title: Generation and characterization of function-blocking anti-ectodysplasin A (EDA) monoclonal antibodies that induce ectodermal dysplasia.
abstract: Development of ectodermal appendages, such as hair, teeth, sweat glands, sebaceous glands, and mammary glands, requires the action of the TNF family ligand ectodysplasin A (EDA). Mutations of the X-linked EDA gene cause reduction or absence of many ectodermal appendages and have been identified as a cause of ectodermal dysplasia in humans, mice, dogs, and cattle. We have generated blocking antibodies, raised in Eda-deficient mice, against the conserved, receptor-binding domain of EDA. These antibodies recognize epitopes overlapping the receptor-binding site and prevent EDA from binding and activating EDAR at close to stoichiometric ratios in in vitro binding and activity assays. The antibodies block EDA1 and EDA2 of both mammalian and avian origin and, in vivo, suppress the ability of recombinant Fc-EDA1 to rescue ectodermal dysplasia in Eda-deficient Tabby mice. Moreover, administration of EDA blocking antibodies to pregnant wild type mice induced in developing wild type fetuses a marked and permanent ectodermal dysplasia. These function-blocking anti-EDA antibodies with wide cross-species reactivity will enable study of the developmental and postdevelopmental roles of EDA in a variety of organisms and open the route to therapeutic intervention in conditions in which EDA may be implicated.
authors.affiliation: From the Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Kowalczyk-Quintas
authors.forename: Laure
authors.initials: L
authors.lastname: Willen
authors.forename: Anh Thu
authors.initials: AT
authors.lastname: Dang
authors.forename: Heidi
authors.initials: H
authors.lastname: Sarrasin
authors.forename: Aubry
authors.initials: A
authors.lastname: Tardivel
authors.forename: Katharina
authors.initials: K
authors.lastname: Hermes
authors.forename: Holm
authors.initials: H
authors.lastname: Schneider
authors.forename: Olivier
authors.initials: O
authors.lastname: Gaide
authors.forename: Olivier
authors.initials: O
authors.lastname: Donzé
authors.forename: Neil
authors.initials: N
authors.lastname: Kirby
authors.forename: Denis J
authors.initials: DJ
authors.lastname: Headon
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000235:genetics / Q000276:immunology / Q000633:toxicity*; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology / Q000633:toxicity*; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology / Q000633:toxicity*; D001483:Base Sequence; D002417:Cattle; D002460:Cell Line; D004285:Dogs; D004476:Ectodermal Dysplasia / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053331:Ectodysplasins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D011247:Pregnancy
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D057134:Antibodies, Neutralizing; D001323:Autoantibodies; C506018:EDA protein, human; D053331:Ectodysplasins; C506019:Eda protein, mouse
keywords: Antibodies; Embryo; Receptors; Tooth; Tumor Necrosis Factor (TNF)