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Oral or Nasal Antigen Induces Regulatory T Cells That Suppress Arthritis and Proliferation of Arthritogenic T Cells in Joint Draining Lymph Nodes

Femke Broere^1,*, Lotte Wieten^*, Elles I. Klein Koerkamp^*, Joel A. G. van Roon, Teun Guichelaar^*, Floris P. J. G. Lafeber and Willem van Eden^*

^* Division of Immunology, Institute of Infectious Diseases and Immunology, University of Utrecht, Utrecht; and Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

The propagation of mucosal tolerance as a therapeutic approach in autoimmune diseases remains a difficult goal to achieve, and therefore further mechanistic studies are necessary to develop potential clinical protocols to induce mucosal regulatory T cells (Tr cells). In this study we addressed whether oral or nasal proteoglycan induced functional Tr cells in the cartilage proteoglycan-induced chronic arthritis model. Both nasal and oral application of human proteoglycan before induction of disease suppressed arthritis severity and incidence. Tolerized mice showed enhanced numbers of IL-10 producing CD4⁺ cells in the paw-draining lymph nodes. Furthermore, CD4⁺ spleen cells displayed enhanced expression of molecules associated with Tr cells, such as IL-10, Foxp3, and TGF-β. Transfer of CD4⁺ spleen cells from mucosally tolerized donors into proteoglycan-immunized mice abolished arthritis and reduced humoral responses, indicative of Tr cells with the capacity to inhibit already induced immune responses. Tr cells were activated upon transfer, because enhanced proliferation was observed in the joint draining lymph nodes compared with activated T cells from nontolerized donors. Upon cotransfer with naive proteoglycan-specific T cells, mucosally induced Tr cells inhibited proliferation of these arthritogenic T cells in vivo. Herein we show that both oral and nasal Ag application induced Tr cells, which had a direct inhibitory effect on already established pathogenic B and T cell 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 Address correspondence and reprint requests to Dr. Femke Broere, Division of Immunology, Institute of Infectious Diseases and Immunology, University of Utrecht, Yalelaan 1, 3584 CL Utrecht, The Netherlands. E-mail address: f.broere{at}uu.nl

² Abbreviations used in this paper: Tr cell, regulatory T cell; DDA, dimethyl dioctadecyl ammonium bromide; DLN, draining lymph node; i.g., intragastric; i.n., intranasal; MPO, myeloperoxidase; PG, proteoglycan; PGIA, proteoglycan-induced arthritis; Q-PCR, quantitative PCR; RA, rheumatoid arthritis; Tg, transgenic.