16 results on '"Mascarell L"'
Search Results
2. Oral macrophage-like cells play a key role in tolerance induction following sublingual immunotherapy of asthmatic mice
- Author
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Mascarell, L, primary, Saint-Lu, N, additional, Moussu, H, additional, Zimmer, A, additional, Louise, A, additional, Lone, Y, additional, Ladant, D, additional, Leclerc, C, additional, Tourdot, S, additional, Van Overtvelt, L, additional, and Moingeon, P, additional
- Published
- 2011
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3. MODERN: Modeling Discourse Entities and Relations for Coherent Machine Translation.
- Author
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POPESCU-BELIS, A., EVERS-VERMEUL, J., FISHEL, M., GRISOT, C., GROEN, M., HOEK, J., LOAICIGA, S., LUONG, N. Q., MASCARELL, L., MEYER, T., MICULICICH, L., MOESCHLER, J., PU, X., RIOS, A., SANDERS, T., VOLK, M., and ZUFFEREY, S.
- Subjects
MACHINE translating ,SENTENCES (Grammar) - Abstract
The MODERN project addresses coherence issues in sentence-by-sentence statistical MT, by propagating across sentences discourse-level information regarding discourse connectives, verb tenses, noun phrases and pronouns. [ABSTRACT FROM AUTHOR]
- Published
- 2016
4. Deciphering Differential Behavior of Immune Responses as the Foundation for Precision Dosing in Allergen Immunotherapy.
- Author
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Magnan A, Nicolas JF, Caimmi D, Vocanson M, Haddad T, Colas L, Scurati S, Mascarell L, and Shamji MH
- Abstract
Like in many fields of medicine, the concept of precision dosing has re-emerged in routine practice in allergology. Only one retrospective study on French physicians' practice has addressed this topic so far and generated preliminary data supporting dose adaptation, mainly based on experience, patient profile understanding and response to treatment. Both intrinsic and extrinsic factors shape the individual immune system response to allergen immunotherapy (AIT). Herein, we focus on key immune cells (i.e., dendritic cells, innate lymphoid cells, B and T cells, basophils and mast cells) involved in allergic disease and its resolution to further understand the effect of AIT on the phenotype, frequency or polarization of these cells. We strive to discriminate differences in immune responses between responders and non-responders to AIT, and discuss the eligibility of a non/low-responder subset for dose adaptation. A differential behavior in immune cells is clearly observed in responders, highlighting the importance of conducting clinical trials with large cohorts of well-characterized subjects to decipher the immune mechanism of AIT. We conclude that there is a need for designing new clinical and mechanistic studies to support the scientific rationale of dose adaptation in the interest of patients who do not properly respond to AIT.
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- 2023
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5. A combined transcriptome and proteome analysis extends the allergome of house dust mite Dermatophagoides species.
- Author
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Bordas-Le Floch V, Le Mignon M, Bussières L, Jain K, Martelet A, Baron-Bodo V, Nony E, Mascarell L, and Moingeon P
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- Allergens chemistry, Allergens genetics, Amino Acid Sequence, Animals, Hypersensitivity blood, Mass Spectrometry, Pyroglyphidae genetics, Sequence Homology, Amino Acid, Allergens metabolism, Proteome, Pyroglyphidae metabolism, Transcriptome
- Abstract
Background: House dust mites (HDMs) such as Dermatophagoides farinae and D. pteronyssinus represent major causes of perennial allergy. HDM proteomes are currently poorly characterized, with information mostly restricted to allergens. As of today, 33 distinct allergen groups have been identified for these 2 mite species, with groups 1 and 2 established as major allergens. Given the multiplicity of IgE-reactive mite proteins, potential additional allergens have likely been overlooked., Objective: To perform a comprehensive characterization of the transcriptomes, proteomes and allergomes of D. farinae and D. pteronyssinus in order to identify novel allergens., Methods: Transcriptomes were analyzed by RNA sequencing and de novo assembly. Comprehensive mass spectrometry-based analyses proteomes were combined with two-dimensional IgE reactivity profiling., Results: Transcripts from D. farinae and D. pteronyssinus were assembled, translated into protein sequences and used to populate derived sequence databases in order to inform immunoproteomic analyses. A total of 527 and 157 proteins were identified by bottom-up MS analyses in aqueous extracts from purified HDM bodies and fecal pellets, respectively. Based on high sequence similarities (>71% identity), we also identified 2 partial and 11 complete putative sequences of currently undisclosed D. pteronyssinus counterparts of D. farinae registered allergens. Immunoprofiling on 2D-gels revealed the presence of unknown 23 kDa IgE reactive proteins in both species. Following expression of non-glycosylated recombinant forms of these molecules, we confirm that these new allergens react with serum IgEs from 42% (8/19) of HDM-allergic individuals., Conclusions: Using combined transcriptome and immunoproteome approaches, we provide a comprehensive characterization of D. farinae and D. pteronyssinus allergomes. We expanded the known allergen repertoire for D. pteronyssinus and identified two novel HDM allergens, now officially referred by the International Union of Immunological Societies (IUIS) Nomenclature Subcommittee as Der f 36 and Der p 36.
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- 2017
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6. Comparative analysis of the oral mucosae from rodents and non-rodents: Application to the nonclinical evaluation of sublingual immunotherapy products.
- Author
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Thirion-Delalande C, Gervais F, Fisch C, Cuiné J, Baron-Bodo V, Moingeon P, and Mascarell L
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- Animals, Cricetinae, Dogs, Glycogen metabolism, Guinea Pigs, Humans, Immunohistochemistry, Mice, Rabbits, Rats, Swine, Tongue cytology, Tongue metabolism, Mouth Mucosa metabolism, Sublingual Immunotherapy methods
- Abstract
Background: A comparative characterization of the oral mucosa in various animals is needed to identify the best animal model(s) for nonclinical evaluation of sublingual immunotherapy products. With this aim, we studied the histological characteristics and immune cell infiltrates of oral mucosae from common animal species., Methods: Three oral regions (i.e. ventral surface of the tongue, mouth floor and cheek) obtained from eight animal species, including rodents (i.e. mice, rats, hamsters, guinea pigs) and non-rodents (i.e. rabbits, dogs, minipigs and monkeys) were characterized by histology and immunohistology in comparison with a human tongue., Results: Rodents exhibit a thin keratinized epithelium with low epithelial extensions, whereas non-rodents, most particularly minipigs and monkeys, display a non-keratinized epithelium with larger rete ridges, similarly to humans. Glycogen-rich cells in the superficial epithelial layers are observed in samples from both minipigs, monkeys and humans. Comparable immune subpopulations detected in the 3 oral regions from rodent and non-rodent species include MHC-II+ antigen presenting cells, mostly CD163+ macrophages, located in the lamina propria (LP) and muscle tissue in the vicinity of resident CD3+CD4+ T cells. Limited numbers of mast cells are also detected in the LP and muscle tissue from all species., Conclusion: The oral mucosae of minipigs and monkeys are closest to that of humans, and the immune networks are quite similar between all rodents and non-rodents. Taking into account the ethical and logistical difficulties of performing research in the latter species, rodents and especially mice, should preferentially be used for pharmacodynamics/efficacy studies. Our data also support the use of minipigs to perform biodistribution and safety studies of sublingual immunotherapy products.
- Published
- 2017
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7. Effector and regulatory dendritic cells display distinct patterns of miRNA expression.
- Author
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Lombardi V, Luce S, Moussu H, Morizur L, Gueguen C, Neukirch C, Chollet-Martin S, Mascarell L, Aubier M, Baron-Bodo V, and Moingeon P
- Subjects
- Cell Differentiation immunology, Conjunctivitis, Allergic pathology, Dendritic Cells pathology, Humans, Rhinitis, Allergic pathology, Th1 Cells immunology, Th1 Cells pathology, Th2 Cells immunology, Th2 Cells pathology, Conjunctivitis, Allergic immunology, Dendritic Cells immunology, Gene Expression Regulation immunology, MicroRNAs immunology, Rhinitis, Allergic immunology
- Abstract
Introduction: MicroRNAs (miRNAs) contribute to the regulation of dendritic cell (DC) polarization, thereby influencing the balance of adaptive immune responses. Herein, we studied the expression of miRNAs in polarized DCs and analyzed whether expression of these miRNAs could be associated with allergic rhinitis and allergen immunotherapy (AIT) outcome., Method: Using specific culture conditions, we differentiated immature human monocyte-derived DCs into DC1, DC2, and DCreg subsets (supporting the differentiation of T
H 1, TH 2 or regulatory T cells, respectively). Profiling of miRNA expression was performed in these DC subpopulations using microarrays. Levels of miRNAs specific for polarized DCs were then evaluated in a cohort of 58 patients with allergic rhinitis and 25 non-allergic controls, as well as in samples from 30 subjects treated with sublingual grass pollen tablets or placebo for four months., Results: We successfully identified 16 miRNAs differentially regulated between immature DCs, DC1, DC2, and DCreg cells. In allergic rhinoconjunctivitis patients, the expression of two of those miRNAs (miR-132 and miR-155), was down-regulated compared to non-allergic individuals. However, the levels of these miRNAs were not significantly modified following four months of grass pollen immunotherapy., Conclusions: Studying polarized DCs and clinical samples from subjects with or without allergic rhinoconjunctivitis, we demonstrated that the expression of two miRNAs linked to effector DCs (i.e., DC1 and/or DC2 cells), was reduced in the blood of patients with allergic rhinoconjunctivitis. Nevertheless, these miRNAs did not represent relevant biomarkers to predict or follow-up AIT efficacy., (© 2017 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd.)- Published
- 2017
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8. Structural and Functional Characterization of the Major Allergen Amb a 11 from Short Ragweed Pollen.
- Author
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Groeme R, Airouche S, Kopečný D, Jaekel J, Savko M, Berjont N, Bussieres L, Le Mignon M, Jagic F, Zieglmayer P, Baron-Bodo V, Bordas-Le Floch V, Mascarell L, Briozzo P, and Moingeon P
- Subjects
- Allergens chemistry, Allergens immunology, Amino Acid Sequence, Animals, Catalytic Domain, Conserved Sequence, Crystallography, X-Ray, Cysteine Proteases immunology, Enzyme Precursors immunology, Female, Hydrogen Bonding, Mice, Inbred BALB C, Models, Molecular, Molecular Sequence Data, Plant Proteins immunology, Protein Processing, Post-Translational, Proteolysis, Rhinitis, Allergic, Seasonal prevention & control, Antigens, Plant immunology, Cysteine Proteases chemistry, Enzyme Precursors chemistry, Plant Extracts immunology, Plant Proteins chemistry, Rhinitis, Allergic, Seasonal immunology
- Abstract
Allergy to the short ragweed (Ambrosia artemisiifolia) pollen is a major health problem. The ragweed allergen repertoire has been recently expanded with the identification of Amb a 11, a new major allergen belonging to the cysteine protease family. To better characterize Amb a 11, a recombinant proform of the molecule with a preserved active site was produced in Escherichia coli, refolded, and processed in vitro into a mature enzyme. The enzymatic activity is revealed by maturation following an autocatalytic processing resulting in the cleavage of both N- and C-terminal propeptides. The 2.05-Å resolution crystal structure of pro-Amb a 11 shows an overall typical C1A cysteine protease fold with a network of molecular interactions between the N-terminal propeptide and the catalytic triad of the enzyme. The allergenicity of Amb a 11 was confirmed in a murine sensitization model, resulting in airway inflammation, production of serum IgEs, and induction of Th2 immune responses. Of note, inflammatory responses were higher with the mature form, demonstrating that the cysteine protease activity critically contributes to the allergenicity of the molecule. Collectively, our results clearly demonstrate that Amb a 11 is a bona fide cysteine protease exhibiting a strong allergenicity. As such, it should be considered as an important molecule for diagnosis and immunotherapy of ragweed pollen allergy., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2016
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9. Allergen immunotherapy for birch pollen-allergic patients: recent advances.
- Author
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Moingeon P, Floch VB, Airouche S, Baron-Bodo V, Nony E, and Mascarell L
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- Animals, Antigens, Plant immunology, Clinical Trials as Topic, Conjunctivitis, Allergic immunology, Desensitization, Immunologic trends, Humans, Plant Extracts therapeutic use, Pollen immunology, Rhinitis, Allergic immunology, Rhinitis, Allergic, Seasonal immunology, Antigens, Plant therapeutic use, Betula immunology, Conjunctivitis, Allergic therapy, Desensitization, Immunologic methods, Recombinant Proteins therapeutic use, Rhinitis, Allergic therapy, Rhinitis, Allergic, Seasonal therapy
- Abstract
As of today, allergen immunotherapy is performed with aqueous natural allergen extracts. Recombinant allergen vaccines are not yet commercially available, although they could provide patients with well-defined and highly consistent drug substances. As Bet v 1 is the major allergen involved in birch pollen allergy, with more than 95% of patients sensitized to this allergen, pharmaceutical-grade recombinant Bet v 1-based vaccines were produced and clinically tested. Herein, we compare the clinical results and modes of action of treatments based on either a birch pollen extract or recombinant Bet v 1 expressed as hypoallergenic or natural-like molecules. We also discuss the future of allergen immunotherapy with improved drugs intended for birch pollen-allergic patients suffering from rhinoconjunctivitis.
- Published
- 2016
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10. Identification of Novel Short Ragweed Pollen Allergens Using Combined Transcriptomic and Immunoproteomic Approaches.
- Author
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Bordas-Le Floch V, Le Mignon M, Bouley J, Groeme R, Jain K, Baron-Bodo V, Nony E, Mascarell L, and Moingeon P
- Subjects
- Allergens chemistry, Allergens isolation & purification, Ambrosia chemistry, Female, Gene Expression Profiling, Humans, Immunoglobulin E chemistry, Male, Plant Proteins chemistry, Plant Proteins isolation & purification, Pollen chemistry, Proteomics, Allergens immunology, Ambrosia immunology, Immunoglobulin E immunology, Plant Proteins immunology, Pollen immunology, Rhinitis, Allergic, Seasonal immunology
- Abstract
Background: Allergy to short ragweed (Ambrosia artemisiifolia) pollen is a serious and expanding health problem in North America and Europe. Whereas only 10 short ragweed pollen allergens are officially recorded, patterns of IgE reactivity observed in ragweed allergic patients suggest that other allergens contribute to allergenicity. The objective of the present study was to identify novel allergens following extensive characterization of the transcriptome and proteome of short ragweed pollen., Methods: Following a Proteomics-Informed-by-Transcriptomics approach, a comprehensive transcriptomic data set was built up from RNA-seq analysis of short ragweed pollen. Mass spectrometry-based proteomic analyses and IgE reactivity profiling after high resolution 2D-gel electrophoresis were then combined to identify novel allergens., Results: Short ragweed pollen transcripts were assembled after deep RNA sequencing and used to inform proteomic analyses, thus leading to the identification of 573 proteins in the short ragweed pollen. Patterns of IgE reactivity of individual sera from 22 allergic patients were assessed using an aqueous short ragweed pollen extract resolved over 2D-gels. Combined with information derived from the annotated pollen proteome, those analyses revealed the presence of multiple unreported IgE reactive proteins, including new Amb a 1 and Amb a 3 isoallergens as well as 7 novel candidate allergens reacting with IgEs from 20-70% of patients. The latter encompass members of the carbonic anhydrase, enolase, galactose oxidase, GDP dissociation inhibitor, pathogenesis related-17, polygalacturonase and UDP-glucose pyrophosphorylase families., Conclusions: We extended the list of allergens identified in short ragweed pollen. These findings have implications for both diagnosis and allergen immunotherapy purposes.
- Published
- 2015
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11. Ectosomes from neutrophil-like cells down-regulate nickel-induced dendritic cell maturation and promote Th2 polarization.
- Author
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Turbica I, Gallais Y, Gueguen C, Tharinger H, Al Sabbagh C, Gorges R, Gary-Gouy H, Kerdine-Römer S, Pallardy M, Mascarell L, Gleizes A, and Chollet-Martin S
- Subjects
- Allergens pharmacology, Antigens, CD genetics, B7-H1 Antigen biosynthesis, B7-H1 Antigen genetics, Cell Differentiation, Coculture Techniques, Dendritic Cells drug effects, Dermatitis, Allergic Contact etiology, HLA-DR Antigens biosynthesis, HLA-DR Antigens genetics, Humans, Leukemia, Myeloid, Acute pathology, Liposomes, Lymphokines genetics, Monocytes cytology, Myeloid Cells ultrastructure, Neutrophils ultrastructure, Nickel pharmacology, Toll-Like Receptor 4 agonists, Toll-Like Receptor 4 immunology, Allergens immunology, Antigens, CD biosynthesis, Cell-Derived Microparticles physiology, Dendritic Cells immunology, Dermatitis, Allergic Contact immunology, Gene Expression Regulation immunology, Lymphokines biosynthesis, Myeloid Cells immunology, Neutrophils immunology, Nickel immunology, Th2 Cells cytology
- Abstract
DCs are the first immune cells to be exposed to allergens, including chemical sensitizers, such as nickel, a human TLR4 agonist that induces DC maturation. In ACD, DCs can interact with PMNs that are recruited and activated, leading, in particular, to ectosome release. The objective of this work was to characterize the effects of PMN-Ect on DC functions in an ACD context. We first developed a standardized protocol to produce, characterize, and quantify ectosomes by use of human PLB-985 cells, differentiated into mature PMN (PLB-Ect). We then studied the in vitro effects of these purified ectosomes on human moDC functions in response to NiSO4 and to LPS, another TLR4 agonist. Confocal fluorescence microscopy showed that PLB-Ect was internalized by moDCs and localized in the lysosomal compartment. We then showed that PLB-Ect down-regulated NiSO4-induced moDC maturation, as witnessed by decreased expression of CD40, CD80, CD83, CD86, PDL-1, and HLA-DR and by decreased levels of IL-1β, IL-6, TNF-α, and IL-12p40 mRNAs. These effects were related to p38MAPK and NF-κB down-regulation. However, no increase in pan-regulatory DC marker genes (GILZ, CATC, C1QA) was observed; rather, levels of effector DC markers (Mx1, NMES1) were increased. Finally, when these PLB-Ect + NiSO4-treated moDCs were cocultured with CD4(+) T cells, a Th2 cytokine profile seemed to be induced, as shown, in particular, by enhanced IL-13 production. Together, these results suggest that the PMN-Ect can modulate DC maturation in response to nickel, a common chemical sensitizer responsible for ADC., (© Society for Leukocyte Biology.)
- Published
- 2015
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12. SLIT prevents the development of eczema in percutaneous allergen-sensitized mice.
- Author
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Vanbervliet B, Tourdot S, Mascarell L, Rouzaire P, Vocanson M, Rozières A, Benetière J, Moingeon P, Nicolas JF, and Hennino A
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- Administration, Sublingual, Allergens pharmacology, Animals, Dermatitis, Atopic immunology, Dermatitis, Atopic prevention & control, Disease Models, Animal, Mice, Skin immunology, Allergens immunology, Eczema immunology, Eczema prevention & control, Immunotherapy methods, Pyroglyphidae immunology
- Published
- 2012
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13. Induction of tolerance via the sublingual route: mechanisms and applications.
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Moingeon P and Mascarell L
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- Administration, Sublingual, Animals, Humans, Hypersensitivity immunology, Hypersensitivity therapy, Immunity, Mucosal, Mouth Mucosa immunology, Vaccines immunology, Vaccines therapeutic use, Allergens administration & dosage, Desensitization, Immunologic, Immune Tolerance
- Abstract
The clinical efficacy of sublingual immunotherapy (SLIT) with natural allergen extracts has been established in IgE-dependent respiratory allergies to grass or tree pollens, as well as house dust mites. Sublingual vaccines have an excellent safety record, documented with approximately 2 billion doses administered, as of today, in humans. The oral immune system comprises various antigen-presenting cells, including Langerhans cells, as well as myeloid and plasmacytoid dendritic cells (DCs) with a distinct localisation in the mucosa, along the lamina propria and in subepithelial tissues, respectively. In the absence of danger signals, all these DC subsets are tolerogenic in that they support the differentiation of Th1- and IL10-producing regulatory CD4(+) T cells. Oral tissues contain limited numbers of mast cells and eosinophils, mostly located in submucosal areas, thereby explaining the good safety profile of SLIT. Resident oral Th1, Th2, and Th17 CD4(+) T cells are located along the lamina propria, likely representing a defence mechanism against infectious pathogens. Second-generation sublingual vaccines are being developed, based upon recombinant allergens expressed in a native conformation, possibly formulated with Th1/T reg adjuvants and/or mucoadhesive particulate vector systems specifically designed to target oral dendritic cells.
- Published
- 2012
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14. Induction of neutralizing antibodies and Th1-polarized and CD4-independent CD8+ T-cell responses following delivery of human immunodeficiency virus type 1 Tat protein by recombinant adenylate cyclase of Bordetella pertussis.
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Mascarell L, Fayolle C, Bauche C, Ladant D, and Leclerc C
- Subjects
- Adenylate Cyclase Toxin metabolism, Animals, Drug Evaluation, Preclinical, Female, HIV Infections blood, Interferon-gamma biosynthesis, Lymphocyte Count, Mice, Mice, Inbred BALB C, Neutralization Tests, Recombinant Proteins immunology, Recombinant Proteins metabolism, Spleen immunology, T-Cell Antigen Receptor Specificity, Th1 Cells immunology, Vaccines, Synthetic immunology, tat Gene Products, Human Immunodeficiency Virus, AIDS Vaccines immunology, Adenylate Cyclase Toxin immunology, CD8-Positive T-Lymphocytes immunology, Gene Products, tat immunology, HIV Antibodies blood, HIV Infections immunology, Immunization
- Abstract
HIV-Tat, a conserved protein playing a key role in the early life cycle of the human immunodeficiency virus (HIV) has been proposed as a potential AIDS vaccine. An HIV-Tat-based vaccine should elicit a broad, long-lasting, and neutralizing immune response. We have previously demonstrated that the adenylate cyclase (CyaA) from Bordetella pertussis targets dendritic cells and delivers CD8(+) and CD4(+) T-cell epitopes into the major histocompatibility complex class I and class II presentation pathways. We have also showed that CyaA induced specific and protective cytotoxic T cell responses in vivo. Here, we designed a prototype vaccine based on the HIV type 1 Tat delivered by CyaA (CyaA-E5-Tat) and tested its capacity to induce HIV-Tat-specific cellular as well as antibody responses. We showed that immunization of mice by CyaA-E5-Tat in the absence of adjuvant elicited strong and long-lasting neutralizing anti-Tat antibody responses more efficient than those obtained after immunization with Tat toxoid in aluminum hydroxide adjuvant. Analyses of the anti-Tat immunoglobulin G isotypes and the cytokine pattern showed that CyaA-E5-Tat induced a Th1-polarized immune response in contrast to the Th2-polarized immune responses obtained with the Tat toxoid. In addition, our data demonstrated that HIV-Tat-specific gamma interferon-producing CD8(+) T cells were generated after vaccination with CyaA-E5-Tat in a CD4(+) T-cell-independent manner. Based on these findings, CyaA-E5-Tat represents an attractive vaccine candidate for both preventive and therapeutic vaccination involving CyaA as an efficient nonreplicative vector for protein delivery.
- Published
- 2005
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15. Differential expression of regulator of G-protein signalling transcripts and in vivo migration of CD4+ naïve and regulatory T cells.
- Author
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Agenès F, Bosco N, Mascarell L, Fritah S, and Ceredig R
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- Animals, Female, Gene Expression immunology, Lymphocyte Activation immunology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Parabiosis, Polymerase Chain Reaction methods, RGS Proteins genetics, RGS Proteins metabolism, Receptors, Interleukin-2 analysis, Signal Transduction immunology, CD4-Positive T-Lymphocytes immunology, Chemotaxis, Leukocyte immunology, RGS Proteins immunology
- Abstract
The immune response of T lymphocytes to pathogens is initiated in draining secondary lymphoid organs, and activated cells then migrate to the site of infection. Thus, control of naive and regulatory CD4+ T-cell migration is crucial; however, it is poorly understood in physiological and pathological conditions. We found that CD4+ subpopulations displayed characteristic regulator of G-protein signalling (RGS) gene expression profiles. Regulatory T cells express higher levels of RGS1, RGS9 and RGS16 than naive cells. These genes are up-regulated upon cell activation and their level of expression correlates with in vivo cell migration. Using parabiosis, we showed that regulatory T lymphocytes migrate less than naive T cells and that migrant naive T cells express even lower RGS levels than their static counterparts. Our results show an inverse correlation between the capacity to migrate and the levels of RGS1, RGS9 and RGS16 for both naive and regulatory T cells. Taken together, these results suggest a role for RGS molecules in chemokine-induced lymphocyte migration and demonstrate the peculiarity of regulatory T cells in terms of phenotype and migration ability, providing new insights into their function.
- Published
- 2005
- Full Text
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16. Characterization of a gene encoding two isoforms of a mitochondrial protein up-regulated by cyclosporin A in activated T cells.
- Author
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Mascarell L, Auger R, Alcover A, Ojcius DM, Jungas T, Cadet-Daniel V, Kanellopoulos JM, and Truffa-Bachi P
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- Alternative Splicing, Amino Acid Sequence, Animals, Apoptosis, Base Sequence, Blotting, Western, Calcineurin metabolism, Cell Line, Cell Membrane metabolism, Cytochromes c metabolism, DNA, Complementary metabolism, Endopeptidase K pharmacology, Flow Cytometry, Genome, Green Fluorescent Proteins, Humans, Immunosuppressive Agents pharmacology, In Vitro Techniques, Intracellular Membranes metabolism, Luminescent Proteins metabolism, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence, Molecular Sequence Data, Necrosis, Peptides chemistry, Plasmids metabolism, Protein Isoforms, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Subcellular Fractions, Time Factors, Tissue Distribution, Transfection, Cyclosporine pharmacology, Membrane Proteins biosynthesis, Membrane Proteins genetics, Mitochondria metabolism, Mitochondrial Proteins biosynthesis, Mitochondrial Proteins genetics, T-Lymphocytes metabolism, Up-Regulation
- Abstract
Cyclosporin A (CSA) is an immunosuppressor used in organ transplantation. A recent proteomic analysis has revealed that activation of T cells in the presence of CSA induces the synthesis of hundreds of new proteins. Here we used representational difference analysis to characterize some of the corresponding induced genes. After cDNA bank screening we focused on one of these genes, which we named CSA-conditional, T cell activation-dependent (CSTAD) gene. This gene produces two mRNAs resulting from alternative splicing events. They encode two proteins of 104 and 141 amino acids, CSTADp-S and CSTADp-L, for the short and long forms, respectively. FK506 had the same effect as CSA, whereas rapamycin did not affect the level of CSTAD gene expression, demonstrating that inhibition of the calcineurin activation pathway is involved in CSTAD gene up-regulation. CSA also led to overexpression of CSTAD in mice immunized in the presence of CSA, confirming the in vitro analysis. Microscopic and cytofluorimetric analysis of cells expressing green fluorescent protein-tagged CSTADp-L and CSTADp-S showed that both proteins colocalize with mitochondrial markers and depolarize the mitochondrial transmembrane potential without causing release of cytochrome c, apoptosis, or necrosis. Both CSTADp isoforms are sensitive to proteinase K, implying that they are located in the mitochondrial outer membrane. These data reveal a new mechanism of action for CSA, which involves up-regulation of a gene whose products are sorted to mitochondria and depolarize the mitochondrial membrane.
- Published
- 2004
- Full Text
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