Clermont-Ferrand, France
Clermont-Ferrand, France

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Vernin C.,University of Lyon | Thenoz M.,University of Lyon | Gessain A.,Institute Pasteur Paris | Gout O.,Rothschild | And 5 more authors.
Cancer Research | Year: 2014

Viruses disrupt the host cell microRNA (miRNA) network to facilitate their replication. Human T-cell leukemia virus type I (HTLV-1) replication relies on the clonal expansion of its host CD4+ and CD8+ T cells, yet this virus causes adult T-cell leukemia/lymphoma (ATLL) that typically has a CD4+ phenotype. The viral oncoprotein Tax, which is rarely expressed in ATLL cells, has long been recognized for its involvement in tumor initiation by promoting cell proliferation, genetic instability, and miRNA dysregulation. Meanwhile, HBZ is expressed in both untransformed infected cells and ATLL cells and is involved in sustaining cell proliferation and silencing virus expression. Here, we show that an HBZ-miRNA axis promotes cell proliferation and genetic instability, as indicated by comet assays that showed increased numbers of DNA-strand breaks. Expression profiling of miRNA revealed that infected CD4+ cells, but not CD8+ T cells, overexpressed oncogenic miRNAs, including miR17 and miR21. HBZ activated these miRNAs via a posttranscriptional mechanism. These effects were alleviated by knocking down miR21 or miR17 and by ectopic expression of OBFC2A, a DNA-damage factor that is downregulated by miR17 and miR21 in HTLV-1-infected CD4+ T cells. These findings extend the oncogenic potential of HBZ and suggest that viral expression might be involved in the remarkable genetic instability of ATLL cells. ©2014 AACR.


Zuber J.,University of Paris Descartes | Le Quintrec M.,Service de Nephrologie et Transplantation Renale | Morris H.,Columbia University | Fremeaux-Bacchi V.,Laboratoire dImmunologie | And 2 more authors.
Transplantation Reviews | Year: 2013

Atypical hemolytic and uremic syndrome (aHUS) is associated with a high rate of recurrence and poor outcomes after kidney transplantation. Fortunately, recent advances in the understanding of the pathogenesis of aHUS have permitted an individualized risk assessment of post-transplant recurrence. Acquired or inherited dysregulation of the alternative complement pathway, thought to be the driving force of the disease, is identified in most aHUS patients. Notably, depending on the mutations involved, the risk of recurrence greatly varies, highlighting the importance of undertaking etiological investigations prior to kidney transplantation. In those with moderate to high risk of recurrence, the use of a prophylactic therapy, consisting in either plasmapheresis or eculizumab therapies, represents a major stride forward in the prevention of aHUS recurrence after kidney transplantation. In those who experience aHUS recurrence, a growing number of observations suggest that eculizumab therapy outperforms curative plasma therapy. The optimal duration of both prophylactic and curative therapies remains an important, yet unaddressed, issue. In this respect, the kidney transplant recipients, continuously exposed to endothelial-insulting factors, referred here as to triggers, might have a sustained high risk of recurrence. A global therapeutic approach should thus attempt to reduce exposure to these triggers. © 2013 Elsevier Inc.


Boutin S.,Laboratoire dImmunologie | Monteilhet V.,Laboratoire dImmunologie | Veron P.,Laboratoire dImmunologie | Leborgne C.,Laboratoire dImmunologie | And 3 more authors.
Human Gene Therapy | Year: 2010

Adeno-associated viruses (AAVs) are small, nonenveloped single-stranded DNA viruses that require helper viruses to facilitate efficient replication. Despite the presence of humoral responses to the wild-type AAV in humans, AAV remains one of the most promising candidates for therapeutic gene transfer to treat many genetic and acquired diseases. Characterization of the IgG subclass responses to AAV and study of the prevalence of both IgG and neutralizing factors to AAV types 1, 2, 5, 6, 8, and 9 in the human population are of importance for the development of new strategies to overcome these immune responses. Natural exposure to AAV types 1, 2, 5, 6, 8, and 9 can result in the production of antibodies from all four IgG subclasses, with a predominant IgG1 response and low IgG2, IgG3, and IgG4 responses. Prevalences of anti-AAV1 and-AAV2 total IgG determined by enzyme-linked immunosorbent assay were higher (67 and 72%) than those of anti-AAV5 (40%), anti-AAV6 (46%), anti-AAV8 (38%), and anti-AAV9 (47%). Furthermore, data showed that cross-reactions are important. The two highest neutralizing factor seroprevalences were observed for AAV2 (59%) and AAV1 (50.5%) and the lowest were observed for AAV8 (19%) and AAV5 (3.2%). Vectors based on AAV5, AAV8, and AAV9 may have an advantage for gene therapy in humans. Furthermore, among individuals seropositive for AAV5, AAV8, and AAV9, about 70-100% present low titers. Better characterization of the preexisting humoral responses to the AAV capsid and cross-reactivity will allow development of new strategies to circumvent AAV acquired immune responses. © Mary Ann Liebert, Inc.


Nouel A.,iGo | Simon Q.,iGo | Jamin C.,iGo | Jamin C.,Laboratoire dimmunologie | And 4 more authors.
Frontiers in Immunology | Year: 2014

Transplantation is the preferred treatment for most end-stage solid organ diseases. Despite potent immunosuppressive agents, chronic rejection remains a real problem in transplantation. For many years, the predominant immunological focus of research into transplant rejection has been T cells. The pillar of immunotherapy in clinical practice is T cell-directed, which efficiently prevents acute T cell-mediated allograft rejection. However, the root of late allograft failure is chronic rejection and the humoral arm of the immune response now emerges as an important factor in transplantation. Thus, the potential effects of Abs and B cell infiltrate on transplants have cast B cells as major actors in late graft rejection. Consequently, a number of recent drugs target either B cells or plasma cells. However, immunotherapies, such as the anti-CD20 B cell-depleting antibody, can generate deleterious effects on the transplant, likely due to the deletion of beneficial population. The positive contribution of regulatory B (Breg) cells or B10 cells has been reported in the case of transplantation, mainly in mice models and highlights the primordial role that some populations of B cells can play in graft tolerance. Yet, this regulatory aspect remains poorly characterized in clinical transplantation. Thus, total B cell depletion treatments should be avoided and novel approaches should be considered that manipulate the different B cell subsets. This article provides an overview of the current knowledge on the link between Breg cells and grafts, and reports a number of data advising Breg cells as a new target for future therapeutic approaches. © 2014 Nouël, Simon, Jamin, Pers and Hillion.


Perl M.,University of Ulm | Lomas-Neira J.,University of Rhode Island | Venet F.,Laboratoire DImmunologie | Chung C.-S.,University of Rhode Island | Ayala A.,University of Rhode Island
Expert Review of Respiratory Medicine | Year: 2011

At present, therapeutic interventions to treat acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) remain largely limited to lung-protective strategies, as no real molecular-pathophysiologic-driven therapeutic intervention has yet become available. This is in part the result of the heterogeneous nature of the etiological processes that contribute to the state of ALI/ARDS. This article sets out to understand the development of ALI resulting from indirect pulmonary insults, such as extrapulmonary sepsis and trauma, shock, burn injury or mass transfusion, as opposed to direct pulmonary challenges, such as pneumonia, aspiration or lung contusion. Here, we consider not only the experimental and clinical data concerning the roles of various immune (neutrophil, macrophage, lymphocyte and dendritic) as well as nonimmune (epithelial and endothelial) cells in orchestrating the development of ALI resulting from indirect pulmonary stimuli, but also how these cell populations might be targeted therapeutically. © 2011 Expert Reviews Ltd.


Demaret J.,Laboratoire dImmunologie
Cytometry. Part B, Clinical cytometry | Year: 2013

Diminished expression of human leukocyte antigen DR on circulating monocytes (mHLA-DR) is a reliable indicator of immunosuppression in critically ill patients, predictive of both adverse outcome and septic complications. The objective of the present work was to test, in an inter-laboratory clinical study, a standardized protocol for mHLA-DR measurement by flow cytometry. mHLA-DR was assessed in fresh whole blood according to a standardized staining protocol. Cells were analyzed on different flow cytometers (FC500, Navios, FACS Canto II) in different laboratories (Lyon and Grenoble). Results were expressed as numbers of antibodies bound per cell (AB/C). Correlations between results were excellent (Pearson and interclass correlation coefficients > 0.98). Coefficients of variations for intra-assay precision ranged from 1.9 to 3.2%. The present report highlights the robustness of this standardized flow cytometric protocol for mHLA-DR measurement in multicentric clinical studies. Copyright © 2012 International Clinical Cytometry Society.


Saison J.,Laboratoire dImmunologie
Cytometry. Part B, Clinical cytometry | Year: 2013

Although likely pivotal, the role of regulatory T cells (Tregs) in HIV pathogenesis remains elusive. This can be partly explained by analytical issues regarding their phenotypic identification in clinical studies. Instead of intracellular FOXP3 staining, CD4+CD25+CD127- phenotype has been proposed as an alternative to identify Tregs in clinical samples. However, its use remains controversial in viremic patients. Therefore, the objective of the present study was to assess the correlation between frequencies of CD4+CD25+CD127- and CD4+CD25+FOXP3+ lymphocytes in viremic and matched aviremic HIV-infected patients. Peripheral blood was collected from HIV-1 infected patients. Eleven viremic patients (Viral Load > 40 copies/mL) were matched (age, sex, CD4+ cell number) with 8 aviremic patients under highly active antiretroviral therapy (HAART). Fresh whole blood was immediately stained to analyze by flow cytometry the correlation between CD4+CD25+CD127- and the reference phenotype CD4+CD25+FOXP3+ lymphocytes in the same tube (four color staining CD4/CD25/CD127/FOXP3 for concomitant analysis of cell surface and intracellular markers). In both groups, no significant differences were observed when comparing CD4+CD25+CD127- and CD4+CD25+FOXP3+ cell frequencies. In line, a strong correlation between CD4+CD25+CD127- and CD4+CD25+FOXP3+ lymphocyte percentages was observed in the whole patient population (r: 0.948, P < 0.001) or each group separately: aviremic (r: 0.968, P < 0.001), viremic (r: 0.9, P < 0.001). Finally, we found that most CD4+FOXP3+ cells were indeed CD25+CD127-, both in viremic and aviremic groups (88.5% and 90.9%, respectively). We observed that CD4+CD25+CD127- phenotype is a good and easy-to-perform surrogate identification strategy for FOXP3+ regulatory T cells in both viremic and aviremic HIV-1-infected subjects. Thus, it represents a useful tool for monitoring Tregs in clinical research studies based on large cohorts of patients prospectively monitored, including HIV-infected subjects. Copyright © 2012 International Clinical Cytometry Society.


Sanmarco M.,Laboratoire dImmunologie | Bardin N.,Laboratoire dImmunologie
Lupus | Year: 2012

The diagnosis of seronegative antiphospholipid syndrome (APS) has been proposed for patients with well-defined clinical APS but persistently negative for the routinely tested antiphospholipid antibodies (aPLs): antibodies to cardiolipin (aCL) and to β2 glycoprotein I (aβ2GPI) and lupus anticoagulant (LA). Antibodies directed to phosphatidylethanolamine (aPE) have been described as the sole aPLs in some patients with clinical manifestations of APS. Here, we briefly summarize the available data on the clinical associations of aPEs and propose their investigation in patients with a clinical profile highly suggestive of seronegative APS. © The Author(s), 2012. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav.


Batteux F.,Laboratoire DImmunologie | Kavian N.,Laboratoire DImmunologie | Servettaz A.,Laboratoire DImmunologie
Current Opinion in Rheumatology | Year: 2011

Purpose of review To discuss the most recent published studies on chemical-induced animal models of systemic sclerosis (SSc) and to precise the important signalling pathways that lead to the initiation and progression of the disease in these models. Recent findings: Environmental factors undoubtedly contribute to the initiation and the development of SSc. Among those factors, bleomycin has been identified as a possible SSc-inducing substance in mice. The bleomycin model mimics the inflammatory changes observed in the early phase of the disease. This model has been extensively studied and has allowed identification of several key pathways activated in the human disease. More recently, a new chemical-induced model of scleroderma has been developed in mice using daily intradermal injections of a solution generating hypochlorous acid (HOCl)-model. This HOCl-model recapitulates the whole spectrum of the human disease, as fibrosis, inflammation, autoimmunity and vasculopathy can be observed in mice and brought new arguments for a major role of reactive oxygen species in the induction of local and systemic fibrosis. Summary: Chemically induced models truly develop a SSc-like disease and argue for a crucial role of ROS in SSc. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Sanmarco M.,Laboratoire dImmunologie
Journal of Immunological Methods | Year: 2010

The aim of this study was to evaluate the influence on the results of the main variables of ELISA used for the detection of antiphosphatidylethanolamine antibodies (aPE). Forty sera from patients with either autoimmune disorders including antiphospholipid syndrome (APS) or the clinical features of APS only were assayed by ELISA performed under different conditions. Variables were sources of PE (egg yolk, soybean, bovine brain or Escherichia coli), microtiter plates (plain or gamma irradiated) and buffer components-fetal calf serum (FCS), adult bovine plasma (ABP), adult bovine serum (ABS) or bovine serum albumin (BSA). aPE binding was decreased with PE from E. coli while the other tested PE gave comparable results. The influence of the type of plates was restricted to IgM isotype with slightly, but significantly higher optical densities with plain than with irradiated plates. Most importantly, the component buffer had the highest impact on the results as shown by a strong decrease of the signal by ABP or ABS. This inhibitory effect was confirmed by using mixtures of FCS or BSA with increasing concentrations of ABS. Partial delipidation of ABS resulted in a recovery of OD levels close to those obtained with FCS. This study is the first to demonstrate that aPE reactivity is dependent on the lipid concentration of the buffer component. These results highlight the need for standardization of aPE-ELISA for a better understanding of their clinical significance. © 2010 Elsevier B.V.

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