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Induction of Adaptive T Regulatory Cells That Suppress the Allergic Response by Coimmunization of DNA and Protein Vaccines¹

Huali Jin^*, Youmin Kang^*, Lin Zhao^*, Chong Xiao^*, Yanxin Hu, Ruiping She, Yang Yu^*, Xiaogang Du^*, Gan Zhao^*, Terry Ng, Hsien-Jue Chu and Bin Wang^2,*,,

^* State Key Laboratory for Agro-Biotechnology, Key Laboratory of Microbiological Resources and Applications of the Ministry of Agriculture, and College of Veterinary Medicine, China Agricultural University, Beijing, China; and Fort Dodge Animal Health, Wyeth, Fort Dodge, IA 50501

Allergen-induced immediate hypersensitivity (AIH) is a health issue of significant concern. This robust inflammatory reaction is initiated by the allergen-specific T cell responsiveness. Severe lesion reactions on skin are consequential problem requiring medical treatment. Effective Ag-specific treatments or preventions are lacking. Using a rodent model of AIH induced by flea allergens, we first report that coimmunization of DNA and protein vaccines encoding the flea salivary specific Ag-1 ameliorated experimental AIH, including Ag-induced wheal formation, elevated T cell proliferation, and infiltration of lymphocytes and mast cells to the site of allergen challenge. The amelioration of AIH was directly related to the induction of a specific population of flea antigenic specific T cells exhibiting a CD4⁺CD25^–FoxP3⁺ phenotype, a characteristic of regulatory T (T_REG) cells. These T_REG cells expressing IL-10, IFN-, and the transcriptional factor T-bet after Ag stimulation were driven by a tolerogenic MHC class II⁺/CD40^low dendritic cell population that was induced by the coimmunization of DNA and protein vaccines. The tolerogenic dendritic cell could educate the naive T cells into CD4⁺CD25^–FoxP3⁺ T_REG cells both in vitro and in vivo. The study identified phenomenon to induce an Ag-specific tolerance via a defined Ag vaccinations and lead to the control of AIH. Exploitation of these cellular regulators and understanding their induction provides a basis for the possible development of novel therapies against allergic and related disorders in humans and animals.

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 an innovative grant from Fort Dodge Animal Health, Wyeth Animal Health (to B.W.), and a research initiation fund from China Agricultural University (to B.W.).

² Address correspondence and reprint requests to Dr. Bin Wang, State Key Laboratory for Agro-Biotechnology, College of Biological Sciences, China Agricultural University, 2 Yuanmingyuan Xi Road, Beijing 100094, China. E-mail address: bwang3{at}cau.edu.cn

³ Abbreviations used in this paper: AIH, allergen-induced immediate hypersensitivity; FSA, flea salivary-specific Ag; DC, dendritic cell; IDT, intradermal test; T_REG, regulatory T; CD62L, CD62 ligand.