Antigen-specific therapy of murine lupus nephritis using nucleosomal peptides: tolerance spreading impairs pathogenic function of autoimmune T and B cells.
In the (SWR x NZB)F1 mouse model of lupus, we previously localized the critical autoepitopes for nephritogenic autoantibody-inducing Th cells in the core histones of nucleosomes at aa positions 10-33 of H2B and 16-39 and 71-94 of H4. A brief therapy with the peptides administered i.v. to 3-mo-old prenephritic (SWR x NZB)F1 mice that were already producing pathogenic autoantibodies markedly delayed the onset of severe lupus nephritis. Strikingly, chronic therapy with the peptides injected into 18-mo-old (SWR x NZB)F1 mice with established glomerulonephritis prolonged survival and even halted the progression of renal disease. Remarkably, tolerization with any one of the nucleosomal peptides impaired autoimmune T cell help, inhibiting the production of multiple pathogenic autoantibodies. However, cytokine production or proliferative responses to the peptides were not grossly changed by the therapy. Moreover, suppressor T cells were not detected in the treated mice. Most interestingly, the best therapeutic effect was obtained with nucleosomal peptide H416-39, which had a tolerogenic effect not only on autoimmune Th cells, but autoimmune B cells as well, because this peptide contained both T and B cell autoepitopes. These studies show that the pathogenic T and B cells of lupus, despite intrinsic defects in activation thresholds, are still susceptible to autoantigen-specific tolerogens.
Kaliyaperumal
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A
Departments of Medicine and Microbiology-Immunology and Multipurpose Arthritis Center, Northwestern University Medical School, Chicago, IL 60611, USA.
Michaels
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MA
Datta
S K
SK
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001323:Autoantibodies / Q000096:biosynthesis; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand; D015536:Down-Regulation; D005260:Female; D006657:Histones / Q000627:therapeutic use*; D007108:Immune Tolerance; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D008181:Lupus Nephritis / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains; D018448:Models, Immunological; D009707:Nucleosomes / Q000276:immunology; D010446:Peptide Fragments / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D006657:Histones; D007140:Immunoglobulin Fab Fragments; D007376:Interleukin-2; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009707:Nucleosomes; D010446:Peptide Fragments; D011994:Recombinant Proteins; D023201:CD40 Ligand; D015847:Interleukin-4