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A Novel Adenovirus Expressing Flt3 Ligand Enhances Mucosal Immunity by Inducing Mature Nasopharyngeal-Associated Lymphoreticular Tissue Dendritic Cell Migration¹

Shinichi Sekine^*, Kosuke Kataoka^*,, Yoshiko Fukuyama^*, Yasuo Adachi, Julia Davydova, Masato Yamamoto, Ryoki Kobayashi^*, Keiko Fujihashi^*, Hideaki Suzuki^*, David T. Curiel, Satoshi Shizukuishi, Jerry R. McGhee^* and Kohtaro Fujihashi^2,*

^* Departments of Pediatric Dentistry and Microbiology, Immunobiology Vaccine Center and Division of Human Gene Therapy, Department of Surgery, Medicine and Pathology, Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Osaka, Japan; and Department of Surgery, University of Minnesota, Minneapolis, MN 55455

Previously, we showed that nasal administration of a naked cDNA plasmid expressing Flt3 ligand (FL) cDNA (pFL) enhanced CD4⁺ Th2-type, cytokine-mediated mucosal immunity and increased lymphoid-type dendritic cell (DC) numbers. In this study, we investigated whether targeting nasopharyngeal-associated lymphoreticular tissue (NALT) DCs by a different delivery mode of FL, i.e., an adenovirus (Ad) serotype 5 vector expressing FL (Ad-FL), would provide Ag-specific humoral and cell-mediated mucosal immunity. Nasal immunization of mice with OVA plus Ad-FL as mucosal adjuvant elicited high levels of OVA-specific Ab responses in external secretions and plasma as well as significant levels of OVA-specific CD4⁺ T cell proliferative responses and OVA-induced IFN- and IL-4 production in NALT, cervical lymph nodes, and spleen. We also observed higher levels of OVA-specific CTL responses in the spleen and cervical lymph nodes of mice given nasal OVA plus Ad-FL than in mice receiving OVA plus control Ad. Notably, the number of CD11b⁺CD11c⁺ DCs expressing high levels of costimulatory molecules was preferentially increased. These DCs migrated from the NALT to mucosal effector lymphoid tissues. Taken together, these results suggest that the use of Ad-FL as a nasal adjuvant preferentially induces mature-type NALT CD11b⁺CD11c⁺ DCs that migrate to effector sites for subsequent CD4⁺ Th1- and Th2-type cytokine-mediated, Ag-specific Ab and CTL responses.

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 DE 12242, AI 43197, AI 18958, AG 025873, and AI 076096 as well as by Grants-in-Aid (C19592403, A19209064) from the Ministry of Education, Science, Sports and Culture of Japan.

² Address correspondence and reprint requests to Dr. Kohtaro Fujihashi, Departments of Pediatric Dentistry and Microbiology, Immunobiology Vaccine Center, University of Alabama at Birmingham, 1919 Seventh Avenue South, School of Dentistry Building 801A1, Birmingham, AL 35294. E-mail address: kohtarof{at}uab.edu

³ Abbreviations used in this paper: S-IgA, secretory IgA; Ad, adenovirus; Ad-FL, adenovirus expressing flt3 ligand; Ad-Luc, adenovirus expressing luciferase; AFC, Ab-forming cell; CLN, cervical lymph node; DC, dendritic cell; FL, flt ligand; NALT, nasopharyngeal-associated lymphoreticular tissue; nCT, native cholera toxin; NP, nasal passage; pFL, plasmid expressing Flt ligand; SMG, submandibular gland.