Dataset Information

Increased Frequency of Peripheral B and T Cells Expressing Granulocyte Monocyte Colony-Stimulating Factor in Rheumatoid Arthritis Patients.

ABSTRACT:

Objectives

Granulocyte monocyte colony-stimulating factor (GM-CSF) is currently considered a crucial inflammatory mediator and a novel therapeutic target in rheumatoid arthritis (RA), despite the fact that its precise cellular sources remain uncertain. We studied the expression of GM-CSF in peripheral lymphocytes from RA patients and its change with antirheumatic therapies.

Methods

Intracellular GM-CSF expression was assessed by flow cytometry in stimulated peripheral B (CD19+) and T (CD3+) cells from RA patients (n?=?40), disease (n?=?31 including osteoarthritis n?=?15, psoriatic arthritis n?=?10, and systemic rheumatic diseases n?=?6) and healthy (n?=?16) controls. The phenotype of GM-CSF+ B cells was assessed as well as longitudinal changes in GM-CSF+ lymphocytes during methotrexate (MTX, n?=?10) or anti-tumor necrosis factor (anti-TNF, n?=?10) therapy.

Results

Among untreated RA patients with active disease (Disease Activity Score 28-C-reactive protein?=?5.6?±?0.89) an expanded population of peripheral GM-CSF+ B (4.1?±?2.2%) and T (3.4?±?1.6%) cells was detected compared with both disease (1.7?±?0.9%, p?p?p?p?p?=?0.001 and 30.49?±?15.04% vs. 2.45?±?1.84%, p?p?DiscussionThis is the first study showing an expanded population of GM-CSF+ B and T lymphocytes in patients with active RA which declined after anti-TNF therapy.

SUBMITTER: Makris A

PROVIDER: S-EPMC5767588 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Increased Frequency of Peripheral B and T Cells Expressing Granulocyte Monocyte Colony-Stimulating Factor in Rheumatoid Arthritis Patients.

Makris Anastasia A Adamidi Sofia S Koutsianas Christos C Tsalapaki Christina C Hadziyannis Emilia E Vassilopoulos Dimitrios D

Frontiers in immunology 20180110

<h4>Objectives</h4>Granulocyte monocyte colony-stimulating factor (GM-CSF) is currently considered a crucial inflammatory mediator and a novel therapeutic target in rheumatoid arthritis (RA), despite the fact that its precise cellular sources remain uncertain. We studied the expression of GM-CSF in peripheral lymphocytes from RA patients and its change with antirheumatic therapies.<h4>Methods</h4>Intracellular GM-CSF expression was assessed by flow cytometry in stimulated peripheral B (CD19+) an ...[more]

PMID: 29375580

Similar Datasets

Project description:BackgroundG-CSF has been shown to increase neuronal survival, which may positively influence the spinal cord microenvironment during the course of muscular dystrophies.Methodology/principal findingsMale MDX mice that were six weeks of age received a left sciatic nerve transection and were treated with intraperitoneal injections of 200 µg/kg/day of G-CSF 7 days before and 7 days after the transection. The axotomy was performed after the cycles of muscular degeneration/regeneration, consistent with previous descriptions of this model of muscular dystrophy. C57BL/10 mice were used as control subjects. Seven days after the surgery, the animals were sacrificed and their lumbar spinal cords were processed for immunohistochemistry (anti-MHC I, anti-Synaptophysin, anti-GFAP and anti-IBA-1) and transmission electron microscopy. MHC I expression increased in both strains of mice after the axotomy. Nevertheless, the MDX mice displayed a significantly smaller MHC I upregulation than the control mice. Regarding GFAP expression, the MDX mice showed a stronger astrogliosis compared with the C57BL/10 mice across all groups. Both groups that were treated with G-CSF demonstrated preservation of synaptophysin expression compared with the untreated and placebo groups. The quantitative analysis of the ultrastructural level showed a preservation of the synaptic covering for the both groups that were treated with G-CSF and the axotomized groups showed a smaller loss of synaptic contact in relation to the treated groups after the lesion.Conclusions/significanceThe reduction of active inputs to the alpha-motoneurons and increased astrogliosis in the axotomized and control groups may be associated with the cycles of muscle degeneration/regeneration that occur postnatally. The G-CSF treated group showed a preservation of the spinal cord microenvironment after the lesion. Moreover, the increase of MHC I expression in the MDX mice that were treated with G-CSF may indicate that this drug performs an active role in regenerative potential after lesions.

Project description:INTRODUCTION:In rheumatoid arthritis (RA), synovial fluid (SF)contains a large number of neutrophils that contribute to the inflammation and destruction of the joints. The SF also contains granulocyte-macrophage colony-stimulating factor (GM-CSF),which sustains viability of neutrophils and activates their functions. Using proteomic surveillance, we here tried to elucidate the effects of GM-CSF on neutrophils. METHODS:Neutrophils stimulated by GM-CSF were divided in to four subcellular fractions: cytosol, membrane/organelle, nuclei,and cytoskeleton. Then, proteins were extracted from each fraction and digested by trypsin. The produced peptides were detected using matrix-assisted laser desorption ionisation-time of-flight mass spectrometry (MALDI-TOF MS). RESULTS:We detected 33 peptide peaks whose expression was upregulated by more than 2.5-fold in GM-CSF stimulated neutrophils and identified 11 proteins out of the 33 peptides using MALDI-TOF/TOF MS analysis and protein database searches. One of the identified proteins was neutrophil gelatinase-associated lipocalin (NGAL). We confirmed that the level of NGAL in SF was significantly higher in patients with RA than in those with osteoarthritis. We next addressed possible roles of the increased NGAL in RA. We analysed proteome alteration of synoviocytes from patients with RA by treatment with NGAL in vitro. We found that, out of the detected protein spots (approximately 3,600 protein spots), the intensity of 21 protein spots increased by more than 1.5-fold and the intensity of 10 protein spots decreased by less than 1 to 1.5-fold as a result of the NGAL treatment. Among the 21 increased protein spots, we identified 9 proteins including transitional endoplasmic reticulum ATPase (TERA), cathepsin D, and transglutaminase 2 (TG2), which increased to 4.8-fold, 1.5-fold and 1.6-fold, respectively. Two-dimensional electrophoresis followed by western blot analysis confirmed the upregulation of TERA by the NGAL treatment and, moreover, the western blot analysis showed that the NGAL treatment changed the protein spots caused by post-translational modification of TERA.Furthermore, NGAL cancelled out the proliferative effects of fibroblast growth factor (FGF)-2 and epidermal growth factor(EGF) on chondrocytes from a patient with RA and proliferative effect of FGF-2 on chondrosarcoma cells.Conclusions Our results indicate that GM-CSF contributes to the pathogenesis of RA through upregulation of NGAL in neutrophils, followed by induction of TERA, cathepsin D and TG2 in synoviocytes. NGAL and the upregulated enzymes may therefore play an important role in RA.

Project description:ObjectiveMavrilimumab, a human monoclonal antibody, targets granulocyte-macrophage colony-stimulating factor receptor α. We undertook to determine the long-term safety and efficacy of mavrilimumab in rheumatoid arthritis patients in 2 phase IIb studies (1071 and 1107) and in 1 open-label extension study (ClinicalTrials.gov identifier: NCT01712399).MethodsIn study 1071, patients with an inadequate response to disease-modifying antirheumatic drugs (DMARDs) received mavrilimumab (30, 100, or 150 mg) or placebo every other week plus methotrexate. In study 1107, patients with an inadequate response to anti-tumor necrosis factor agents and/or DMARDs received 100 mg mavrilimumab every other week or 50 mg golimumab every 4 weeks plus methotrexate. Patients entering the open-label extension study received 100 mg mavrilimumab every other week plus methotrexate. Long-term safety and efficacy of mavrilimumab were assessed.ResultsA total of 442 patients received mavrilimumab (14 of 245 patients from study 1071, 9 of 70 patients from study 1107, and 52 of 397 patients from the open-label extension study discontinued mavrilimumab treatment throughout the studies). The cumulative safety exposure was 899 patient-years; the median duration of mavrilimumab treatment was 2.5 years (range 0.1-3.3 years). The most common treatment-emergent adverse events (AEs) were nasopharyngitis (n = 69; 7.68 per 100 patient-years) and bronchitis (n = 51; 5.68 per 100 patient-years). At weeks 74 and 104, 3.5% and 6.2% of patients, respectively, demonstrated reduction in forced expiratory volume in 1 second, while 2.9% and 3.4% of patients, respectively, demonstrated reduction in forced vital capacity (>20% reduction from baseline to <80% predicted). Most pulmonary changes were transient and only infrequently associated with AEs. Mavrilimumab at 100 mg every other week demonstrated sustained efficacy; at week 122, 65.0% of patients achieved a Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) of <3.2, and 40.6% of patients achieved a DAS28-CRP of <2.6.ConclusionLong-term treatment with mavrilimumab maintained response and was well-tolerated with no increased incidence of treatment-emergent AEs. Safety data were comparable with those from both phase IIb qualifying studies.

Project description:BackgroundNamilumab (AMG203) is an immunoglobulin G1 monoclonal antibody that binds with high affinity to the GM-CSF ligand. This was a phase 1b, randomized, double-blind study (PRIORA) to assess namilumab in active, mild-to-moderate rheumatoid arthritis (RA). The primary outcome was the safety and tolerability of repeated subcutaneous injections of namilumab in patients with mild-to-moderate RA.MethodsAdults with mild-to-moderate RA on stable methotrexate doses for ≥12 weeks were eligible. Patients received three subcutaneous injections of namilumab 150 or 300 mg, or placebo on days 1, 15, and 29, with 12 weeks' follow-up. Primary objective was safety/tolerability.ResultsPatients in cohort 1 were randomized to namilumab 150 mg (n = 8) or placebo (n = 5). In cohort 2, patients were randomized to namilumab 300 mg (n = 7) or placebo (n = 4). Incidence of treatment-emergent adverse events (TEAEs) was similar across the three groups (namilumab 150 mg: 63%; namilumab 300 mg: 57%; placebo: 56%). TEAEs in ≥10% of patients were nasopharyngitis (17%) and exacerbation/worsening of RA (13%). No anti-namilumab antibodies were detected. The pharmacokinetics of namilumab were linear and typical of a monoclonal antibody with subcutaneous administration. In a post hoc efficacy, per protocol analysis (n = 21), patients randomized to namilumab showed greater improvement in Disease Activity Score 28 (erythrocyte sedimentation rate and C-reactive protein [CRP]), swelling joint counts and tender joint counts compared with placebo. Difference in mean DAS28-CRP changes from baseline between namilumab and placebo favored namilumab at both doses and at all time points. In addition area under the curve for DAS28-CRP was analyzed as time-adjusted mean change from baseline. A significant improvement in DAS28-CRP was shown with namilumab (150 and 300 mg groups combined) compared with placebo at day 43 (p = 0.0117) and also 8 weeks after last dosing at day 99 (p = 0.0154).ConclusionsSubcutaneous namilumab was generally well tolerated. Although namilumab demonstrated preliminary evidence of efficacy, patient numbers were small; phase 2 studies are ongoing.Trial registrationClinicalTrials.gov, NCT01317797 . Registered 18 February 2011.

Dataset Information

Increased Frequency of Peripheral B and T Cells Expressing Granulocyte Monocyte Colony-Stimulating Factor in Rheumatoid Arthritis Patients.

Objectives

Methods

Results

Publications

Increased Frequency of Peripheral B and T Cells Expressing Granulocyte Monocyte Colony-Stimulating Factor in Rheumatoid Arthritis Patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets