENA