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Autoantigen-Specific IL-10-Transduced T Cells Suppress Chronic Arthritis by Promoting the Endogenous Regulatory IL-10 Response¹

Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, The Netherlands

Deficient T cell regulation can be mechanistically associated with development of chronic autoimmune diseases. Therefore, combining the regulatory properties of IL-10 and the specificity of autoreactive CD4⁺ T cells through adoptive cellular gene transfer of IL-10 via autoantigen-specific CD4⁺ T cells seems an attractive approach to correct such deficient T cell regulation that avoids the risks of nonspecific immunosuppressive drugs. In this study, we studied how cartilage proteoglycan-specific CD4⁺ T cells transduced with an active IL-10 gene (T_IL-10) may contribute to the amelioration of chronic and progressive proteoglycan-induced arthritis in BALB/c mice. TCR-transgenic proteoglycan-specific T_IL-10 cells ameliorated arthritis, whereas T_IL-10 cells with specificity for OVA had no effect, showing the impact of Ag-specific targeting of inflammation. Furthermore, proteoglycan-specific T_IL-10 cells suppressed autoreactive proinflammatory T and B cells, as T_IL-10 cells caused a reduced expression of IL-2, TNF-, and IL-17 and a diminished proteoglycan-specific IgG2a Ab response. Moreover, proteoglycan-specific T_IL-10 cells promoted IL-10 expression in recipients but did not ameliorate arthritis in IL-10-deficient mice, indicating that T_IL-10 cells suppress inflammation by propagating the endogenous regulatory IL-10 response in treated recipients. This is the first demonstration that such targeted suppression of proinflammatory lymphocyte responses in chronic autoimmunity by IL-10-transduced T cells specific for a natural Ag can occur via the endogenous regulatory IL-10 response.

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 a grant (to C.P.B.) from the Netherlands Organization for Scientific Research (NWO Grant 016.026.010).

² Address correspondence and reprint requests to Dr. Willem van Eden, Division of Immunology, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands. E-mail address: W.vanEden{at}uu.nl

³ Abbreviations used in this paper: RA, rheumatoid arthritis; Tg, transgenic; Treg, regulatory T cell; Tr1, T regulatory 1; PGIA, proteoglycan-induced arthritis; MSCV, murine stem cell virus; DC, dendritic cell; LN, lymph node; HPRT, hypoxanthine phosphoribosyltransferase; T_IL-10, IL-10/GFP-transduced T cell; T_GFP, GFP-transduced T cell; T_resp, responder T; T_eff, effector T; IRES, internal ribosomal entry site.