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Exosomes from Bronchoalveolar Fluid of Tolerized Mice Prevent Allergic Reaction¹

Noela Prado^*, Eva G. Marazuela^*, Elodie Segura^,, Héctor Fernández-García, Mayte Villalba^*, Clotilde Théry^,, Rosalía Rodríguez^* and Eva Batanero^2,*

^* Departamento de Bioquímica y Biología Molecular, Facultad de Química, Universidad Complutense, Madrid, Spain; Institut National de la Santé et de la Recherche Médicale Unite 653, Paris, France; Institut Curie, Paris, France; and Área de Histología y Anatomía Patológica, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Spain

Exosomes are nanovesicles originating from multivesicular bodies that are secreted by a variety of cell types. The dual capability of exosomes to promote immunity or to induce tolerance has prompted their clinical use as vehicles for vaccination against different human diseases. In the present study, the effect of allergen-specific exosomes from tolerized mice on the development of allergen-induced allergic response was determined using a mouse model. Mice were tolerized by respiratory exposure to the olive pollen allergen Ole e 1. Exosome-like vesicles were isolated from bronchoalveolar lavage fluid of the animals by the well-established filtration and ultracentrifugation procedure, characterized by electron microscopy, Western blot, and FACS analyses, and assessed in a prophylactic protocol. To this end, BALB/c mice were intranasally treated with tolerogenic exosomes or naive exosomes as control, 1 wk before sensitization/challenge to Ole e 1. Blood, lungs, and spleen were collected and analyzed for immune responses. Intranasal administration of tolerogenic exosomes inhibited the development of IgE response, Th2 cytokine production, and airway inflammation—cardinal features of allergy— and maintained specific long-term protection in vivo. This protective effect was associated with a concomitant increase in the expression of the regulatory cytokine TGF-β. These observations demonstrate that exosomes can induce tolerance and protection against allergic sensitization in mice. Thus, exosome-based vaccines could represent an alternative to conventional therapy for allergic diseases in humans.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants SAF2002-02711 and SAF05-01847 from the Ministerio de Ciencia y Tecnología (Spain) to R.R.

² Address correspondence and reprint requests to Dr. Eva Batanero, Departamento de Bioquímica y Biología Molecular, Facultad de Química, Universidad Complutense de Madrid, 28040 Madrid, Spain. E-mail address: ameva{at}bbm1.ucm.es

³ Abbreviations used in this paper: DC, dendritic cell; BALF, bronchoalveolar lavage fluid; EM, electron microscopy; Exo_Con, exosomes isolated from naive mice; Exo_Tol, exosomes isolated from mice tolerized against Ole e 1; i.n., intranasal; MVB, multivesicular body; SP-B, surfactant protein B.