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Nasal Anti-CD3 Antibody Ameliorates Lupus by Inducing an IL-10-Secreting CD4⁺CD25^–LAP⁺ Regulatory T Cell and Is Associated with Down-Regulation of IL-17⁺CD4⁺ICOS⁺CXCR5⁺ Follicular Helper T Cells¹

Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

Lupus is an Ab-mediated autoimmune disease. One of the potential contributors to the development of systemic lupus erythematosus is a defect in naturally occurring CD4⁺CD25⁺ regulatory T cells. Thus, the generation of inducible regulatory T cells that can control autoantibody responses is a potential avenue for the treatment of systemic lupus erythematosus. We have found that nasal administration of anti-CD3 mAb attenuated lupus development as well as arrested ongoing lupus in two strains of lupus-prone mice. Nasal anti-CD3 induced a CD4⁺CD25^–latency-associated peptide (LAP)⁺ regulatory T cell that secreted high levels of IL-10 and suppressed disease in vivo via IL-10- and TFG-β-dependent mechanisms. Disease suppression also occurred following adoptive transfer of CD4⁺CD25^–LAP⁺ regulatory T cells from nasal anti-CD3-treated animals to lupus-prone mice. Animals treated with nasal anti-CD3 had less glomerulonephritis and diminished levels of autoantibodies as measured by both ELISA and autoantigen microarrays. Nasal anti-CD3 affected the function of CD4⁺ICOS⁺CXCR5⁺ follicular helper T cells that are required for autoantibody production. CD4⁺ICOS⁺CXCR5⁺ follicular helper T cells express high levels of IL-17 and IL-21 and these cytokines were down-regulated by nasal anti-CD3. Our results demonstrate that nasal anti-CD3 induces CD4⁺CD25^–LAP⁺ regulatory T cells that suppress lupus in mice and that it is associated with down-regulation of T cell help for autoantibody production.

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 National Institutes of Health Grants AI435801 and NS38037 (to H.L.W.).

² Address correspondence and reprint requests to Dr. Howard L. Weiner, Harvard Institutes of Medicine, Room 720, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail address: hweiner{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; LAP, latency-associated peptide; EAE, experimental autoimmune encephalomyelitis; SNF1, (NZB x SWR)F₁; BWF1, (NZB x NZW)F₁; IC, isotype control; CLN, cervical lymph node; PLN, peripheral lymph node; PAS, periodic acid-Schiff.

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