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Asthma-Related Environmental Fungus, Alternaria, Activates Dendritic Cells and Produces Potent Th2 Adjuvant Activity¹

Takao Kobayashi^*,¶, Koji Iijima^*, Suresh Radhakrishnan, Vinay Mehta^2,*, Robert Vassallo, Christopher B. Lawrence^||, Jong-Chol Cyong, Larry R. Pease, Katsuji Oguchi^¶ and Hirohito Kita^3,*

^* Division of Allergic Diseases, Department of Internal Medicine, Department of Immunology, and Division of Pulmonary and Critical Care and Internal Medicine, Mayo Clinic, Rochester, MN 55905; Department of Integrative Medicine, Nihon Pharmaceutical University, Saitama, Japan; ^¶ Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan; and ^|| Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060

Asthma is thought to result from dysregulated Th2-like airway inflammatory responses to the environment. Although the etiology of asthma is not fully understood in humans, clinical and epidemiological evidence suggest a potential link between exposure to environmental fungi, such as Alternaria, and development and/or exacerbation of asthma. The goal of this project was to investigate the mechanisms of airway Th2 responses by using Alternaria as a clinically relevant model for environmental exposure. Airway exposure of naive animals to an experimental Ag, OVA, or a common allergen, short ragweed pollen, induced no or minimal immune responses to these Ags. In contrast, mice developed strong Th2-like immune responses when they were exposed to these Ags in the presence of Alternaria extract. Extracts of other fungi, such as Aspergillus and Candida, showed similar Th2 adjuvant effects, albeit not as potently. Alternaria stimulated bone marrow-derived dendritic cells (DCs) to express MHC class II and costimulatory molecules, including OX40 ligand, in vitro. Importantly, Alternaria inhibited IL-12 production by activated DCs, and DCs exposed to Alternaria enhanced Th2 polarization of CD4⁺ T cells. Furthermore, adoptive airway transfer of DCs, which had been pulsed with OVA in the presence of Alternaria, showed that the recipient mice had enhanced IgE Ab production and Th2-like airway responses to OVA. Thus, the asthma-related environmental fungus Alternaria produces potent Th2-like adjuvant effects in the airways. Such immunogenic properties of certain environmental fungi may explain their strong relationships with human asthma and allergic diseases.

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 National Institutes of Health Grants AI49235 and AI71106 and the Mayo Foundation.

² Current address: Center for Allergy, Asthma and Immunology, Creighton University, Omaha, NE 68178.

³ Address correspondence and reprint requests to Dr. Hirohito Kita, Division of Allergic Disease, Department of Immunology and Department of Medicine, Guggenheim 4, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail address: kita.hirohito{at}mayo.edu

⁴ Abbreviations used in this paper: SRW, short ragweed pollen; BAL, bronchoalveolar lavage; BM, bone marrow; DC, dendritic cell; MHC-II, MHC class II; MLN, mediastinal lymph node; TSLP, thymic stromal lymphopoietin; L, ligand.