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CD11c⁺CD11b⁺ Dendritic Cells Play an Important Role in Intravenous Tolerance and the Suppression of Experimental Autoimmune Encephalomyelitis¹

Hongmei Li^*, Guang-Xian Zhang^*, Youhai Chen, Hui Xu^*, Denise C. Fitzgerald^*, Zhao Zhao^* and Abdolmohamad Rostami^2,*

^* Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107; and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19107

The central role of T cells in the induction of immunological tolerance against i.v. Ags has been well documented. However, the role of dendritic cells (DCs), the most potent APCs, in this process is not clear. In the present study, we addressed this issue by examining the involvement of two different DC subsets, CD11c⁺CD11b⁺ and CD11c⁺CD8⁺ DCs, in the induction of i.v. tolerance. We found that mice injected i.v. with an autoantigen peptide of myelin oligodendrocyte glycoprotein (MOG) developed less severe experimental autoimmune encephalomyelitis (EAE) following immunization with MOG peptide but presented with more CD11c⁺CD11b⁺ DCs in the CNS and spleen. Upon coculturing with T cells or LPS, these DCs exhibited immunoregulatory characteristics, including increased production of IL-10 and TGF-β but reduced IL-12 and NO; they were also capable of inhibiting the proliferation of MOG-specific T cells and enhancing the generation of Th2 cells and CD4⁺CD25⁺Foxp3⁺ regulatory T cells. Furthermore, these DCs significantly suppressed ongoing EAE upon adoptive transfer. These results indicate that CD11c⁺CD11b⁺ DCs, which are abundant in the CNS of tolerized animals, play a crucial role in i.v. tolerance and EAE and may be a candidate cell population for immunotherapy of autoimmune 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 grants from the National Institutes of Health and the National Multiple Sclerosis Society.

² Address correspondence and reprint requests to: A.M. Rostami, MD, PhD, Ste. 200 JHN, 900 Walnut St., Philadelphia, PA 19107. E-mail: a.m.rostami{at}jefferson.edu or Guang-Xian Zhang, MD, PhD, Ste. 300 JHN, 900 Walnut St., Philadelphia, PA 19107. E-mail: guang-xian.zhang{at}jefferson.edu

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; DCs, dendritic cells; p.i. postimmunization; Treg cell, regulatory T cell; MNC, mononuclear cell; GA, glatiramer acetate.

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