Abstract
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-beta-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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antibodies, Monoclonal / administration & dosage*
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Antibodies, Monoclonal / therapeutic use
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Antigens, Differentiation, T-Lymphocyte / biosynthesis
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Antigens, Differentiation, T-Lymphocyte / metabolism
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CD3 Complex / immunology*
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CD4 Antigens / biosynthesis
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Cells, Cultured
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Down-Regulation / immunology*
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Female
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Germinal Center / cytology
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Germinal Center / immunology
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Germinal Center / metabolism
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Growth Inhibitors / administration & dosage*
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Growth Inhibitors / therapeutic use
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Inducible T-Cell Co-Stimulator Protein
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Interleukin-10 / metabolism*
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Interleukin-17 / antagonists & inhibitors
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Interleukin-17 / biosynthesis
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Interleukin-2 Receptor alpha Subunit / metabolism
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Latent TGF-beta Binding Proteins / biosynthesis
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Lupus Erythematosus, Systemic / genetics
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Lupus Erythematosus, Systemic / immunology*
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Lupus Erythematosus, Systemic / prevention & control
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Male
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Mice
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Mice, Inbred NZB
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Nasal Mucosa / immunology*
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Receptors, CXCR5 / antagonists & inhibitors
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Receptors, CXCR5 / biosynthesis
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T-Lymphocytes, Helper-Inducer / cytology
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Helper-Inducer / metabolism
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
Substances
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Antibodies, Monoclonal
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Antigens, Differentiation, T-Lymphocyte
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CD3 Complex
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CD4 Antigens
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CXCR5 protein, mouse
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Growth Inhibitors
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Icos protein, mouse
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Inducible T-Cell Co-Stimulator Protein
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Interleukin-17
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Interleukin-2 Receptor alpha Subunit
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Latent TGF-beta Binding Proteins
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Receptors, CXCR5
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Interleukin-10