Development of effector cell-targeted treatment for the inhibition of type 1 diabetes

• Project/Area Number: 24591334
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Nagasaki University
• Principal Investigator: ABIRU Noriio 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (00380981)
• Co-Investigator(Kenkyū-buntansha): AKAZAWA Satoru 長崎大学, 病院(医学系), 助教 (50549409)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 1型糖尿病 / NODマウス / Ｔ細胞 / サイトカイン / IRF4 / グランザイムＢ / 樹状細胞 / IRF-4 / Th17細胞 / Th1細胞 / T細胞

Outline of Final Research Achievements

In order to identify the candidate molecules for the development of the effector cell-targeted treatment for the inhibition of type 1 diabetes, we have developed IL-17/IFN-gamma receptor-double-deficient, Granzyme B-deficient, IRF4-deficient NOD mice. IL-17/IFN-gamma R double-deficiency significantly suppressed the development of diabetes, while independent deletion of IL-17 or IFN-gammaR did not alter the disease susceptibility in NOD mice. Granzyme B-deficient NOD mice spontaneously developed diabetes with similar kinetics to wild-type NOD mice. Diabetes/insulitis and autoantibody production were completely suppressed in IRF4-deficient heterozygous as well as homozygous NOD mice. These suggest that the an IRF4-targeted strategy may be useful for modulating autoimmunity in type 1 diabetes.

Research Products

• [Journal Article] NODマウスモデルにおける1型糖尿病の成因 (2015)
  • Author(s): 阿比留教生
  • Journal Title: 月刊糖尿病 医学出版 Volume: 7（5） Pages: 13-19
• [Journal Article] Novel enzyme-linked immunosorbent assay for bivalent ZnT8 autoantibodies. (2014)
  • Author(s): Kawasaki E, Tanaka M, Miwa M, Abiru N, Kawakami A.
  • Journal Title: Acta Diabetol Volume: 51 Issue: 3 Pages: 429-434
  • DOI: 10.1007/s00592-013-0532-4
  • NAID: 120006986447
  • Peer Reviewed / Open Access
• [Journal Article] Uptake of Aortic 18F-FDG Is Correlated with Low-Density Lipoprotein Cholesterol and Leptin in a General Population. (2014)
  • Author(s): Haraguchi A, Hayashida N, Kamasaki T, Miyamoto I, Usui T, Ando T, Abiru N, Yamasaki H, Chiba K, Kudo T, Kawakami A, Takamura N.
  • Journal Title: PLoS One Volume: 9（11） Issue: 11 Pages: e111990-e111990
  • DOI: 10.1371/journal.pone.0111990
  • NAID: 120006986351
  • Peer Reviewed / Open Access
• [Journal Article] The A>T polymorphism of the tribbles homolog 1 gene is associated with serum triglyceride concentrations in Japanese community-dwelling women. (2014)
  • Author(s): Ikeoka T, Hayashida N, Nakazato M, Sekita T, Murata-Mori F, Ando T, Abiru N, Yamasaki H, Kudo T, Maeda T, Kawakami A, Takamura N
  • Journal Title: Tohoku J Exp Med Volume: 233（2） Pages: 149-153
  • NAID: 130004822418
  • Peer Reviewed
• [Journal Article] Multiple drug combination of anti-diabetic agents as a predictor for poor clinical response to liraglutide. (2014)
  • Author(s): Haraguchi A, Fujishima K, Ando T, Mori F, Imaizumi M, Abiru N, Yamasaki H, Matsumoto K, Takamura N, Kawakami A
  • Journal Title: Minerva Endocrinol Volume: 39（4） Pages: 12-12
  • Peer Reviewed
• [Journal Article] Association of the GCKR rs780094 polymorphism with metabolic traits including carotid intima-media thickness in Japanese community-dwelling men, but not in women (2014)
  • Author(s): Murata-MoriF, Hayashida N, Ando T, Ikeoka T, Nakazato M, Sekita H, Abiru N, Yamasaki H, Maeda T, Kawakami A, Takamura N
  • Journal Title: Clin Chem Lab Med Volume: 52(2) Issue: 2 Pages: 289-295
  • DOI: 10.1515/cclm-2013-0092
  • NAID: 120006986505
  • Peer Reviewed
• [Journal Article] Double deficiency in IL-17 and IFN-γ signalling significantly suppresses the development of diabetes in the NOD mouse. (2013)
  • Author(s): Kuriya G, Uchida T, Akazawa S, Kobayashi M, Nakamura K, Satoh T, Horie I, Kawasaki E, Yamasaki H, Yu L, Iwakura Y, Sasaki H, Nagayama Y, Kawakami A, Abiru N.
  • Journal Title: Diabetologia Volume: 56 Issue: 8 Pages: 1773-1780
  • DOI: 10.1007/s00125-013-2935-8
  • Peer Reviewed
• [Journal Article] Genetic deletion of granzyme B does not confer resistance to the development of spontaneous diabetes in non-obese diabetic mice. (2013)
  • Author(s): Kobayashi M, Kaneko-Koike C, Abiru N, Uchida T, Akazawa S, Nakamura K, Kuriya G, Satoh T, Ida H, Kawasaki E, Yamasaki H, Nagayama Y, Sasaki H, Kawakami A
  • Journal Title: Clin Exp Immunol. Volume: 173(3) Issue: 3 Pages: 411-418
  • DOI: 10.1111/cei.12134
  • Peer Reviewed
• [Journal Article] Sequential elevation of autoantibodies to thyroglobulin and glutamic acid decarboxylase in type 1 diabetes. (2013)
  • Author(s): Kawasaki E, Yasui J, Tsurumaru M, Takashima H, Ikeoka T, Mori F, Akazawa S, Ueki I, Kobayashi M, Kuwahara H, Abiru N, Yamasaki H, Kawakami A.
  • Journal Title: World J Diabetes Volume: 4 Issue: 5 Pages: 227-230
  • DOI: 10.4239/wjd.v4.i5.227
  • Peer Reviewed
• [Journal Article] Adoptive transfer of antithyrotropin receptor (TSHR) autoimmunity from TSHR knockout mice to athymic nude mice (2012)
  • Author(s): Nakahara M, Johnson K, Eckstein A, Taguchi R, Yamada M, Abiru N, Nagayama Y.
  • Journal Title: Endocrinology Volume: 153 Issue: 4 Pages: 2034-2042
  • DOI: 10.1210/en.2011-1846
  • NAID: 120006985412
  • Peer Reviewed
• [Journal Article] Prophylactic and therapeutic efficacies of a selective inhibitor of the immunoproteasome for Hashimoto's thyroiditis, but not for Graves' hyperthyroidism, in mice. (2012)
  • Author(s): Nagayama Y, Nakahara M, Shimamura M, Horie I, Arima K, Abiru N.
  • Journal Title: Clin Exp Immunol Volume: 168 Issue: 3 Pages: 268-273
  • DOI: 10.1111/j.1365-2249.2012.04578.x
  • Peer Reviewed
• [Presentation] L-17/IFN- receptor double-deficiency lacks systemic expansion of lymphocytes after weaning period which might be associated with disease susceptibility in the NOD mice (2015)
  • Author(s): Akazawa S, Abiru N, Kobayashi M, Kawakami Ａ
  • Organizer: Immunology of Diabetes Society 14th International Congress
  • Place of Presentation: ヒルトンミュンヘンパーク(ミュンヘン）
  • Year and Date: 2015-04-12 – 2015-04-16
• [Presentation] IL-17/IFNγ受容体ダブル欠損ＮＯＤマウスにおけるリンパ球phenotype解析 (2015)
  • Author(s): 赤澤諭，古林正和，山崎浩則，川上純，阿比留教生
  • Organizer: 日本糖尿病・肥満動物学会 年次学術集会
  • Place of Presentation: 芝蘭会館（京都）
  • Year and Date: 2015-02-13 – 2015-02-14
• [Presentation] エフェクター細胞を標的にした1型糖尿病発症抑制の試み (2014)
  • Author(s): 阿比留教生，赤澤諭，古林正和
  • Organizer: 1型糖尿病研究会
  • Place of Presentation: イーグレひめじあいめっせホール（姫路）
  • Year and Date: 2014-11-01 – 2014-11-02
  • Invited
• [Presentation] インターフェロン誘発１型糖尿病における治療中断後の抗GAD抗体価とインスリン分泌能の推移 (2014)
  • Author(s): 阿比留教生，赤澤諭，野崎彩，原口愛，池岡俊幸，安井順一，堀江一郎，古林正和，安藤隆雄，川崎英二，山崎浩則，川上純
  • Organizer: 日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪国際会議場（大阪）
  • Year and Date: 2014-05-22 – 2014-05-25
• [Presentation] IL-17/IFN-受容体遺伝子ダブル欠損NODマウスにおけるリンパ球phenotypeの経時的変化 (2014)
  • Author(s): 赤澤諭，阿比留教生，古林正和，堀江一郎，安藤隆雄，山崎浩則，川上純
  • Organizer: 日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪国際会議場（大阪）
  • Year and Date: 2014-05-22 – 2014-05-25
• [Presentation] IRF4遺伝子欠損マウスにおける自己免疫性糖尿病の完全抑制 (2013)
  • Author(s): 赤澤 諭, 阿比留教生, 古林正和, 厨 源平, 川﨑英二, 山崎浩則, 川上 純
  • Organizer: 日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本市国際交流会館
• [Presentation] Haploinsufficiency of Interferon regulatory factor 4 strongly protects from autoimmune diabetes in the non-obese diabetic mice (2013)
  • Author(s): Akazawa S, Kobayashi M, Kawasaki E, Nagayama Y, Yui K, Matsuyama T, Kawakami A, Abiru N
  • Organizer: Immunology of Diabetes Society 13th International Congress
  • Place of Presentation: Lone,Australia
• [Presentation] Interferon regulatory factor-4（IRF-4）欠損NODマウスにおける糖尿病の完全抑制 (2013)
  • Author(s): 赤澤諭、阿比留教生、古林正和、厨源平、川崎英二、川上純
  • Organizer: 日本糖尿病肥満動物学会
  • Place of Presentation: 東京
• [Presentation] ＩL-17/IFN-g受容体遺伝子ダブル欠損NODマウスにおける糖尿病発症抑制の相乗効果 (2013)
  • Author(s): 阿比留教生, 厨源平, 内田隆寛, 赤澤諭, 古林正和, 川崎英二, 川上純
  • Organizer: 日本糖尿病肥満動物学会
  • Place of Presentation: 東京
• [Presentation] nterferon regulatory factor 4 silencing suppresses autoimmunity in the nonobese diabetic mice (2012)
  • Author(s): Akazawa S, Abiru N, Uchida T, Nakamura K, Kuriya G, Satoh T, Kobayashi M, Kawasaki E, Yui K, Nagayama Y, Kawakami A
  • Organizer: International Conference of the Immunology of Diabetes
  • Place of Presentation: Victoria Canada
• [Presentation] IL-17/IFN- receptor double-knockout significantly suppresses the development of diabetes compared to the IL-17 single-knockout in the NOD mouse (2012)
  • Author(s): Kuriya G, Uchida T, Abiru N, Akazawa S, Kobayashi M, Nakamura K, Kawasaki E, Yamasaki H, Nagayama Y, Kanagawa O, Iwakura Y, Kawakami A
  • Organizer: International Conference of the Immunology of Diabetes
  • Place of Presentation: Victoria Canada
• [Book] 最新臨床糖尿病学 上巻 １型糖尿病の免疫制御と発症阻止法の臨床試験 (2012)
  • Author(s): 古林正和、阿比留教生
  • Total Pages: 823
  • Publisher: 日本臨床