title: Prophylactic and therapeutic efficacies of a selective inhibitor of the immunoproteasome for Hashimoto's thyroiditis, but not for Graves' hyperthyroidism, in mice.
abstract: Major histocompatibility complex (MHC) class I-restricted T cell epitopes are generated mainly by the immunoproteasome in antigen-presenting cells. Therefore, inhibition of activity of this proteolytic complex molecule is thought to be a potential treatment for cell-mediated autoimmune diseases. We therefore studied the efficacy of an immunoproteasome inhibitor, ONX 0914 (formerly PR-957), for the treatment of autoimmune thyroid diseases, including cell-mediated Hashimoto's thyroiditis and autoantibody-mediated Graves' hyperthyroidism using mouse models. Our data show that ONX 0914 was effective prophylactically and therapeutically at suppressing the degree of intrathyroidal lymphocyte infiltration and, to a lesser degree, the titres of anti-thyroglobulin autoantibodies in non-obese diabetic (NOD)-H2(h4)  mice, an iodine-induced autoimmune thyroiditis model. It also inhibited differentiation of T cells to T helper type 1 (Th1) and Th17 cells, effector T cell subsets critical for development of thyroiditis in this mouse strain. In contrast, its effect on the Graves' model was negligible. Although ONX 0914 exerts its immune-suppressive effect through not only suppression of immune proteasome but also other mechanism(s), such as inhibition of T cell differentiation, the present results suggest that the immunoproteasome is a novel drug target in treatment of Hashimoto's thyroiditis in particular and cell-mediated autoimmune diseases in general.
authors.affiliation: Department of Molecular Medicine, Atomic Bomb Disease Institute Division of Immunology, Endocrinology and Metabolism, Department of Medical and Dental Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. nagayama@nagasaki-u.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Nagayama
authors.forename: M
authors.initials: M
authors.lastname: Nakahara
authors.forename: M
authors.initials: M
authors.lastname: Shimamura
authors.forename: I
authors.initials: I
authors.lastname: Horie
authors.forename: K
authors.initials: K
authors.lastname: Arima
authors.forename: N
authors.initials: N
authors.lastname: Abiru
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001323:Autoantibodies / Q000097:blood; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006111:Graves Disease / Q000188:drug therapy* / Q000276:immunology; D050031:Hashimoto Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007455:Iodine / Q000008:administration & dosage; D051379:Mice; D016688:Mice, Inbred NOD; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D061988:Proteasome Inhibitors; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013954:Thyroglobulin / Q000276:immunology; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology
chemical_list: D001323:Autoantibodies; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C542291:PR-957; D061988:Proteasome Inhibitors; D013954:Thyroglobulin; D007455:Iodine