title: B cell-targeted therapy with anti-CD20 monoclonal antibody in a mouse model of Graves' hyperthyroidism.
abstract: Graves' disease is a B cell-mediated and T cell-dependent autoimmune disease of the thyroid which is characterized by overproduction of thyroid hormones and thyroid enlargement by agonistic anti-thyrotrophin receptor (TSHR) autoantibody. In addition to antibody secretion, B cells have recently been recognized to function as antigen-presenting/immune-modulatory cells. The present study was designed to evaluate the efficacy of B cell depletion by anti-mouse (m) CD20 monoclonal antibody (mAb) on Graves' hyperthyroidism in a mouse model involving repeated injection of adenovirus expressing TSHR A-subunit (Ad-TSHR289). We observe that a single injection of 250 µg/mouse anti-mCD20 mAb eliminated B cells efficiently from the periphery and spleen and to a lesser extent from the peritoneum for more than 3 weeks. B cell depletion before immunization suppressed an increase in serum immunoglobulin (Ig)G levels, TSHR-specific splenocyte secretion of interferon (IFN)-γ, anti-TSHR antibody production and development of hyperthyroidism. B cell depletion 2 weeks after the first immunization, a time-point at which T cells were primed but antibody production was not observed, was still effective at inhibiting antibody production and disease development without inhibiting splenocyte secretion of IFN-γ. By contrast, B cell depletion in hyperthyroid mice was therapeutically ineffective. Together, these data demonstrate that B cells are critical not only as antibody-producing cells but also as antigen-presenting/immune-modulatory cells in the early phase of the induction of experimental Graves' hyperthyroidism and, although therapeutically less effective, B cell depletion is highly efficient for preventing disease development.
authors.affiliation: Department of Medical Gene Technology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Ueki
authors.forename: N
authors.initials: N
authors.lastname: Abiru
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: M
authors.initials: M
authors.lastname: Nakahara
authors.forename: T
authors.initials: T
authors.lastname: Ichikawa
authors.forename: K
authors.initials: K
authors.lastname: Eguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Nagayama
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D002452:Cell Count; D004195:Disease Models, Animal; D005260:Female; D006111:Graves Disease / Q000097:blood / Q000276:immunology* / Q000517:prevention & control* / Q000628:therapy; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D018828:Immunoglobulins, Thyroid-Stimulating / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D010529:Peritoneal Cavity / Q000166:cytology; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013974:Thyroxine / Q000097:blood; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D007074:Immunoglobulin G; D018828:Immunoglobulins, Thyroid-Stimulating; D011989:Receptors, Thyrotropin; D019444:Vaccines, DNA; D007371:Interferon-gamma; D013974:Thyroxine