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23 results on '"Feriel Hacini-Rachinel"'

1. Oral probiotic control skin inflammation by acting on both effector and regulatory T cells.

Author

Feriel Hacini-Rachinel, Hanane Gheit, Jean-Benoit Le Luduec, Fariel Dif, Stéphane Nancey, and Dominique Kaiserlian

Subjects
Medicine, Science
Abstract

Probiotics are believed to alleviate allergic and inflammatory skin disorders, but their impact on pathogenic effector T cells remains poorly documented. Here we show that oral treatment with the probiotic bacteria L. casei (DN-114 001) alone alleviates antigen-specific skin inflammation mediated by either protein-specific CD4(+) T cells or hapten-specific CD8(+) T cells. In the model of CD8(+) T cell-mediated skin inflammation, which reproduces allergic contact dermatitis in human, inhibition of skin inflammation by L. casei is not due to impaired priming of hapten-specific IFNgamma-producing cytolytic CD8(+) effector T cells. Alternatively, L. casei treatment reduces the recruitment of CD8(+) effector T cells into the skin during the elicitation (i.e. symptomatic) phase of CHS. Inhibition of skin inflammation by L. casei requires MHC class II-restricted CD4(+) T cells but not CD1d-restricted NK-T cells. L casei treatment enhanced the frequency of FoxP3(+) Treg in the skin and increased the production of IL-10 by CD4(+)CD25(+) regulatory T cells in skin draining lymph nodes of hapten-sensitized mice. These data demonstrate that orally administered L. casei (DN-114 001) efficiently alleviate T cell-mediated skin inflammation without causing immune suppression, via mechanisms that include control of CD8(+) effector T cells and involve regulatory CD4(+) T cells. L. casei (DN-114 001) may thus represent a probiotic of potential interest for immunomodulation of T cell-mediated allergic skin diseases in human.

Published
2009
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2. Transcriptomic characterization of prurigo nodularis and the therapeutic response to nemolizumab

Author

J. Michelle Kahlenberg, Valérie Julia, Allison C. Billi, Sonja Ständer, Anne Lazzari, Paul Fogel, Xianying Xing, Feriel Hacini-Rachinel, Matthew Patrick, Celine C. Berthier, Lam C. Tsoi, Johann E. Gudjonsson, Christophe Piketty, Jayendra Kumar Krishnaswamy, François Rousseau, and Henning Wiegmann

Subjects
Nemolizumab, Epidermis (botany), business.industry, Pruritus, medicine.medical_treatment, Immunology, Cutaneous nerve, Antibodies, Monoclonal, Humanized, medicine.disease, Proinflammatory cytokine, Pathogenesis, medicine.anatomical_structure, Cytokine, Chronic Disease, Cancer research, Cytokines, Humans, Immunology and Allergy, Medicine, Prurigo, Transcriptome, business, Keratinocyte, Prurigo nodularis
Abstract

Background Prurigo nodularis (PN) is a debilitating, difficult-to-treat, intensely pruritic, chronic inflammatory skin disease characterized by hyperkeratotic skin nodules. The pathogenesis of PN is not well understood but is believed to involve cross talk between sensory nerve fibers, immune cells, and the epidermis. It is centered around the neuroimmune cytokine IL-31, driving an intractable itch–scratch cycle. Objective We sought to provide a comprehensive view of the transcriptomic changes in PN skin and characterize the mechanism of action of the anti–IL-31 receptor inhibitor nemolizumab. Method RNA sequencing of biopsy samples obtained from a cohort of patients treated with the anti–IL-31 receptor inhibitor nemolizumab and taken at baseline and week 12. Generation and integration of patient data with RNA-Seq data generated from reconstructed human epidermis stimulated with IL-31 and other proinflammatory cytokines. Results Our results demonstrate that nemolizumab effectively decreases IL-31 responses in PN skin, leading to effective suppression of downstream inflammatory responses including TH2/IL-13 and TH17/IL-17 responses. This is accompanied by decreased keratinocyte proliferation and normalization of epidermal differentiation and function. Furthermore, our results demonstrate how transcriptomic changes associated with nemolizumab treatment correlate with improvement in lesions, pruritus, stabilization of extracellular matrix remodeling, and processes associated with cutaneous nerve function. Conclusion These data demonstrate a broad response to IL-31 receptor inhibition with nemolizumab and confirm the critical upstream role of IL-31 in PN pathogenesis.

Published
2022

3. Single-cell analysis of human skin identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriasis

Author

Tan Siyun Lucinda, Charles-Antoine Dutertre, Mark B Y Tang, Satoshi Nakamizo, Josephine Lum, Laurent Yvan-Charvet, Shawn Lim, Feriel Hacini-Rachinel, Geraldine Koh, Florent Ginhoux, Emma Guttman-Yassky, Masashi Iwata, Tsuyoshi Goto, Charlene Foong, Pearly Yong, Kaori Tomari, Reiko Sato, Xiaomeng Zhang, Kenji Kabashima, Rintaro Shibuya, Ahad Khalilnezhad, Valérie Julia, Colin Theng, Kahbing Jasmine Tan, Benoit Malleret, Helen He, and Baptiste Janela

Subjects
0301 basic medicine, CD14, T cell, Immunology, Population, Interleukin-1beta, Lipopolysaccharide Receptors, Gene Expression, Human skin, Biology, Dermatitis, Atopic, 03 medical and health sciences, 0302 clinical medicine, Single-cell analysis, Psoriasis, medicine, Immunology and Allergy, Macrophage, Humans, Gene Regulatory Networks, education, Interleukin-15, education.field_of_study, Macrophages, Dendritic cell, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Langerhans Cells, Interleukin-23 Subunit p19, Single-Cell Analysis
Abstract

Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)–mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD and PSO skin to identify macrophages and all DC subsets, including the newly described mature LAMP3+BIRC3+ DCs enriched in immunoregulatory molecules (mregDC) and CD14+ DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14+ DC3s increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathological in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14+ DC3s as potential promoters of inflammation in PSO.

Published
2020

4. Discovery and process development of a novel TACE inhibitor for the topical treatment of psoriasis

Author

Craig S. Harris, Isabelle Cardinaud, Feriel Hacini-Rachinel, Nicolas Rodeville, Audrey Beillard, Arnaud Reitz, Marilyne Bourotte, Benoit Deprez, Laetitia Bonnary, Catherine Comino, Corinne Millois, Delphine Spiesse, Claire Bouix-Peter, Denis Duvert, Jean-Guy Boiteau, Jean-Marie Arlabosse, Yushma Bhurruth-Alcor, Anne-Pascale Luzy, Laurent F. Hennequin, Gaëlle Polge, Emmanuel Vial, Loïc Tomas, Samuel Tabet, Kevin Reverse, Arnaud Mathieu, Artur Pinto, Angélique Feret, Karine Bouquet, Gilles Ouvry, Stéphanie Astri, Nicolas Orsini, Jonathan Pascau, Nathalie Taquet, David Piwnica, and Patricia Rossio

Subjects
0301 basic medicine, Process development, Administration, Topical, Clinical Biochemistry, Druggability, Pharmaceutical Science, Topical treatment, ADAM17 Protein, Pharmacology, Hydroxamic Acids, Skin Diseases, 01 natural sciences, Biochemistry, Mice, 03 medical and health sciences, In vivo, Psoriasis, Drug Discovery, medicine, Animals, Humans, Enzyme Inhibitors, Molecular Biology, Mice, Hairless, Sulfonamides, Tumor Necrosis Factor-alpha, 010405 organic chemistry, Chemistry, Organic Chemistry, Oxazolone, medicine.disease, Tace inhibitor, 0104 chemical sciences, 030104 developmental biology, Solubility, Drug Design, Microsomes, Liver, Molecular Medicine, Female
Abstract

Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield.

Published
2018

5. Identification of novel TACE inhibitors compatible with topical application

Author

Arnaud Reitz, Corinne Millois, Marilyne Bourotte, Feriel Hacini-Rachinel, Carine Rosignoli, Arnaud Mathieu, Sandrine Chambon, Denis Duvert, Anne-Pascale Luzy, Laetitia Bonnary, Gwenaëlle Duvert, Gilles Ouvry, Jonathan Pascau, Craig S. Harris, Benoit Deprez, Laurent F. Hennequin, Catherine Comino, Yushma Bhurruth-Alcor, Yaël Berton, Nathalie Taquet, Claire Bouix-Peter, Gaëlle Polge, Kevin Reverse, Artur Pinto, and Karine Bouquet

Subjects
0301 basic medicine, Cellular activity, Side effect, Administration, Topical, Clinical Biochemistry, Pharmaceutical Science, Context (language use), ADAM17 Protein, Pharmacology, Hydroxamic Acids, 01 natural sciences, Biochemistry, 03 medical and health sciences, Psoriasis, Drug Discovery, medicine, Humans, Enzyme Inhibitors, Molecular Biology, Tumor necrosis factor α, ADME, chemistry.chemical_classification, 010405 organic chemistry, Organic Chemistry, medicine.disease, 0104 chemical sciences, 030104 developmental biology, Enzyme, chemistry, Molecular Medicine
Abstract

Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.

Published
2017

6. A Subset of Type I Conventional Dendritic Cells Controls Cutaneous Bacterial Infections through VEGF alpha-Mediated Recruitment of Neutrophils

Author

Sandra Hubert, Martin Guilliams, Carlos G. Briseño, Benoit Malleret, Lai Guan Ng, Baptiste Janela, Mai Chan Lau, Josephine Lum, Kenneth M. Murphy, Philippe Musette, Yannick Simoni, Leen Vanhoutte, Bernard Malissen, Laurent F. Hennequin, Christian Wohn, Wan Ting Kong, Amit Patel, Michael G. Fehlings, Michael Poidinger, Rasha Msallam, Florent Ginhoux, Ansuman T. Satpathy, Emmanuel Vial, Jinmiao Chen, Chi Ching Goh, Francesca Zolezzi, Feriel Hacini-Rachinel, Evan W. Newell, Alexander A. Maini, Simon Yona, Agency for science, technology and research [Singapore] (A*STAR), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Toronto, Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Microbiology & Immunology [Singapore] (Yong Loo Lin School of Medicine), National University of Singapore (NUS), Department of Biotechnology and Biosciences, Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Washington University school of medicine, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Universiteit Gent = Ghent University [Belgium] (UGENT), Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Nestle Skin Health GALDERMA R&D, Service de Dermatologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Hôpital Charles Nicolle [Rouen], Galderma International S.A.S. [Paris, France], Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University (UGENT), École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Genopolis Consortium, University of Milano-Bicocca, Ghent University [Belgium] (UGENT), and Hôpital Charles Nicolle [Rouen]-CHU Rouen

Subjects
0301 basic medicine, Vascular Endothelial Growth Factor A, Injections, Intradermal, Neutrophils, medicine.medical_treatment, Immunology, Antigen presentation, Biology, 03 medical and health sciences, Propionibacterium acnes, Mice, 0302 clinical medicine, Immune system, Immunity, Acne Vulgaris, medicine, Immunology and Allergy, Animals, Humans, RNA, Messenger, Ear, External, Gram-Positive Bacterial Infections, Antigen Presentation, integumentary system, Monocyte, Dendritic cell, Dendritic Cells, biology.organism_classification, 3. Good health, Mice, Inbred C57BL, Chemotaxis, Leukocyte, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, MRNA Sequencing, Cytokine, Gene Ontology, Gene Expression Regulation, Neutrophil Infiltration, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Single-Cell Analysis
Abstract

Skin conventional dendritic cells (cDCs) exist as two distinct subsets, cDC1s and cDC2s, which maintain the balance of immunity to pathogens and tolerance to self and microbiota. Here, we examined the roles of dermal cDC1s and cDC2s during bacterial infection, notably Propionibacterium acnes (P. acnes). cDC1s, but not cDC2s, regulated the magnitude of the immune response to P. acnes in the murine dermis by controlling neutrophil recruitment to the inflamed site and survival and function therein. Single-cell mRNA sequencing revealed that this regulation relied on secretion of the cytokine vascular endothelial growth factor alpha (VEGF-alpha) by a minor subset of activated EpCAM(+)CD59(+) Ly-6D(+) cDC1s. Neutrophil recruitment by dermal cDC1s was also observed during S. aureus, bacillus Calmette-Guerin (BCG), or E. coli infection, as well as in a model of bacterial insult in human skin. Thus, skin cDC1s are essential regulators of the innate response in cutaneous immunity and have roles beyond classical antigen presentation.

Published
2019

7. Sulfoximines as potent RORγ inverse agonists

Author

Etienne Thoreau, Craig S. Harris, David Froude, Franck Bihl, Gilles Ouvry, Delphine Spiesse, Patricia Rossio, Christophe Feret, Emmanuel Vial, Laurent F. Hennequin, Jonathan Pascau, Coralie Pascau, Romain Pierre, Claire Defoin-Platel, Nathalie Taquet, Catherine Hervouet, Veronique Parnet, Olivier Christin, Guillaume Lafitte, Sophie Deret, Catherine Raffin, Claire Bouix-Peter, Anne-Pascale Luzy, Feriel Hacini-Rachinel, Branislav Musicki, Danielle Orfila, Rodolphe Vatinel, Laboratoire de synthèse organique (DCSO), École polytechnique (X)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Nestle Skin Health GALDERMA R&D, Religions et croyances (LARHRA REC ), LAboratoire de Recherche Historique Rhône-Alpes - UMR5190 (LARHRA), École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire d'Immunologie et Immunopathologie [CHU Poitiers] (CNRS URA 1172), Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre National de la Recherche Scientifique (CNRS), Mucosal Immunity, Vaccination, and Biometrics -- Immunité des muqueuses, vaccinations et biothérapies, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Transporteurs et Imagerie, Radiothérapie en Oncologie et Mécanismes biologiques des Altérations du Tissu Osseux (TIRO-MATOs - UMR E4320), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-UMR E4320 (TIRO-MATOs), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA), Nestlé Institute of Health Sciences SA [Lausanne, Switzerland], GALDERMA R&D, Galderma Recherche et Développement [Biot, France] (Galderma R&D), Virologie humaine, École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), AstraZeneca, Cancer and Infection Research, Université Nice Sophia Antipolis (... - 2019) (UNS), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), UMR E4320 (TIRO-MATOs), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, and École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Drug Inverse Agonism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Pharmaceutical Science, Context (language use), Pharmacology, Ligands, 010402 general chemistry, 01 natural sciences, Biochemistry, Structure-Activity Relationship, chemistry.chemical_compound, In vivo, Drug Discovery, Animals, Humans, Inverse agonist, Potency, [CHIM]Chemical Sciences, Hydroxymethyl, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Mice, Inbred BALB C, Sulfonamides, Molecular Structure, 010405 organic chemistry, Organic Chemistry, Stereoisomerism, Biological activity, Nuclear Receptor Subfamily 1, Group F, Member 3, 0104 chemical sciences, 3. Good health, chemistry, Nuclear receptor, Sulfoxides, Lipophilicity, Molecular Medicine, Female, Imines
Abstract

Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model.

Published
2018

8. Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis

Author

Coralie Pascau, Nicolas Atrux-Tallau, Laurent F. Hennequin, Christophe Feret, Gilles Ouvry, Feriel Hacini-Rachinel, Craig S. Harris, Claire Defoin-Platel, Nathalie Taquet, Sophie Deret, Mathieu Forissier, Hélène Huguet, Etienne Thoreau, Benjamin Ozello, Olivier Christin, Emmanuel Vial, Guillaume Lafitte, Danielle Orfila, Isabelle Carlavan, Franck Bihl, David Froude, Jean-François Fournier, Denis Duvert, Anne-Pascale Luzy, Delphine Spiesse, Patricia Rossio, Marie-Josée Cuadrado, Jonathan Pascau, Catherine Raffin, Aline Bondu, Claire Bouix-Peter, Catherine Hervouet, Guillaume Peluchon, Veronique Parnet, David Piwnica, Branislav Musicki, Rodolphe Vatinel, Romain Pierre, Laboratoire de synthèse organique (DCSO), École polytechnique (X)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Nestle Skin Health GALDERMA R&D, Religions et croyances (LARHRA REC ), LAboratoire de Recherche Historique Rhône-Alpes - UMR5190 (LARHRA), École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire d'Immunologie et Immunopathologie [CHU Poitiers] (CNRS URA 1172), Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre National de la Recherche Scientifique (CNRS), Mucosal Immunity, Vaccination, and Biometrics -- Immunité des muqueuses, vaccinations et biothérapies, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Transporteurs et Imagerie, Radiothérapie en Oncologie et Mécanismes biologiques des Altérations du Tissu Osseux (TIRO-MATOs - UMR E4320), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-UMR E4320 (TIRO-MATOs), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA), Nestlé Institute of Health Sciences SA [Lausanne, Switzerland], Institut de Recherches SERVIER (IRS), GALDERMA R&D, Galderma Recherche et Développement [Biot, France] (Galderma R&D), Virologie humaine, École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), UMR E4320 (TIRO-MATOs), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, and École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Keratinocytes, Administration, Topical, [SDV]Life Sciences [q-bio], Retinoic acid, Drug Evaluation, Preclinical, Pharmacology, 01 natural sciences, Biochemistry, Interleukin-23, chemistry.chemical_compound, Mice, Drug Discovery, heterocyclic compounds, General Pharmacology, Toxicology and Pharmaceutics, ComputingMilieux_MISCELLANEOUS, Orphan receptor, Mice, Inbred BALB C, Sulfonamides, Interleukin-17, Nuclear Receptor Subfamily 1, Group F, Member 3, 3. Good health, Molecular Medicine, medicine.symptom, Drug Inverse Agonism, Inflammation, Topical treatment, Skin Diseases, 03 medical and health sciences, Inhibitory Concentration 50, Structure-Activity Relationship, In vivo, Psoriasis, medicine, Inverse agonist, Animals, Humans, [CHIM]Chemical Sciences, 010405 organic chemistry, business.industry, Organic Chemistry, medicine.disease, 0104 chemical sciences, Disease Models, Animal, 030104 developmental biology, chemistry, Mouse skin, Th17 Cells, business
Abstract

With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL-23-induced mouse skin inflammation model.

Published
2018

10. Topical ivermectin improves allergic skin inflammation

Author

Patricia Rossio, Valérie Julia, Jean-François Nicolas, Emmanuel Vial, Léo Laoubi, A. Rozieres, Andre Jomard, Erwan Ventre, Floriane Albert, Lauriane Ulmann, Marc Vocanson, David Dombrowicz, Bart Staels, Feriel Hacini-Rachinel, Vanina Lenief, Immunité et lymphocytes cytotoxiques – Immunity and cytotoxic lymphocytes, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Autophagie infection et immunité - Autophagy Infection Immunity (APY), Immunologie de l'allergie cutanée et vaccination – Immunology of skin allergy and vaccination, Nestle Skin Health GALDERMA R&D, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Enzyme-Linked Immunospot Assay, Administration, Topical, medicine.medical_treatment, Dermatitis, medicine.disease_cause, Lymphocyte Activation, Fragile X Mental Retardation Protein, Mice, T-cell immunity, 0302 clinical medicine, Allergen, Ivermectin, T-Lymphocyte Subsets, Receptors, Dermatophagoides, Immunology and Allergy, Mice, Knockout, atopic dermatitis, Atopic dermatitis, 3. Good health, Cytokine, topical treatment, Topical, embryonic structures, Administration, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cytokines, Purinergic P2X4, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, Inflammation Mediators, medicine.drug, Knockout, Immunology, Inflammation, Atopic, Dermatitis, Atopic, Proinflammatory cytokine, Cell Line, 03 medical and health sciences, Antigen, In vivo, medicine, Animals, Humans, Antigens, Dermatophagoides, Antigens, business.industry, urogenital system, Animal, Macrophages, Dendritic Cells, Allergens, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Disease Models, Animal, skin inflammatory diseases, 030104 developmental biology, Disease Models, business, Receptors, Purinergic P2X4, 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND: Ivermectin (IVM) is widely used in both human and veterinary medicine to treat parasitic infections. Recent reports have suggested that IVM could also have anti-inflammatory properties. METHODS: Here, we investigated the activity of IVM in a murine model of atopic dermatitis (AD) induced by repeated exposure to the allergen Dermatophagoides farinae, and in standard cellular immunological assays. RESULTS: Our results show that topical IVM improved allergic skin inflammation by reducing the priming and activation of allergen-specific T cells, as well as the production of inflammatory cytokines. While IVM had no major impact on the functions of dendritic cells in vivo and in vitro, IVM impaired T-cell activation, proliferation, and cytokine production following polyclonal and antigen-specific stimulation. CONCLUSION: Altogether, our results show that IVM is endowed with topical anti-inflammatory properties that could have important applications for the treatment of T-cell-mediated skin inflammatory diseases.

Published
2017

11. Low-Allergenic Hydrolyzed Egg Induces Oral Tolerance in Mice

Author

Carine Blanchard, Sophie Nutten, Audrey Demont, Annick Mercenier, Guénolée Prioult, Rémi Doucet-Ladevèze, Yvonne M. Vissers, Marie Perrot, Feriel Hacini-Rachinel, and Alexandre Panchaud

Subjects
Allergy, Ovalbumin, Immunology, Enzyme-Linked Immunosorbent Assay, Immunoglobulin E, Mass Spectrometry, Mice, Immune system, Food allergy, Immune Tolerance, medicine, Animals, Immunology and Allergy, IL-2 receptor, Egg Hypersensitivity, biology, business.industry, Hydrolysis, FOXP3, Hypoallergenic, General Medicine, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, Desensitization, Immunologic, Egg allergy, biology.protein, business, Chromatography, Liquid
Abstract

Background: Egg allergy is one of the most common food allergies in children. The standard therapy for egg allergy is strict avoidance. Yet, there is considerable clinical and scientific interest in primary or secondary prevention. A major drawback of oral tolerance (OT) induction protocols, however, is the possibility of severe side effects; thus, we have formulated a hypoallergenic egg product and demonstrate its in vivo capacity to modulate the immune system in the current study. Methods: Hydrolyzed egg (HE) was produced using a combination of moderate heat treatment and enzymatic hydrolysis. The capacity of HE to induce OT was tested in experimental models and compared to whole egg (WE). Delayed-type hypersensitivity (DTH) responses, immune markers and potential early markers of OT were analyzed. Results: Allergic responses, assessed by both DTH responses upon OVA challenge and serum OVA-specific IgE and IgG1, were decreased after treatment with HE and WE compared to the control group. Additionally, feeding WE and HE significantly decreased Th2 cytokine induction and cell proliferation, induced the activation of effector CD4+ T cells and increased numbers and percentages of ICOS+CD4+CD25+Foxp3+ cells. Furthermore, DO11.10 mouse experiments showed that HE contains other peptides than the OVA323-339 peptide that are able to induce tolerance to OVA. Conclusions: Altogether, results showed that HE induces OT in mice in a dose-dependent manner. Due to its low allergenicity compared to WE, it may represent a safer alternative for OT induction in at-risk subjects or oral immunotherapy in allergic patients.

Published
2014

12. Intestinal dendritic cell licensing through Toll-like receptor 4 is required for oral tolerance in allergic contact dermatitis

Author

Gilles Boschetti, Feriel Hacini-Rachinel, Ludovic Moro-Sibilot, Dominique Kaiserlian, Reem Kanjarawi, Claire Macari, Emilie Bardel, Bertrand Dubois, Jean-Benoît Le Luduec, Mercedes Gomez de Agüero, Philippe Langella, Mucosal Immunity, Vaccination, and Biometrics -- Immunité des muqueuses, vaccinations et biothérapies, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Autophagie infection et immunité - Autophagy Infection Immunity (APY), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, INSERM, Leonardo Da Vinci Program, Fondation pour la Recherche Medicale, ITMO IHP, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Autophagie infections immunité – Autophagy Infection Immunity, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Adoptive cell transfer, [SDV]Life Sciences [q-bio], Immunology, contact dermatitis, Biology, Oral tolerance, T-Lymphocytes, Regulatory, 03 medical and health sciences, Interferon-gamma, Mice, 0302 clinical medicine, medicine, microbiota, Immune Tolerance, Immunology and Allergy, Mesenteric lymph nodes, Animals, Allergic contact dermatitis, Mice, Knockout, Toll-like receptor, FOXP3, Dendritic cell, Dendritic Cells, medicine.disease, 3. Good health, Gastrointestinal Microbiome, Intestines, Toll-Like Receptor 4, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, Dermatitis, Allergic Contact, TLR4, Dinitrofluorobenzene, 030215 immunology
Abstract

Background Induction of oral tolerance to haptens is an efficient way to prevent allergic contact dermatitis (ACD) in mice. Toll-like receptor (TLR)–mediated sensing of the microbiota contributes to gut homeostasis, yet whether it contributes to induction of oral tolerance has not been documented. Objective We examined whether oral tolerance to the contact sensitizer 2,4-dinitro-fluorobenzene (DNFB) depends on microbiota/TLRs and evaluated the role of TLR4 on the tolerogenic function of intestinal dendritic cells (DCs). Methods Oral tolerance was induced by DNFB gavage in germ-free and mice deficient in several TLRs. Tolerance was assessed by means of suppression of contact hypersensitivity and hapten-specific IFN-γ–producing effector T cells. The tolerogenic function of intestinal DCs was tested by adoptive transfer experiments, ex vivo hapten presentation, and forkhead box p3 regulatory T-cell conversion. Results Oral tolerance induced by DNFB gavage was impaired in germ-free mice and TLR4-deficient mice. Bone marrow chimeras revealed that TLR4 expression on hematopoietic cells was necessary for oral tolerance induction. TLR4 appeared to be essential for the ability of intestinal dendritic cells from DNFB-fed mice to inhibit ACD on adoptive transfer. Indeed, TLR4 conditioned the in vivo mobilization to mesenteric lymph nodes of intestinal migratory CD103 + DCs carrying oral DNFB, especially the CD103 + CD11b + DC subset expressing the vitamin A–converting enzyme retinaldehyde dehydrogenase and specialized in forkhead box p3–positive regulatory T-cell conversion. Conclusions Our data demonstrate that TLR4 conditions induction of oral tolerance to DNFB through licensing tolerogenic gut DCs. Oral biotherapy with TLR4 ligands might be useful to potentiate oral tolerance to haptens and alleviate ACD in human subjects.

Published
2016

13. Topical Ivermectin 10~mg/g and Oral Doxycycline 40~mg Modified-Release: Current Evidence on the Complementary Use of Anti-Inflammatory Rosacea Treatments

Author

Martin Steinhoff, Feriel Hacini-Rachinel, Johannes Voegel, Marc Vocanson, Gregor Schäfer, Department of Dermatology [Dublin, Ireland] (UCD Charles Institute of Dermatology), University College Dublin [Dublin] (UCD), Department of Dermatology [San Diego, CA, USA], University of California [San Diego] (UC San Diego), University of California-University of California, Department of Neurosciences [Davis, CA, USA], University of California [Davis] (UC Davis), Immunologie de l'allergie cutanée et vaccination – Immunology of skin allergy and vaccination, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Galderma International S.A.S. [Paris, France], University of California (UC)-University of California (UC), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Cheval, Christelle

Subjects
0301 basic medicine, Administration, Topical, Anti-Inflammatory Agents, Administration, Oral, Review, Pharmacology, 030207 dermatology & venereal diseases, 0302 clinical medicine, Ivermectin, Pharmacology (medical), [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Doxycycline, Medicine(all), General Medicine, 3. Good health, Treatment Outcome, Topical, Combination, Administration, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Drug Therapy, Combination, medicine.symptom, medicine.drug, Oral, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.drug_class, Inflammation, Dermatology, Mechanism of action, Anti-inflammatory, 03 medical and health sciences, Therapeutic approach, Drug Therapy, Internal medicine, medicine, Humans, business.industry, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Rheumatology, 030104 developmental biology, Rosacea, Delayed-Action Preparations, Combined therapy, Therapy, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business
Abstract

Rosacea is a common, chronic inflammatory skin disease that can present with a variety of signs and symptoms. The potentially simultaneous occurrence of different signs and symptoms is due to different underlying inflammatory pathways, emphasizing the need for complementary treatment approaches. Topical ivermectin cream (10 mg/g) and systemic, oral anti-inflammatory doxycycline (40 mg modified-release) are both approved for the treatment of papulopustular rosacea (PPR). Whether or not a combined therapeutic approach may be more beneficial than monotherapy for patients with PPR remains to be tested. Here, we summarize underlying inflammatory pathways implicated in rosacea and clarify the impact of these two agents on selective pathways during inflammation, due to specific characteristics of their individual mechanisms of action (MoA). Based on the complementary MoA of doxycycline modified-release and ivermectin, a scientific rationale for a combined therapy targeting inflammatory lesions in rosacea is given. We propose that topical ivermectin cream is a promising new candidate as first-line treatment to target the inflammatory lesions of rosacea, which can be used in combination with systemic doxycycline modified-release to provide an optimal treatment approach considering all inflammatory pathways involved in PPR. Funding Galderma.

Published
2016

14. LB1578 Identification and characterization of highly optimized RORγ inverse agonists for the topical treatment of psoriasis

Author

Sophie Deret, Emmanuel Vial, Valérie Julia, Laurent F. Hennequin, Branislav Musicki, C. Chaussade, Gilles Ouvry, Catherine Hervouet, Craig S. Harris, C. Bouix-peter, Franck Bihl, Jonathan Pascau, David Piwnica, and Feriel Hacini-Rachinel

Subjects
business.industry, Psoriasis, medicine, Inverse agonist, Topical treatment, Identification (biology), Cell Biology, Dermatology, Pharmacology, medicine.disease, business, Molecular Biology, Biochemistry
Published
2018

15. Live and heat-treated probiotics differently modulate IL10 mRNA stabilization and microRNA expression

Author

Catherine Ngom-Bru, Carine Blanchard, Annick Mercenier, Audrey Demont, Guénolée Prioult, Rémi Doucet-Ladevèze, and Feriel Hacini-Rachinel

Subjects
0301 basic medicine, Regulation of gene expression, Hot Temperature, Probiotics, Immunology, MRNA stabilization, Biology, Molecular biology, Cell biology, Interleukin-10, 03 medical and health sciences, Interleukin 10, Lactobacillus, MicroRNAs, 030104 developmental biology, 0302 clinical medicine, Gene Expression Regulation, microRNA, Heat treated, Leukocytes, Mononuclear, Immunology and Allergy, Humans, Biomarkers, 030215 immunology
Published
2015

16. 348 Topical RORγ inverse agonist alleviate preclinical models of psoriasis

Author

C. Chaussade, Emmanuel Vial, Catherine Hervouet, Laurent F. Hennequin, Valérie Julia, Gilles Ouvry, C. Bouix-peter, Franck Bihl, David Piwnica, and Feriel Hacini-Rachinel

Subjects
business.industry, Psoriasis, Medicine, Inverse agonist, Cell Biology, Dermatology, Pharmacology, business, medicine.disease, Molecular Biology, Biochemistry
Published
2017

17. Langerhans cells protect from allergic contact dermatitis in mice by tolerizing CD8+ T cells and activating Foxp3+ regulatory T cells

Author

Marc Vocanson, Adrien Kissenpfennig, Mercedes Gomez de Agüero, Dominique Kaiserlian, Bernard Malissen, Tim Sparwasser, Feriel Hacini-Rachinel, Morgan Taillardet, Bertrand Dubois, and INSERM, U851, Lyon, France.

Subjects
Adoptive cell transfer, Antigen presentation, Mice, Transgenic, chemical and pharmacologic phenomena, Cell Communication, Biology, CD8-Positive T-Lymphocytes, Lymphocyte Activation, T-Lymphocytes, Regulatory, Immune tolerance, Inducible T-Cell Co-Stimulator Protein, Mice, Antigen, Antigens, CD, Cell Movement, medicine, Immune Tolerance, Cytotoxic T cell, Animals, Allergic contact dermatitis, Cells, Cultured, Antigen Presentation, integumentary system, FOXP3, Forkhead Transcription Factors, General Medicine, Allergens, medicine.disease, Mice, Inbred C57BL, Tolerance induction, Dinitrobenzenes, Langerhans Cells, Immunology, Dermatitis, Allergic Contact, Commentary, Lymph Nodes, Epidermis, Research Article
Abstract

Allergic contact dermatitis is the most frequent occupational disease in industrialized countries. It is caused by CD8(+) T cell-mediated contact hypersensitivity (CHS) reactions triggered at the site of contact by a variety of chemicals, also known as weak haptens, present in fragrances, dyes, metals, preservatives, and drugs. Despite the myriad of potentially allergenic substances that can penetrate the skin, sensitization is relatively rare and immune tolerance to the substance is often induced by as yet poorly understood mechanisms. Here we show, using the innocuous chemical 2,4-dinitrothiocyanobenzene (DNTB), that cutaneous immune tolerance in mice critically depends on epidermal Langerhans cells (LCs), which capture DNTB and migrate to lymph nodes for direct presentation to CD8(+) T cells. Depletion and adoptive transfer experiments revealed that LCs conferred protection from development of CHS by a mechanism involving both anergy and deletion of allergen-specific CD8(+) T cells and activation of a population of T cells identified as ICOS(+)CD4(+)Foxp3(+) Tregs. Our findings highlight the critical role of LCs in tolerance induction in mice to the prototype innocuous hapten DNTB and suggest that strategies targeting LCs might be valuable for prevention of cutaneous allergy.

Published
2012

18. Probiotics and Atopic Dermatitis

Author

Annick Mercenier, Feriel Hacini-Rachinel, Anurag Singh, and Ivana Jankovic

Subjects
medicine.medical_specialty, business.industry, Medicine, Atopic dermatitis, business, medicine.disease, Dermatology
Published
2012

19. Infant gut microbiota is protective against cow's milk allergy in mice despite immature ileal T-cell response

Author

Ioannis Nicolis, Deborah Moine, Marie-José Butel, Anne Bruttin, Chantal Labellie, Catherine Ngom-Bru, Annick Mercenier, Guénolée Prioult, Feriel Hacini-Rachinel, Bernard Berger, Anne-Judith Waligora-Dupriet, and Bertrand Rodriguez

Subjects
T-Lymphocytes, Milk allergy, Gut flora, medicine.disease_cause, digestive system, Applied Microbiology and Biotechnology, Microbiology, T-Lymphocytes, Regulatory, Feces, Mice, fluids and secretions, Immunity, Food allergy, Ileum, medicine, Animals, Bacteroides, Germ-Free Life, Humans, Sensitization, Bifidobacterium, Immunity, Cellular, Mice, Inbred C3H, Ecology, biology, food and beverages, Infant, biology.organism_classification, medicine.disease, Gastrointestinal Tract, Disease Models, Animal, medicine.anatomical_structure, Milk, Immunoglobulin G, Immunology, Allergic response, Metagenome, Milk Hypersensitivity
Abstract

Faecal microbiota of healthy infant displays a large abundance of Bifidobacterium spp. and Bacteroides spp. Although some studies have reported an association between these two genera and allergy, these findings remain a subject of debate. Using a gnotobiotic mouse model of cow's milk allergy, we investigated the impact of an infant gut microbiota – mainly composed of Bifidobacterium and Bacteroides spp. – on immune activation and allergic manifestations. The transplanted microbiota failed to restore an ileal T-cell response similar to the one observed in conventional mice. This may be due to the low bacterial translocation into Peyer's patches in gnotobiotic mice. The allergic response was then monitored in germ-free, gnotobiotic, and conventional mice after repeated oral sensitization with whey proteins and cholera toxin. Colonized mice displayed a lower drop of rectal temperature upon oral challenge with b-lactoglobulin, lower plasma mMCP-1, and lower anti-BLG IgG1 than germ-free mice. The foxp3 gene was highly expressed in the ileum of both colonized mice that were protected against allergy. This study is the first demonstration that a transplanted healthy infant microbiota mainly composed of Bifidobacterium and Bacteroides had a protective impact on sensitization and food allergy in mice despite altered T-cell response in the ileum.

Published
2011

20. Beneficial effect of hydrolyzed egg in allergy

Author

Annick Mercenier, Guénolée Prioult, Antoine Wermeille, Sébastien Holvoet, Rodolphe Fritsché, Feriel Hacini-Rachinel, Sophie Nutten, and Alexandre Panchaud

Subjects
Pulmonary and Respiratory Medicine, chemistry.chemical_classification, Allergy, biology, Immunology, RC581-607, medicine.disease_cause, medicine.disease, In vitro, Ovalbumin, Enzyme, chemistry, Antigen, In vivo, Poster Presentation, embryonic structures, Allergic response, biology.protein, medicine, Immunology and Allergy, Weaning, Food science, Immunologic diseases. Allergy
Abstract

There is clinical evidence to recommend the use of partially hydrolyzed infant formulas (HA-IF) for at risk children as an option for prevention of allergic diseases, particularly atopic dermatitis/eczema (Szajewska et al. 2010). As cow's milk allergic infants are at risk of developing allergy to newly introduced foods at weaning, we aimed to extend the concept of HA-IF to egg, another potentially allergenic food. Hydrolyzed egg (HA egg) was produced using a specific combination of heat and enzymatic treatments of whole egg. Characterization and reproducibility of the product was assessed using Size Exclusion Chromatography. Residual antigenic proteins (ovalbumin and ovomucoid) were quantified using ELISA. Allergenicity of the HA egg was tested both in vitro (serotonin release assay) and in vivo (rat model of allergy to ovalbumin). The capability of HA egg to induce oral tolerance to ovalbumin was assessed in both rat and mouse models. HA egg production was shown to be highly reproducible in terms of peptide profiling, residual allergenic proteins and in vivo benefits. Composition of HA egg, as compared to whole egg showed a clear shift towards peptides

Published
2011

21. CD4+ T cells and Lactobacillus casei control relapsing colitis mediated by CD8+ T cells

Author

Bernard Flourié, Feriel Hacini-Rachinel, Fatima Sardi, Pierre-Yves Durand, Rémi Doucet-Ladevèze, Stéphane Nancey, Gilles Boschetti, and Dominique Kaiserlian

Subjects
CD4-Positive T-Lymphocytes, Male, T cell, Immunology, Priming (immunology), Biology, CD8-Positive T-Lymphocytes, Interleukin 21, Mice, Recurrence, medicine, Immunology and Allergy, Cytotoxic T cell, Animals, Genetic Predisposition to Disease, IL-2 receptor, Colitis, Acute colitis, Cells, Cultured, Mice, Knockout, Mice, Inbred BALB C, FOXP3, medicine.disease, Coculture Techniques, Immunity, Innate, Mice, Inbred C57BL, Lacticaseibacillus casei, medicine.anatomical_structure
Abstract

Evidence that CD4(+) regulatory T cells can control Ag-specific CD8(+) T cell-mediated colitis in immunocompetent mice is poorly documented. To examine the potential of CD4(+) T cells to control colitis, we used our model of CD8(+) T cell-mediated colitis induced by intracolonic sensitization followed by challenge with the hapten 2,4-dinitrobenzene sulfonic acid. The defect of CD4(+) T cells in MHC class II-deficient (Abeta(degrees/degrees)) mice allowed priming of 2,4-dinitrobenzene sulfonic acid-specific IFN-gamma-producing CD8 colitogenic effectors and development of colitis in the otherwise resistant C57BL/6 strain. Cotransfer experiments in RAG2(degrees/degrees) mice and ex vivo studies showed that CD4(+)CD25(+) T cells completely prevented CD8(+) T cell-mediated colitis and controlled CD8(+) T cell activation, respectively. In the susceptible BALB/c strain, Ab depletion revealed that lack of CD4(+) regulatory T cells resulted in 1) acute colitis elicited by a suboptimal dose of hapten challenge and 2) more severe relapsing episodes of colitis induced by effector/memory CD8(+) T cell-mediated colitis at an optimal dose of hapten challenge, even when CD4 depletion was performed just before the second challenge. Oral administration of the probiotic strain Lactobacillus casei DN-114 001 alleviated colitis and increased the suppressive function of Foxp3(+)CD4(+) regulatory T cells of colon lamina propria. These data demonstrate that CD4(+) regulatory T cells exert a protective effect on colitis by controlling colitogenic effector/memory CD8(+) T cells during the effector (symptomatic) phase of acute and relapsing colitis, respectively. Probiotics with natural adjuvant effects on mucosal regulatory T cells may represent a valuable approach to alleviate the colitogenic effect of Tc1-type CD8(+) effectors.

Published
2009

22. Oral probiotic control skin inflammation by acting on both effector and regulatory T cells

Author

Jean-Benoît Le Luduec, Feriel Hacini-Rachinel, Hanane Gheit, Fariel Dif, Dominique Kaiserlian, and Stéphane Nancey

Subjects
Cell Transplantation, Immunology, Priming (immunology), Administration, Oral, lcsh:Medicine, Dermatology, Microbial Sensitivity Tests, T-Lymphocytes, Regulatory, Interleukin 21, Mice, Immune system, T-Lymphocyte Subsets, Cytotoxic T cell, Animals, Humans, IL-2 receptor, lcsh:Science, Cells, Cultured, Skin, Inflammation, Multidisciplinary, integumentary system, Chemistry, Probiotics, lcsh:R, FOXP3, Interleukin-10, Mice, Inbred C57BL, Interleukin 10, Dermatitis, Allergic Contact, Female, lcsh:Q, Immunology/Allergy and Hypersensitivity, CD8, Research Article
Abstract

Probiotics are believed to alleviate allergic and inflammatory skin disorders, but their impact on pathogenic effector T cells remains poorly documented. Here we show that oral treatment with the probiotic bacteria L. casei (DN-114 001) alone alleviates antigen-specific skin inflammation mediated by either protein-specific CD4(+) T cells or hapten-specific CD8(+) T cells. In the model of CD8(+) T cell-mediated skin inflammation, which reproduces allergic contact dermatitis in human, inhibition of skin inflammation by L. casei is not due to impaired priming of hapten-specific IFNgamma-producing cytolytic CD8(+) effector T cells. Alternatively, L. casei treatment reduces the recruitment of CD8(+) effector T cells into the skin during the elicitation (i.e. symptomatic) phase of CHS. Inhibition of skin inflammation by L. casei requires MHC class II-restricted CD4(+) T cells but not CD1d-restricted NK-T cells. L casei treatment enhanced the frequency of FoxP3(+) Treg in the skin and increased the production of IL-10 by CD4(+)CD25(+) regulatory T cells in skin draining lymph nodes of hapten-sensitized mice. These data demonstrate that orally administered L. casei (DN-114 001) efficiently alleviate T cell-mediated skin inflammation without causing immune suppression, via mechanisms that include control of CD8(+) effector T cells and involve regulatory CD4(+) T cells. L. casei (DN-114 001) may thus represent a probiotic of potential interest for immunomodulation of T cell-mediated allergic skin diseases in human.

Published
2009

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