Suppression of murine SLE by oral anti-CD3: inducible CD4+CD25-LAP+ regulatory T cells control the expansion of IL-17+ follicular helper T cells.
Lupus is an antibody-mediated autoimmune disease. The production of pathogenic, class switched and affinity maturated autoantibodies in lupus is dependent on T cell help. A potential mechanism of disease pathogenesis is a lack of control of pathogenic T helper cells by regulatory T cells in lupus. It has been repeatedly shown that the naturally occurring CD4+CD25+ regulatory T cells in lupus prone mice and patients with SLE are defective both in frequency and function. Thus, the generation of inducible regulatory T cells that can control T cell help for autoantibody production is a potential avenue for the treatment of SLE. We have found that oral administration of anti-CD3 monoclonal antibody attenuated lupus development and arrested on-going disease in lupus prone SNF1 mice. Oral anti-CD3 induces a CD4+CD25-LAP+ regulatory T cell that secrets high levels of TGF-beta and suppresses in vitro in TFG-beta-dependent fashion. Animals treated with oral anti-CD3 had less glomerulonephritis and diminished levels of anti-dsDNA autoantibodies. Oral anti-CD3 led to a downregulation of IL-17+CD4+ICOS-CXCR5+ follicular helper T cells, CD138+ plasma cells and CD73+ mature memory B cells. Our results show that oral anti-CD3 induces CD4+CD25-LAP+ regulatory T cells that suppress lupus in mice and is associated with downregulation of T cell help for autoantibody production.
Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts, USA. hwu@rics.bwh.harvard.edu
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D000284:Administration, Oral; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001323:Autoantibodies / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D017252:CD3 Complex / Q000276:immunology*; D049109:Cell Proliferation; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005921:Glomerulonephritis / Q000517:prevention & control; D020381:Interleukin-17 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D007668:Kidney / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB; D013154:Spleen / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology*
D000906:Antibodies; D001323:Autoantibodies; D017252:CD3 Complex; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D004247:DNA