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.
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.
Kang
Hee-Kap
HK
Division of Rheumatology, Departments of Medicine and Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, 240 East Huron Street, Chicago, IL 60611, USA.
Liu
Michael
M
Datta
Syamal K
SK
D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000188:drug therapy*; D001402:B-Lymphocytes / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000276:immunology; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000276:immunology; D007165:Immunosuppression Therapy; D020381:Interleukin-17 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D015850:Interleukin-6 / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy*; D051379:Mice; D009707:Nucleosomes / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000627:therapeutic use*; D010455:Peptides / Q000008:administration & dosage / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D001323:Autoantibodies; D001324:Autoantigens; D015704:CD4 Antigens; D016827:CD8 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C521482:H4(71-94) peptide; D006657:Histones; D007074:Immunoglobulin G; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D009707:Nucleosomes; D010446:Peptide Fragments; D010455:Peptides; D051217:Toll-Like Receptor 9; D016212:Transforming Growth Factor beta