title: In Silico Adjuvant Design and Validation.
abstract: Adjuvants are substances that boost the protective immune response to vaccine antigens. The majority of known adjuvants have been identified through the use of empirical approaches. Our aim was to identify novel adjuvants with well-defined cellular and molecular mechanisms by combining a knowledge of immunoregulatory mechanisms with an in silico approach. CD4+CD25+FoxP3+regulatory T cells (Tregs) inhibit the protective immune responses to vaccines by suppressing the activation of antigen presenting cells such as dendritic cells (DCs). In this chapter, we describe the identification and functional validation of small molecule antagonists to CCR4, a chemokine receptor expressed on Tregs. The CCR4 binds the chemokines CCL22 and CCL17 that are produced in large amounts by activated innate cells including DCs. In silico identified small molecule CCR4 antagonists inhibited the migration of Tregs both in vitro and in vivo and when combined with vaccine antigens, significantly enhanced protective immune responses in experimental models.
authors.affiliation: Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, Division of Molecular Pathology, The Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Davies
authors.affiliation: INSERM U970 PARCC (Paris Cardiovascular Research Center), Université Paris Descartes, Sorbonne Paris Cité, Paris, 75015, France.|Hôpital Européen Georges-Pompidou, Service d'Immunologie Biologique, AP-HP, Paris, 75015, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Pere
authors.affiliation: Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium.
authors.forename: Iris
authors.initials: I
authors.lastname: Bosschem
authors.affiliation: Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium.
authors.forename: Freddy
authors.initials: F
authors.lastname: Haesebrouck
authors.affiliation: Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium.
authors.forename: Bram
authors.initials: B
authors.lastname: Flahou
authors.affiliation: INSERM U970 PARCC (Paris Cardiovascular Research Center), Université Paris Descartes, Sorbonne Paris Cité, Paris, 75015, France.|Hôpital Européen Georges-Pompidou, Service d'Immunologie Biologique, AP-HP, Paris, 75015, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Tartour
authors.affiliation: School of Life and Health Sciences, University of Aston, Aston Triangle, Birmingham, B4 7ET, UK.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Flower
authors.affiliation: Epinova Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Medicines Discovery Centre, SG1 2NY, Stevenage, UK.
authors.forename: David F
authors.initials: DF
authors.lastname: Tough
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1138, Paris, 75006, France. jagadeesh.bayry@crc.jussieu.fr.|Equipe-Immunopathology and Therapeutic Immunointervention, Centre de Recherche des Cordeliers, 15 rue de l'Ecole de Médicine, Paris, 75006, France. jagadeesh.bayry@crc.jussieu.fr.|Sorbonne Universités, UPMC Universités Paris 06, UMR S 1138, Paris, 75006, France. jagadeesh.bayry@crc.jussieu.fr.|Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, 75006, France. jagadeesh.bayry@crc.jussieu.fr.
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Bayry
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D054414:Chemokine CCL17 / Q000276:immunology; D054422:Chemokine CCL22 / Q000276:immunology; D003198:Computer Simulation; D015195:Drug Design; D005260:Female; D006801:Humans; D051379:Mice; D018448:Models, Immunological; D054398:Receptors, CCR4 / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; C106230:CCL17 protein, human; C515482:CCL22 protein, human; C515354:CCR4 protein, human; C499538:Ccl17 protein, mouse; C515483:Ccl22 protein, mouse; C515355:Ccr4 protein, mouse; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D054398:Receptors, CCR4
keywords: Adjuvant; CCR4; Dendritic cells; Regulatory T cell; Small molecule; Vaccine in silico