Olivier Boyer

Université de Caen Basse-Normandie, Caen, Lower Normandy, France

Are you Olivier Boyer?

Claim your profile

Publications (147)706.3 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Anti-synthetase syndrome (anti-SS) is frequently associated with myositis and interstitial lung disease (ILD). We evaluated prospectively, in a multicenter, open-label, phase II study, the efficacy of rituximab on muscle and lung outcomes. Methods: Patients were enrolled if they were refractory to conventional treatments (prednisone and at least 2 immunosuppressants). They received 1 g of rituximab at D0, D15, and M6. The primary endpoint was muscular improvement based on manual muscular testing (MMT10, Kendall score in 10 muscles) at M12. Secondary endpoints were normalization of creatine kinase (CK) level, ILD improvement based on forced vital capacity and/or diffuse capacity for carbon monoxide, and number and/or doses of associated immunosuppressants. Results: Twelve patients were enrolled, and 10 completed the study. Only 2 patients presented an improvement of at least 4 points on at least two muscle groups (primary end-point). Overall, seven patients had an increase of at least 4 points on MMT10. CK level decreased from 399 IU/L (range, 48-11,718) to 74.5 IU/L (range, 40-47,857). Corticosteroid doses decreased from 52.5 mg/d (range, 10-70) to 9 mg/d (range, 7-65) and six patients had a decrease in the burden of their associated immunosuppressants. At baseline, all 10 patients presented with ILD. At M12, improvement of ILD was observed in 5 out of the 10 patients, stabilization in 4, and worsening in 1. Conclusions: This pilot study of rituximab treatment in patients with refractory anti-SS provided data on evolution of muscular and pulmonary parameters. Rituximab should now be evaluated in a larger, controlled study for this homogenous group of patients. Trial registration: Clinicaltrials.gov NCT00774462.
    PLoS ONE 11/2015; 10(11):e0133702. DOI:10.1371/journal.pone.0133702 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: The recent growth of innovating biologics has opened fascinating avenues for the management of patients. In rheumatoid arthritis, many biologics are currently available, the choice of which being mostly determined empirically. Importantly, a given biologic may not be active in a fraction of patients and may even provoke side effects. Here, we conducted a comparative proteomics study in attempt to identify a predictive theranostic signature of non-response in patients with rheumatoid arthritis treated by etanercept/methotrexate combination. Methods: A serum sample was collected prior to treatment exposure from a cohort of 22 patients with active RA. A proteomic "label free" approach was then designed to quantitate protein biomarkers using mass spectrometry. To verify these results, a relative quantification followed by an absolute quantification of interesting protein candidates were performed on a second cohort. The criterion of judgment was the response to etanercept/methotrexate combination according to the EULAR criteria assessed at 6 months of treatment. Results: These investigations led to the identification of a set of 12 biomarkers with capacity to predict treatment response. A targeted quantitative analysis allowed to confirm the potential of 7 proteins from the latter combination on a new cohort of 16 patients. Two highly discriminating proteins, PROS and CO7, were further evaluated by ELISA on this second cohort. By combining the concentration threshold of each protein associated to a right classification (responders vs non-responders), the sensitivity and specificity reached 88.9 % and 100 %, respectively. Conclusion: Prior to methotrexate/etanercept treatment, abundance of several sera proteins, notably PROS and CO7, were associated to response status of RA patients 6 month after treatment initiation.
    Theranostics 09/2015; 5(11):1214-24. DOI:10.7150/thno.12403 · 8.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: To evaluate the ability of the glycolytic enzyme alpha-enolase (ENO1) or its immunodominant peptide (pEP1) to reduce the severity of CIA in DBA/1 mice when injected in a prophylactic way. Methods: Mice were treated with mouse ENO1 or pEP1 one day prior to collagen II immunization. Clinical assessment was evaluated using 4 parameters (global and articular scores, ankle thickness and weight). Titers of serum anti-ENO1, anti-cyclic citrullinated peptides (anti-CCP) and anti-CII (total IgG and IgG1/IgG2a isotypes) antibodies were measured by ELISA at different time-points. Disease activity was assessed by histological analysis of both anterior and hind paws at the end of experimentation. Results: Prophylactic injection of 100 μg of ENO1 reduced severity of CIA. Serum levels of anti-CII antibodies were reduced in ENO1-treated mice. Concordantly, ENO1-treated mice joints presented less severe histological signs of arthritis. ENO1 did not induce a shift toward a Th2 response since IgG1/IgG2a ratio of anti-CII antibodies remained unchanged and IL-4 serum levels were similar to those measured in the control group. Conclusions: Pre-immunization with ENO1 or its immunodominant peptide pEP1 reduces CIA severity at the clinical, immunological and histological levels. Effects of pEP1 were less pronounced. This immunomodulatory effect is associated with a reduction in anti-CII antibodies production but is not due to a Th1/Th2 shift.
    PLoS ONE 08/2015; 10(8):e0136359. DOI:10.1371/journal.pone.0136359 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gene therapy represents a feasible strategy to treat inherited monogenic diseases and intramuscular (i.m.) injection of recombinant adeno-associated viral (AAV) vector is now recognized as a convenient and safe method of gene transfer. However, this approach is hampered by immune responses directed against the vector and against the transgenic protein. We used here to reproduce this situation a mouse model where robust immune responses are induced following injection of an AAV vector coding for an immunogenic transgenic protein. We show that prophylactic oral administration of the immunogenic protein before AAV-mediated gene transfer completely prevented antibody formation and cytotoxic CD8(+) T cell response. Consistently, prophylactic oral-tolerization considerably improved long-term transgene persistence and expression. Mechanistically, inhibition of the cytotoxic immune response involved abortive proliferation of antigen-specific cytotoxic CD8(+) T cells, up-regulation of the PD-1 immunoregulatory molecule, down-regulation of the Bcl-2 anti-apoptotic factor, and their deletion in the context of AAV-mediated gene transfer. Hence, gene therapy may represent an ideal situation where oral-tolerization can be adopted before or at the same time as vector injection to efficiently prevent deleterious immune responses directed against the transgenic protein.Molecular Therapy (2015); doi:10.1038/mt.2015.146.
    Molecular Therapy 08/2015; DOI:10.1038/mt.2015.146 · 6.23 Impact Factor
  • Source

  • Source
    Dataset: direct link

  • The Lancet 06/2015; DOI:10.1016/S0140-6736(15)60068-X · 45.22 Impact Factor

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The P2X7 receptor is an adenosine triphosphate (ATP)-gated cation channel that is expressed by several cells of the immune system. P2X7 is best known for its proinflamma-tory role in promoting inflammasome formation and release of mature interleukin (IL)-1β by innate immune cells. Mounting evidence indicates that P2X7 is also an important regulatory receptor of murine and human T cell functions. Murine T cells express a sensitive splice variant of P2X7 that can be activated either by non-covalent binding of ATP or, in the presence of nicotinamide adenine dinucleotide, by its covalent ADP-ribosylation catalyzed by the ecto-ADP-ribosyltransferase ARTC2.2. Prolonged activation of P2X7 by either one of these pathways triggers the induction of T cell death. Conversely, lower concentrations of ATP can activate P2X7 to enhance T cell proliferation and production of IL-2. In this review, we will highlight the molecular and cellular consequences of P2X7 activation on mouse T cells and its versatile role in T cell homeostasis and activation. Further, we will discuss important differences in the function of P2X7 on human and murine T cells.
    Frontiers in Immunology 05/2015; 6(204). DOI:10.3389/fimmu.2015.00204
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Antiphospholipid syndrome (APS), induces endothelial dysfunction, oxidative stress and systemic inflammation that may be mediated by TNFα. Thus, we investigated the possible protective effect of the anti- TNFα antibody infliximab (5μg/g) on endothelial function in a mouse APS model (induced by injection of purified human anti-β2GP1-IgG). Seven days after Anti-β2GPI-IgG injection, we observed an increase in plasma sVCAM-1 and sE-selectin levels and in aortic mRNA expression of VCAM-1 and E-selectin. This was associated with a decreased endothelium-dependent relaxation of isolated mesenteric arteries to acetylcholine, together with decreased mesenteric eNOS mRNA expression and increased eNOS uncoupling, accompanied by increased iNOS and gp91phox mRNA and increased left ventricular GSH/GSSH ratio. Infliximab significantly improved the NO-mediated relaxing responses to acetylcholine, and induced a decrease in iNOS and gp91phox mRNA expression. The pro-adhesive and pro-coagulant phenotypes induced by the anti-β2GP1-IgG were also reversed. This study provides the first evidence that TNFα antagonism improves endothelial dysfunction in APS and suggests that endothelial dysfunction is mediated by TNFα and oxidative stress. Therefore, infliximab may be of special relevance in clinical practice. Copyright © 2015. Published by Elsevier Inc.
    Vascular Pharmacology 04/2015; 71. DOI:10.1016/j.vph.2015.03.014 · 3.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Control of immunologic tolerance and homeostasis rely on Foxp3(+)CD4(+)CD25(+) regulatory T cells (Tregs) that constitutively express the high affinity receptor for Interleukin-2, CD25. Tregs proliferate in response to injections of IL-2/anti-IL-2 antibody complexes or low doses of IL-2. However, little is known about endogenous mechanisms that regulate the sensitivity of CD25 to signaling by IL-2. Here we demonstrate that CD25 is ADP-ribosylated at Arg35 in the IL-2 binding site by ecto-ADP-ribosyltransferase ARTC2.2, a toxin-related GPI-anchored ecto-enzyme. ADP-ribosylation inhibits binding of IL-2 by CD25, IL-2- induced phosphorylation of STAT5, and IL-2-dependent cell proliferation. Our study elucidates an as-yet-unrecognized mechanism to tune IL-2 signaling. This newly found mechanism might thwart Tregs at sites of inflammation and thereby permit a more potent response of activated effector T cells.
    Scientific Reports 03/2015; 5. DOI:10.1038/srep08959 · 5.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Rheumatoid arthritis (RA) is the most common inflammatory arthritis. B and T cells play a key role in the RA pathophysiology. RasGRP is a member of the CDC25 family of Ras guanyl nucleotide exchange factors. RasGRP1 is expressed in T and B cells whereas RasGRP3 is only expressed in B cells. In previous studies, we have shown that RasGRP3 gene expression level significantly decreased in peripheral blood mononuclear cells from RA patients responders to adalimumab and etanercept (anti-TNFa drugs), leading to the question of TNFα involvement in RasGRP1 and RasGRP3 pathways. Objectives To study TNFα effects on RasGRP1 and RasGRP3 expression levels in vitro. Materials and methods We measured, by qRT-PCR and western-blot, RasGRP1 and RasGRP3 expression levels in B and T cells isolated from buffy coat. In each condition, cells were cultured with or without TNFα for 24 or 48 h. Cell proliferation was evaluated by [3H] thymidine incorporation. To investigate the TNFα implication on signalling pathways, MAPK and apoptosis protein arrays were used. Results In B cells, TNFα induced an increase of RasGRP1 and RasGRP3 gene expression levels without effect on B cells proliferation and BCR pathway phosphorylations, but apoptotic pathways were inhibited. In T cells, TNFα increased RasGRP1 gene expression level but RasGRP1 protein expression level decreased, inhibiting T cell proliferation and TCR pathway phosphorylations. Conclusions This study suggests a link, never described previously, between RasGRP1 or RasGRP3 and the TNFa effects on T and B cells. While the response to anti-TNFα treatments in RA patients modulates RasGRP3 gene expression, TNFα inhibits RasGRP1 protein expression leading to TCR pathway inhibition, in vitro, in pathophysiological condition. The better understanding of TNFα effects on RasGRP proteins could permit a better understanding of the mechanisms of action of TNFα blocking agents on T and B cells.
    Annals of the Rheumatic Diseases 02/2015; 74(Suppl 1):A18-A19. DOI:10.1136/annrheumdis-2015-207259.43 · 10.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sporadic inclusion body myositis (sIBM) is the most frequently acquired myopathy in patients over 50 years of age. It is imperative that neurologists and rheumatologists recognize this disorder which may, through clinical and pathological similarities, mimic other myopathies, especially polymyositis. Whereas polymyositis responds to immunosuppressant drug therapy, sIBM responds poorly, if at all. Controversy reigns as to whether sIBM is primarily an inflammatory or a degenerative myopathy, the distinction being vitally important in terms of directing research for effective specific therapies. We review here the pros and the cons for the respective hypotheses. A possible scenario, which our experience leads us to favour, is that sIBM may start with inflammation within muscle. The rush of leukocytes attracted by chemokines and cytokines may induce fibre injury and HLA-I overexpression. If the protein degradation systems are overloaded (possibly due to genetic predisposition, particular HLA-I subtypes or ageing), amyloid and other protein deposits may appear within muscle fibres, reinforcing the myopathic process in a vicious circle.
    Acta Neuropathologica 01/2015; 129(5). DOI:10.1007/s00401-015-1384-5 · 10.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Colitis-Associated Cancer (CAC), a complication of inflammatory bowel disease (IBD), is enhanced by chronic inflammation. Binding of extracellular ATP (eATP) to the purinergic P2X7 receptor (P2RX7) has recently emerged as a key signaling molecule in the control of intestinal inflammation by regulating cytokine production, regulatory T cell (Tregs) survival, mast cell-dependent intestinal inflammation and death of enteric neurons. In this study, we investigated the effect of P2RX7 blockade in a mouse model of dextran sodium sulfate-induced CAC. Using genetic and pharmacological tools, we demonstrated that while P2RX7 promoted an inflammatory response, it unexpectedly acted as a tumor suppressor during early CAC tumorigenesis. Indeed, we reported that the absence of P2RX7 activity enhanced proliferation of intestinal epithelial cells and protected them from apoptosis. Further, we demonstrated that P2RX7 blockade influenced immune cell infiltration and notably promoted Treg accumulation within lesions of the digestive system. Finally, we showed that P2RX7 inactivation increased TGFB1 (TGF-β1) production, which stimulated the proliferation of intestinal epithelial cells. Taken together, our findings define a novel and unexpected role for P2RX7 in protecting against CAC. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 01/2015; 75(5). DOI:10.1158/0008-5472.CAN-14-1778 · 9.33 Impact Factor

  • La Revue de Médecine Interne 12/2014; 35. DOI:10.1016/j.revmed.2014.10.031 · 1.07 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: One way to optimize the drug prescription in rheumatoid arthritis (RA) is to identify predictive biomarkers of drug responsiveness. Here, we investigated the potential "theranostic" value of proteins of the S100 family by monitoring levels of both S100A8 and S100A9 in blood samples from RA patients. For proteomic analysis, peripheral blood mononuclear cells (PBMC) and serum samples were collected in patients prior to initiation of the methotrexate/etanercept (MTX/ETA) combination. Firstly, relative mass spectrometry (MS) quantification focusing on S100A8 and S100A9 proteins was carried out from PBMCs samples to identify potential biomarkers. The same approach was also performed from serum samples from responder (R) and non responder (NR) patients. Finally, to confirm these results, an absolute quantification of S100A8, S100A9 proteins and calprotectin (heterodimer of S100A8/S100A9) was carried out on the serum samples using ELISA. MS analyses revealed that both S100A8 and S100A9 proteins were significantly accumulated in PBMC from responders. In contrast to PBMC, only the S100A9 protein was significantly overexpressed in the serum of R patients. Absolute quantification by ELISA confirmed this result and pointed out a similar expression level of S100A8 protein and calprotectin in sera from both R and NR groups. Thus, the S100A9 protein revealed to be predictive of MTX/ETA responsiveness, contrarily to parameters of inflammation and auto-antibodies which did not allow significant discrimination. This is the first report of an overexpression of S100A9 protein in both PBMCs and serum of patients with subsequent response to the MTX/ETA combination. This protein thus represents an interesting biomarker candidate of therapeutic response in RA.
    PLoS ONE 12/2014; 9(12):e115800. DOI:10.1371/journal.pone.0115800 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Our objective was to evaluate the contribution of monitoring B cell subset depletion after rituximab in patients with rheumatoid arthritis (RA) in order to guide reintroduction to forestall relapse. This prospective, monocentre study included all RA patients receiving two 1‐g rituximab infusions at a 15‐day interval. The patients were followed clinically and biologically every 2 months until rituximab reintroduction. The physician was blinded to lymphocyte‐typing results to diagnose relapse and, hence, retreatment. Among the 39 patients included between March 2010 and December 2011 and followed until April 2013, seven received two rituximab cycles, yielding a total of 46 cycles for analysis. After the two rituximab cycles, the total number of CD19+ B cells decreased significantly (0·155 versus 0·0002 G/l, P +CD38++CD24++ (transitional) (P +CD27+ (memory) B lymphocytes. A significant majority of patients relapsed within the 4 months following repopulation of total B (P = 0·036), B transitional (P = 0·007) and B memory (P = 0·01) lymphocytes. CD19+ B lymphocyte repopulation preceded clinical RA relapse and enabled its prediction 4 months in advance. Hence, monitoring of CD19+ B lymphocytes could serve as a tool to predict those relapses.
    Clinical & Experimental Immunology 11/2014; 180(1). DOI:10.1111/cei.12481 · 3.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective To assess the role of Toll-like receptors (TLRs) in antiphospholipid antibody (aPL)-mediated vascular abnormalities in patients with primary arterial antiphospholipid syndrome (APS).Methods Forty-eight subjects participated in the study. Arterial function and structure and TLR pathway activation were determined in patients with primary arterial APS and matched controls. The pathogenic effects of aPL isolated from patients were assessed in wild-type (WT) and TLR-knockout mice.ResultsAPS patients had endothelial dysfunction, arterial stiffening, and hypertrophy, as evidenced by decreased brachial artery endothelium-dependent flow-mediated dilation (FMD) and increased aortic pulse wave velocity and carotid intima-media thickness (IMT), as compared with controls. Plasma samples from APS patients revealed decreased nitric oxide (NO) availability and a pro-oxidative, proinflammatory, and prothrombotic state illustrated by a decrease in nitrite and an increase in lipid peroxidation, tumor necrosis factor α levels, and tissue factor (TF) levels. Furthermore, TLR pathway activation was found in APS patients with increased TLR-2 and TLR-4 messenger RNA expression and increased protein levels of the activated TLR transduction protein interleukin-1 receptor-associated kinase 1 in peripheral blood mononuclear cells. Moreover, agonist-stimulated cell-surface expression of TLR-2 and TLR-4 in circulating monocytes was higher in APS patients than in controls. These changes were positively associated with IMT and negatively associated with FMD. Finally, aPL injection decreased mesenteric endothelium-dependent relaxation and increased TF expression in WT mice but not in TLR-2- or TLR-4-knockout mice.Conclusion This translational study supports the notion that TLR-2 and TLR-4 play a role in mediating vascular abnormalities in patients with primary arterial APS. TLRs thus constitute a promising pharmacologic target for preventing cardiovascular complications in APS.
    Arthritis and Rheumatology 11/2014; 66(11). DOI:10.1002/art.38785
  • [Show abstract] [Hide abstract]
    ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
    Leukemia 08/2014; 28(12). DOI:10.1038/leu.2014.237 · 10.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ADP-ribosyltransferases comprise a family of enzymes originally discovered as bacterial toxins and later characterised also in mammals. In mice, the ADP-ribosyltransferase ARTC2.2 is expressed at the surface of T lymphocytes and has been studied extensively. In the presence of extracellular NAD(+), ARTC2.2 ADP-ribosylates several cell surface target proteins and thereby regulates their function. P2X7, an ATP-gated cation channel, has been discovered as a prominent ARTC2.2 target at the surface of mouse T cells. ADP-ribosylation of P2X7 in the presence of low micromolar extracellular NAD(+) induces long-lasting P2X7 activation and triggers cell death. Regulatory T cell subsets (Tregs and NKT cells) are remarkably sensitive to NAD(+)-induced cell death (NICD). Thus, liberation of endogenous NAD(+) by stressed cells is now viewed as a danger signal promoting immune responses by hindering regulatory T cells. This review will highlight the recent discoveries on the in vivo role of the ARTC2.2/P2X7 pathway triggered by the endogenous release of extracellular NAD(+), the relative sensitivity of lymphocytes subsets to this regulatory pathway and its pharmacological manipulation using camelid-derived ARTC2.2-blocking nanobodies.
    Current topics in microbiology and immunology 07/2014; 384. DOI:10.1007/82_2014_420 · 4.10 Impact Factor

Publication Stats

2k Citations
706.30 Total Impact Points


  • 2014-2015
    • Université de Caen Basse-Normandie
      Caen, Lower Normandy, France
  • 2007-2015
    • Université de Rouen
      • Microbiology Signals and Microenvironment Lab (LMSM) (EA 4312)
      Mont-Saint-Aignan, Haute-Normandie, France
  • 2006-2014
    • Centre Hospitalier Universitaire Rouen
      Rouen, Haute-Normandie, France
  • 2013
    • La Chartreuse Hospital
      Villefranche, Midi-Pyrénées, France
  • 1999-2013
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      • Service de Médecine Interne 1
      Lutetia Parisorum, Île-de-France, France
  • 2008-2010
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2002-2006
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 1995-2005
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2000
    • UPMC
      Pittsburgh, Pennsylvania, United States
  • 1996
    • Hôpital Ambroise Paré – Hôpitaux universitaires Paris Ile-de-France Ouest
      Billancourt, Île-de-France, France