Intranasal tolerance induction in an established model of asthma limits eosinophils recruitment and IgE production via CD4-dependent mechanisms

Abstract

Asthma Limits Eosinophils Recruitment and IgE Production Via CD4-Dependent Mechanisms C. Longaretti, C. Barbey, E. Pradervand, F. Spertini; Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, SWITZERLAND. RATIONALE: We have recently shown that prophylactic induction of tolerance via the nasal route in ovalbumin (OVA) allergic mice was generating IL-10 producing regulatory CD4+ T cells. The aim of this study was to characterize, in an established model of asthma, the mechanisms leading to effective immune tolerance via the mucosal route. METHODS: OVA-sensitized asthmatic mice were intranasally treated with 1.5 mg OVA for 3 days. Mice were challenged by OVA aerosol 10 days later. Cells implicated in protection were characterized by transfer experiments. RESULTS: Upon challenge, intranasal OVA treatment (INT) drastically reduced inflammatory cell recruitment into bronchoalveolar lavage fluid (BALF), including eosinophils, inhibited OVA specific IgE rise and decreased bronchial hyperreactivity. T cell proliferation of ex vivo purified bronchial lymph node cells was inhibited as well as TH2 and TH1 cytokine production. Protection was effective for an extended period of time and was not associated with eotaxin reduction. Cell transfer experiment of CD4+ cells from INT OVA animals limited recruitment of inflammatory cells, including eosinophils, into BALF of recipient mice. CONCLUSIONS: INT with OVA was able to markedly limit asthmatic inflammation upon allergen challenge. CD4+ regulatory T cells appears to play a crucial role in this protection via mechanisms to be defined. Funding: Swiss National Science Foundation 1049 Preventive Use of the Co-administration of Immunostimulatory DNA Sequences (ISS-ODN) With Olive Pollen Proteins in a Mouse Model of Allergic Asthma L. Conejero1,2, Y. Higaki1,2, M. J. Fernandez-Bohorquez1, I. VarelaNieto2, M. L. Baeza1, J. M. Zubeldia1; 1Allergy Department, Hospital Gregorio Maranon, Madrid, SPAIN, 2Instituto Investigaciones Biomedicas Alberto Sols-CSIC, Madrid, SPAIN. RATIONALE: ISS-ODNs are potent immunomodulators and stimulators of innate immunity. We studied the effects of the co-administration of these sequences with olive pollen proteins (Olea) given prior to Olea sensitization in a mouse model of allergic asthma. METHODS: BALB/c mice were distributed in different groups and immunized by intradermal injections of ISS-ODN and Olea, ISS-ODN, Olea, or saline (SS) on days 0, 7 and 14. Mice were then sensitized by subcutaneous injections with Olea in alum twice. Blood samples were collected weekly to measure immunoglobulin levels. Mice were sacrificed and splenocytes were cultured with and without the allergen for 3 days. Supernatants were assayed to determine the level of different cytokines. Finally, bronchial reactivity to methacholine was determined by Whole Body Plethysmography. RESULTS: Concomitant administration of ISS-ODN with Olea before the mice were sensitized resulted in significant changes in the immunological and functional parameters: a) Production of Olea-specific IgE was greatly reduced (p= 0.05); b) Significant higher levels of specific IgG2a, IFNand IL-18 production were detected (p< 0.05); and c) Pulmonary function test revealed a greater reduction in the bronchial hypereactivity to methacholine (p< 0.05). CONCLUSIONS: The co-administration of ISS-ODN with Olea prior to sensitization prevents the development of an allergic phenotype in our mouse model of bronchial asthma. Funding: FIS 01/0598