Mus musculus
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ABSTRACT:
PROVIDER: PRJNA116721 | ENA |
REPOSITORIES: ENA
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Project description:Immune responses in hemophilia A patients to replacement factor VIII can be either tolerogenic or immunogenic, the latter resulting in induction of non-neutralizing anti-factor VIII antibodies or neutralizing antibodies called inhibitors. Since these inhibitors render replacement FVIII treatment essentially ineffective, preventing or eliminating them are of top priority in disease management. The extended half-life recombinant factor VIII Fc fusion protein (rFVIIIFc) is an approved therapy for hemophilia A patients. In addition, it has been reported that rFVIIIFc can induce tolerance to FVIII in hemophilia A patients that have developed inhibitors. Given that the IgG1 Fc region has the potential to interact with immune cells expressing Fc receptors and thereby affect the immune response to rFVIII, we investigated how human macrophages, expressing both Fc receptors and receptors reported to bind FVIII, respond to rFVIIIFc. We show herein that rFVIIIFc, but not rFVIII, uniquely skews macrophages towards an alternatively activated regulatory phenotype. rFVIIIFc initiates signaling events that result in morphological changes, as well as a specific gene expression and metabolic profile that is characteristic of the regulatory type Mox/M2-like macrophages. Further, these changes are dependent on rFVIIIFc-Fc receptor interactions. Our findings elucidate mechanisms of potential immunomodulatory properties of rFVIIIFc.
2018-11-20 | GSE118157 | GEO
Project description:<p>Rare individuals are highly resistant to infection with human immunodeficiency virus (HIV). Studies of candidate genes resulted in the discovery of a 32bp deletion in the CC-chemokine receptor 5 gene (CCR5Δ32), which rendered this critical co-receptor for primary HIV infection to be non-functional. Pharmacologic and vaccine-induced blockade of CCR5 is being pursued to treat and prevent HIV infection and other conditions.</p> <p>The allele frequency of CCR5Δ32 among persons of European ancestry is approximately 10%. CCR5Δ32/Δ32 homozygotes are almost totally resistant to HIV infection. People with severe hemophilia A require frequent replacement with clotting Factor VIII (FVIII) to control hemorrhage. Prior to the discovery of HIV in 1984 and licensure of recombinant FVIII in the late 1980s, people with severe hemophilia A were treated with plasma-derived FVIII and thus were intensively exposed to HIV. Only 5% of such patients were not infected with HIV. Of these, approximately 1/3 were CCR5Δ32/Δ32 homozygotes. The remaining 2/3 of these people who were highly resistant to HIV remain unexplained. This project seeks to discover genome variations among people who are highly resistant to HIV infection. Such variation is likely to serve as a target for reducing the morbidity and incidence of HIV. </p>
| phs000445 | dbGaP
Project description:To investigate the gene expression in dendritic cells after treating hemiphilic mice with HBSS, plasma derived or recombinant factor VIII Gene expression in dendritic cells were measured 24 hours post treatment
2009-04-30 | GSE15809 | GEO
Project description:We compared scRNA expression analysis of 3 populations of regulatory CD4+ T cells induced in oral tolerance to factor VIII in a mouse model of hemophilia: FoxP3+LAP-, FoxP3+LAP+, FoxP3-LAP+
2023-09-16 | GSE242919 | GEO
Project description:To investigate the gene expression in dendritic cells after treating hemiphilic mice with HBSS, plasma derived or recombinant factor VIII Gene expression in dendritic cells were measured 24 hours post treatment Hemophilic mice with treated with either (HBSS, rFVIII or pdFVIII) 24 hours post treatment the spleens were isolated and CD11+ DCs were purified. The gene expression in the DCs were then investigated by microarray studies.
2010-05-19 | E-GEOD-15809 | biostudies-arrayexpress
Project description:Replacement therapy with coagulation factor VIII (FVIII) products concurrent with bleeds (on-demand) in hemophilia A (HA) patients, seems to increase the risk for developing anti-drug antibodies (i.e. inhibitors). A danger signal environment characterized by tissue damage and inflammation at the site of a bleed is thought to contribute to the anti-FVIII response. The nature of this inflammatory reaction is however not fully known. The purpose of this study was to characterize the inflammatory response, locally and systemically, during the first 24h following a knee joint bleed in the HA rat. HA rats received either a needle induced knee joint bleed (n=83) or a sham procedure (n=41). Blood samples were collected at selected time-points from 0-24h post injury/sham. Synovial fluid as well as intra-articular knee tissue and popliteal lymph nodes were collected at 24h. Cytokine and chemokine concentrations and mRNA gene expression on tissue samples were measured. Gene expression analysis revealed a rapid inflammatory response in the injured knees, accompanied by significantly increased levels of specific gene products in the synovial fluid; IL-1β, TNFα, KC/GRO, IL-6, Eotaxin, MCP-1, MCP-3, MIP-1α, MIP-2, RANTES, A2M and AGP. Plasma analysis demonstrated significantly increased systemic levels of KC/GRO, IL-6 and AGP in the blood of injured rats, already few hours following the injury. In conclusion, a rapid pro-inflammatory response, both locally and systemically, characteristic of innate immunity, was demonstrated following an induced knee joint bleed in the HA rat. Results reveal a more comprehensive inflammatory picture than previously shown, with resemblance to human hemophilic arthropathy.
2017-12-01 | GSE85051 | GEO
Project description:Hemophilia A (HA) is a bleeding disorder caused by deficiency of functional plasma clotting factor VIII (FVIII). In addition to genetic mutations in the gene encoding FVIII (F8), there is evidence that other molecular mechanisms may be involved in the pathobiology of HA. In this study, global small ncRNA expression profiling analysis of whole blood from HA patients, and controls, was performed using high-throughput ncRNA microarrays. Patients were further sub-divided into those that developed neutralizing-anti-FVIII antibodies (inhibitors) and those that did not. Selected differentially expressed ncRNAs were validated by quantitative reverse transcriptionpolymerase chain reaction (qRT-PCR) analysis. We identified several ncRNAs, and among them, hsa-miR-1246 was significantly up-regulated in HA patients. In addition, miR-1246 showed a six-fold higher expression in HA patients without inhibitors. We have identified an miR-1246 target site in the noncoding region of F8 mRNA and were able to confirm the suppressory role of hsa-miR-1246 on F8 expression in a stable lymphoblastoid cell line expressing FVIII. These findings suggest several testable hypotheses vis-M-CM- -vis the role of nc-RNAs in the regulation of F8 expression and the development of anti-drug antibodies to FVIII infusions used to treat HA. Whole blood samples from nine patients with hemophilia A and five controls were obtained. Among those patients with hemophilia A, three of them were patients who developed neutralizing-anti-FVIII antibodies (inhibitors) and the others are patients without FVIII inhibitors. RNA was isolated and purified from all samples using the RiboPure Blood Kit (Life Technologies) according to the manufacturerM-bM-^@M-^Ys protocol with modifications to enhance the enrichment of low molecular weight RNAs. All RNA samples were poly (A)-tailed and biotin-labeled using the FlashTag Biotin HSR RNA Labeling Kit (Affymetrix, Santa Clara, CA, USA). After labeling, the enzyme linked oligosorbent assays (ELOSA) were performed to confirm that the biotin labeling processes were successful. Biotin-labeled RNA samples (500 ng/sample) were hybridized on GeneChip miRNA 3.0 microarrays (Affymetrix). Microarray data were analyzed to identify ncRNAs that were differentially expressed in hemophilia A groups compared to controls.
2015-02-04 | E-GEOD-65581 | biostudies-arrayexpress
Project description:In this study we examined the influence of seminal plasma on gene expression in human Ect1 ectocervical epithelial cells, and the extent to which recombinant TGFβ3 elicits comparable changes. Ect1 cells were incubated with recombinant human TGFβ3 (5 ng/ml), 10% pooled human seminal plasma (v/v), or medium alone for 10h. RNA was reverse transcribed into cDNA and hybridized to Affymetrix GeneChip® Human Genome U133 plus 2.0 microarrays (Affymetrix, Santa Clara, CA). Exposure of Ect1 cells to seminal plasma resulted in differential expression of a total of 3955 probe sets, identified using high stringency criteria with MAS 5.0 analysis. These corresponded to 1338 genes up-regulated and 1343 genes down-regulated by seminal plasma. TGFβ3 treatment of Ect1 cells resulted in differential expression of 884 probe sets, corresponding to 346 up-regulated genes and 229 down-regulated genes. The genes differentially regulated by seminal plasma included several genes associated with cytokine–cytokine receptor interaction, TGFβ signalling, JAK/STAT signalling or VEGF signalling pathways, as specified by the KEGG database. Of 47 genes in these families, 17 (36.1%) were similarly regulated by both seminal plasma and TGFβ3. These data, together with additional experiments showing all three TGFβ isoforms can regulate inflammatory cytokine expression in Ect1 cells, identify TGFβ isoforms as key agents in seminal plasma that signal induction of pro-inflammatory cytokine synthesis in cervical cells.
2012-02-16 | GSE35830 | GEO
Project description:In this study we examined the influence of seminal plasma on gene expression in human Ect1 ectocervical epithelial cells, and the extent to which recombinant TGFβ3 elicits comparable changes. Ect1 cells were incubated with recombinant human TGFβ3 (5 ng/ml), 10% pooled human seminal plasma (v/v), or medium alone for 10h. RNA was reverse transcribed into cDNA and hybridized to Affymetrix GeneChip® Human Genome U133 plus 2.0 microarrays (Affymetrix, Santa Clara, CA). Exposure of Ect1 cells to seminal plasma resulted in differential expression of a total of 3955 probe sets, identified using high stringency criteria with MAS 5.0 analysis. These corresponded to 1338 genes up-regulated and 1343 genes down-regulated by seminal plasma. TGFβ3 treatment of Ect1 cells resulted in differential expression of 884 probe sets, corresponding to 346 up-regulated genes and 229 down-regulated genes. The genes differentially regulated by seminal plasma included several genes associated with cytokine–cytokine receptor interaction, TGFβ signalling, JAK/STAT signalling or VEGF signalling pathways, as specified by the KEGG database. Of 47 genes in these families, 17 (36.1%) were similarly regulated by both seminal plasma and TGFβ3. These data, together with additional experiments showing all three TGFβ isoforms can regulate inflammatory cytokine expression in Ect1 cells, identify TGFβ isoforms as key agents in seminal plasma that signal induction of pro-inflammatory cytokine synthesis in cervical cells. RNA from each of four biological replicates, each comprising pooled material from separate sets of 4 replicate wells, was analysed for each treatment. Total RNA was reverse transcribed into cDNA and sent to the Australian Genome Research Facility (AGRF; Melbourne, Australia) for single-cycle labeling and hybridization to 12 Affymetrix GeneChip® Human Genome U133 plus 2.0 microarrays (Affymetrix, Santa Clara, CA).
2012-02-16 | E-GEOD-35830 | biostudies-arrayexpress
Project description:Comparisons among breast cancer metastases at different organs revealed distinct microenvironments as characterized by cytokine content. Such microenvironment distinction might be important to dictate how the cancer cells adapt to survival before they successfully colonize. This SuperSeries is composed of the following subset Series:; GSE14017: Metastases of breast cancer (U133plus2); GSE14018: Metastases of breast cancer (U133A) Experiment Overall Design: Refer to individual Series
2009-05-08 | E-GEOD-14020 | biostudies-arrayexpress