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Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells^1,2

Division of Rheumatology, Departments of Medicine and Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

Subnanomolar doses of an unaltered, naturally occurring nucleosomal histone peptide epitope, H4_71–94, when injected s.c. into lupus-prone mice, markedly prolong lifespan by generating CD4⁺25⁺ and CD8⁺ regulatory T cells (Treg) producing TGF-. The induced Treg cells suppress nuclear autoantigen-specific Th and B cells and block renal inflammation. Splenic dendritic cells (DC) captured the s.c.-injected H4_71–94 peptide rapidly and expressed a tolerogenic phenotype. The DC of the tolerized animal, especially plasmacytoid DC, produced increased amounts of TGF-, but diminished IL-6 on stimulation via the TLR-9 pathway by nucleosome autoantigen and other ligands; and those plasmacytoid DC blocked lupus autoimmune disease by simultaneously inducing autoantigen-specific Treg and suppressing inflammatory Th17 cells that infiltrated the kidneys of untreated lupus mice. Low-dose tolerance with H4_71–94 was effective even though the lupus immune system is spontaneously preprimed to react to the autoepitope. Thus, H4_71–94 peptide tolerance therapy that preferentially targets pathogenic autoimmune cells could spare lupus patients from chronically receiving toxic agents or global immunosuppressants and maintain remission by restoring autoantigen-specific Treg cells.

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 (R37-AR39157 and R01-AI41985) and the Solovy Arthritis Research Society (to S.K.D.) and the Arthritis National Research Foundation (to H.-K.K.).

² Preliminary results on the mechanism of low-dose peptide tolerance were presented as an abstract at the 2005 Annual Meeting of the American College of Rheumatology, Basic Research Conference, San Diego, CA, November 12–17 (H.-K. Kang, M. Liu, and S. K. Datta, 2005. Arthritis Rheum. 52:S32, Abstract BRC4).

³ Address correspondence and reprint requests to Dr. Syamal K. Datta, Division of Rheumatology, Feinberg School of Medicine, Northwestern University, 240 East Huron Street, McGaw No. M300, Chicago, IL 60611. E-mail address: skd257{at}northwestern.edu

⁴ Abbreviations used in this paper: MHC II, MHC class II; DC, dendritic cell; pDC, plasmacytoid DC; T reg, regulatory T cell; IDO, indoleamine 2,3 dioxygenase; MFI, mean fluorescence intensity.

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