title: Very low-dose tolerance with nucleosomal peptides controls lupus and induces potent regulatory T cell subsets.
abstract: We induced very low-dose tolerance by injecting lupus prone (SWR x NZB)F1 (SNF1) mice with 1 mug nucleosomal histone peptide autoepitopes s.c. every 2 wk. The subnanomolar peptide therapy diminished autoantibody levels and prolonged life span by delaying nephritis, especially by reducing inflammatory cell reaction and infiltration in kidneys. H4(71-94) was the most effective autoepitope. Low-dose tolerance therapy induced CD8+, as well as CD4+ CD25+ regulatory T (Treg) cell subsets containing autoantigen-specific cells. These adaptive Treg cells suppressed IFN-gamma responses of pathogenic lupus T cells to nucleosomal epitopes at up to a 1:100 ratio and reduced autoantibody production up to 90-100% by inhibiting nucleosome-stimulated T cell help to nuclear autoantigen-specific B cells. Both CD4+ CD25+ and CD8+ Treg cells produced and required TGF-beta1 for immunosuppression, and were effective in suppressing lupus autoimmunity upon adoptive transfer in vivo. The CD4+ CD25+ T cells were partially cell contact dependent, but CD8+ T cells were contact independent. Thus, low-dose tolerance with highly conserved histone autoepitopes repairs a regulatory defect in systemic lupus erythematosus by generating long-lasting, TGF-beta-producing Treg cells, without causing allergic/anaphylactic reactions or generalized immunosuppression.
authors.affiliation: Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Hee-Kap
authors.initials: HK
authors.lastname: Kang
authors.forename: Marissa A
authors.initials: MA
authors.lastname: Michaels
authors.forename: Beate R
authors.initials: BR
authors.lastname: Berner
authors.forename: Syamal K
authors.initials: SK
authors.lastname: Datta
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001324:Autoantigens / Q000008:administration & dosage / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D000939:Epitopes / Q000008:administration & dosage / Q000235:genetics; D005260:Female; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008181:Lupus Nephritis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000628:therapy; D051379:Mice; D008814:Mice, Inbred NZB; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D009707:Nucleosomes / Q000276:immunology*; D010455:Peptides / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D000974:Antibodies, Antinuclear; D001324:Autoantigens; D000939:Epitopes; D009687:Nuclear Proteins; D009707:Nucleosomes; D010455:Peptides; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta