title: Oral tolerance is inefficient in neonatal mice due to a physiological vitamin A deficiency.
abstract: Increased risk of allergy during early life indicates deficient immune regulation in this period of life. To date, the cause for inefficient neonatal immune regulation has never been elucidated. We aimed to define the ontogeny of oral tolerance and to identify necessary conditions specific for this stage of life. Ovalbumin (OVA) was administered orally to mice through breast milk and efficiency of systemic tolerance to OVA was assessed in adulthood using a model of allergic airway inflammation. Oral tolerance induction was fully efficient starting third week of life. Inefficiency in neonates was a consequence of abnormal antigen transfer across the gut barrier and retinaldehyde dehydrogenase expression by mesenteric lymph node CD103(+) neonatal dendritic cells, resulting in inefficient T-cell activation. Neonates' serum retinol levels were three times lower than in adult mice, and vitamin A supplementation was sufficient to rescue neonatal defects and allow tolerance induction from birth. The establishment of oral tolerance required the differentiation of Th1 lymphocytes in both vitamin A-supplemented neonates and 3-week-old unsupplemented mice. This knowledge should guide the design of interventions for allergy prevention that are adapted to the neonatal stage of life such as vitamin A supplementation.
authors.affiliation: University of Nice Sophia Antipolis, TIM, EA 6302, Nice, France.
authors.forename: M
authors.initials: M
authors.lastname: Turfkruyer
authors.affiliation: University of Nice Sophia Antipolis, TIM, EA 6302, Nice, France.
authors.forename: A
authors.initials: A
authors.lastname: Rekima
authors.affiliation: Institute of Biomedical Sciences-University of São Paulo, São Paulo, Brazil.
authors.forename: P
authors.initials: P
authors.lastname: Macchiaverni
authors.affiliation: University of Nice Sophia Antipolis, TIM, EA 6302, Nice, France.
authors.forename: L
authors.initials: L
authors.lastname: Le Bourhis
authors.affiliation: Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic medical center, Amsterdam, The Netherlands.
authors.forename: V
authors.initials: V
authors.lastname: Muncan
authors.affiliation: Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic medical center, Amsterdam, The Netherlands.
authors.forename: G R
authors.initials: GR
authors.lastname: van den Brink
authors.affiliation: University of Nice Sophia Antipolis, TIM, EA 6302, Nice, France.|International Inflammation Network (in-FLAME) of the World Universities Network, Perth, Australia.
authors.forename: M K
authors.initials: MK
authors.lastname: Tulic
authors.affiliation: University of Nice Sophia Antipolis, TIM, EA 6302, Nice, France.|International Inflammation Network (in-FLAME) of the World Universities Network, Perth, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Verhasselt
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D000833:Animals, Suckling; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D015870:Gene Expression; D007108:Immune Tolerance / Q000187:drug effects*; D039001:Integrin alpha Chains / Q000235:genetics / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D008643:Mesentery / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D014801:Vitamin A / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism; D014802:Vitamin A Deficiency / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D015703:Antigens, CD; D039001:Integrin alpha Chains; C091367:alpha E integrins; D014801:Vitamin A; D010047:Ovalbumin