Abstract
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-beta. 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-beta, 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Autoantibodies / immunology
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Autoantigens / immunology
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Autoimmune Diseases / drug therapy*
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B-Lymphocytes / immunology
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CD4 Antigens / analysis
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CD8 Antigens / analysis
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Dendritic Cells / immunology*
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Forkhead Transcription Factors / analysis
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Forkhead Transcription Factors / metabolism
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Histones / chemistry
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Histones / immunology
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Immune Tolerance
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Immunoglobulin G / immunology
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Immunosuppression Therapy*
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Interleukin-17 / metabolism
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Interleukin-2 Receptor alpha Subunit / analysis
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Interleukin-6 / metabolism
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Lupus Erythematosus, Systemic / drug therapy*
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Mice
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Nucleosomes / immunology
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Peptide Fragments / administration & dosage
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Peptide Fragments / therapeutic use*
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Peptides / administration & dosage
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Peptides / therapeutic use
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T-Lymphocytes, Regulatory / immunology*
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Toll-Like Receptor 9 / agonists
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Toll-Like Receptor 9 / metabolism
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Transforming Growth Factor beta / metabolism
Substances
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Autoantibodies
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Autoantigens
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CD4 Antigens
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CD8 Antigens
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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H4(71-94) peptide
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Histones
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Immunoglobulin G
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Interleukin-17
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Interleukin-2 Receptor alpha Subunit
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Interleukin-6
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Nucleosomes
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Peptide Fragments
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Peptides
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Toll-Like Receptor 9
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Transforming Growth Factor beta