title: Immunomodulation with eicosapentaenoic acid supports the treatment of autoimmune small-vessel vasculitis.
abstract: Small-vessel vasculitis is a life-threatening autoimmune disease that is frequently associated with anti-neutrophil cytoplasmic antibodies (ANCAs). Conventional immunotherapy including steroids and cyclophosphamide can cause serious adverse events, limiting the efficacy and safety of treatment. Eicosapentaenoic acid (EPA), a key component of fish oil, is an omega-3 polyunsaturated fatty acid widely known to be cardioprotective and beneficial for vascular function. We report two elderly patients with systemic ANCA-associated vasculitis (AAV) in whom the administration of EPA in concert with steroids safely induced and maintained remission, without the use of additioal immunosuppressants. To explore the mechanisms by which EPA enhances the treatment of AAV, we employed SCG/Kj mice as a spontaneous murine model of AAV. Dietary enrichment with EPA significantly delayed the onset of crescentic glomerulonephritis and prolonged the overall survival. EPA-derived anti-inflammatory lipid mediators and their precursors were present in the kidney, plasma, spleen, and lungs in the EPA-treated mice. Furthermore, a decrease in ANCA production and CD4/CD8-double negative T cells, and an increase in Foxp3(+) regulatory T cells in the lymph nodes of the kidney were observed in the EPA-treated mice. These clinical and experimental observations suggest that EPA can safely support and augment conventional therapy for treating autoimmune small-vessel vasculitis.
authors.affiliation: 1] Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo [2] Apheresis and Dialysis Center, School of Medicine, Keio University.
authors.forename: Junichi
authors.initials: J
authors.lastname: Hirahashi
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo.
authors.forename: Kimito
authors.initials: K
authors.lastname: Kawahata
authors.affiliation: 1] Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo [2].
authors.forename: Makoto
authors.initials: M
authors.lastname: Arita
authors.affiliation: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo.
authors.forename: Ryo
authors.initials: R
authors.lastname: Iwamoto
authors.affiliation: Department of Advanced Nephrology and Regenerative Medicine, Graduate School of Medicine, The University of Tokyo.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hishikawa
authors.affiliation: 1] Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo [2].
authors.forename: Mie
authors.initials: M
authors.lastname: Honda
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Hamasaki
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo.
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo.
authors.forename: Koshu
authors.initials: K
authors.lastname: Okubo
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo.
authors.forename: Miho
authors.initials: M
authors.lastname: Kurosawa
authors.affiliation: Department of Advanced Nephrology and Regenerative Medicine, Graduate School of Medicine, The University of Tokyo.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takase
authors.affiliation: Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakakuki
authors.affiliation: Pharmaceutical Research Laboratories, Nippon Kayaku Co. Ltd.
authors.forename: Kan
authors.initials: K
authors.lastname: Saiga
authors.affiliation: Inflammation Program, Chiba University Graduate School of Medicine.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Division of Anesthesia, Surgical Operation Department, National Center for Global Health and Medicine.
authors.forename: Shoji
authors.initials: S
authors.lastname: Kawachi
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tojo
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo.
authors.forename: George
authors.initials: G
authors.lastname: Seki
authors.affiliation: Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Marumo
authors.affiliation: Apheresis and Dialysis Center, School of Medicine, Keio University.
authors.forename: Matsuhiko
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: 1] Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo [2] Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
mesh_terms: D000368:Aged; D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015118:Eicosapentaenoic Acid / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D056747:Immunomodulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; D015118:Eicosapentaenoic Acid