Inflammatory monocyoid expression and epitope cloning of immunoglobulin in patients with IgG4-related disease

• Project/Area Number: 15K09510
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kanazawa Medical University
• Principal Investigator: MASAKI Yasufumi 金沢医科大学, 医学部, 教授 (40238895)
• Co-Investigator(Kenkyū-buntansha): 河南 崇典 金沢医科大学, 医学部, 講師 (20350762) ; 中村 拓路 金沢医科大学, 医学部, 助教 (90725003)
• Research Collaborator: ITOH Kunihiko 静岡県立大学
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 濾胞樹状細胞 / CD14 / リンパ濾胞形成 / ファージディスプレイ / ランダムペプチドライブラリー / 多クローン性高ガンマグロブリン血症 / 多施設共同研究 / 多施設共同前方視研究 / CD21 / 多クローン性高γグロブリン血症 / 炎症性単球

Outline of Final Research Achievements

We conducted a multicenter phase II prospective clinical trial of glucocorticoid for patients with untreated IgG4-related disease. Of the 44 patients with definite IgG4-RD, 29 (65.9%) achieved CR, and the ORR was
93.2%. No patient was refractory to primary treatment.
By phage displayed random peptide assay, we got 8 clone that react to patients' serum, however further analysis of reactive clone was failed. Pathological findings of tissue samples from patients with IgG4-RD (N= 22), reactive hyperplasia (N=3), multicentric Castleman’s disease (N=3), and Sjogren’s syndrome (N = 13) were analyzed. CD14-positive lymphoid follicles were observed only in patients with IgG4-RD, and CD14-positive cells were identified as follicular dendritic cells by multicolor immunohistochemistry.The presence of CD14+ follicular dendritic cells in lymphoid follicles may play a pathophysiological role in IgG4-RD.

Academic Significance and Societal Importance of the Research Achievements

IgG4関連疾患は21世紀に入り日本より発信された疾患であるが、鑑別診断が極めて重要であり、診断さえ確実であれば中等量ステロイド治療が有効である事が示された。
また、IgG4関連疾患の病因病態として近年幾つかの自己抗原が同定されてはいるが、それだけで全ての本疾患の病態を説明するのは不可能である。増加している多クローン性のガンマグロブリンの反応エピトープが判明すれば別な意味での病因論が展開できる。
また本疾患においてCD14陽性濾胞樹状細胞が組織の病態形成において重要な可能性が示され、ここを標的とした治療の開発も期待できる。

Research Products

• [Journal Article] IgG4関連疾患の治療 (2018)
  • Author(s): 正木康史
  • Journal Title: 日医雑誌 Volume: 147(2) Pages: 255-259
  • Peer Reviewed
• [Journal Article] IgG4関連疾患：内科の立場から「教育セミナー3 IgG4関連疾患 耳鼻咽喉科と内科の立場から」 (2018)
  • Author(s): 正木康史
  • Journal Title: 口咽科 Volume: 31（1） Pages: 77-81
  • Peer Reviewed
• [Journal Article] Tentative diagnostic criteria and disease severity classification for Castleman disease: A report of the research group on Castleman disease in Japan. (2018)
  • Author(s): Fujimoto S, Koga T, Kawakami A, Kawabata H, Okamoto S, Mizuki M, Yano S, Ide M, Uno K, Yagi K, Kojima T, Mizutani M, Tokumine Y, Nishimoto N, Fujiwara H, Nakatsuka SI, Shiozawa K, Iwaki N, Masaki Y, Yoshizaki K.
  • Journal Title: Mod Rheumatol Volume: 28 Issue: 1 Pages: 161-167
  • DOI: 10.1080/14397595.2017.1366093
  • Peer Reviewed / Open Access
• [Journal Article] A Host-Dependent Prognostic Model for Elderly Patients with Diffuse Large B-Cell Lymphoma. (2017)
  • Author(s): Miura K, Konishi J, Miyake T, Makita M, Hojo A, Masaki Y, Uno M, Ozaki J, Yoshida C, Niiya D, Kitazume K, Maeda Y, Takizawa J, Sakai R, Yano T, Yamamoto K, Sunami K, Hiramatsu Y, Kazutoshi Aoyama, Tsujimura H, Murakami J, Hatta Y, Kanno M.
  • Journal Title: Oncologist Volume: 22 Issue: 5 Pages: 554-560
  • DOI: 10.1634/theoncologist.2016-0260
  • Peer Reviewed / Open Access
• [Journal Article] The Standard International Prognostic Index for Predicting the Risk of CNS Involvement in DLBCL without Specific Prophylaxis. (2017)
  • Author(s): Tomita N, Yokoyama M, Yamamoto W, Watanabe R, Shimazu Y, Masaki Y, Tsunoda S, Hashimoto C, Murayama K, Yano T, Okamoto R, Kikuchi A, Tamura K, Sato K, Sunami K, Shibayama H, Takimoto R, Ohshima R, Takahashi H, Moriuchi Y, Kinoshita T, Yamamoto M, Numata A, Nakajima H, Miura I, Takeuchi K.
  • Journal Title: Leuk Lymphoma Volume: 59 Issue: 1 Pages: 1-8
  • DOI: 10.1080/10428194.2017.1330541
  • Peer Reviewed / Open Access
• [Journal Article] A multicenter phase II prospective clinical trial of glucocorticoid for patients with untreated IgG4-related disease. (2016)
  • Author(s): Masaki Y, Matsui S, Saeki T, Tsuboi H, Dobashi H, Susaki K, Morimoto H, Takagi K, Kawano M, Origuchi T, Wada Y, Takahashi N, Horikoshi M, Ogishima, H, Suzuki Y, Kawanami T, Kawanami (Iwao) H, Sakai T, Suzuki R, Morikawa Y, Yoshino T, Nakamura S, Kojima M, Kurose N, Sugai S, Sumida T.
  • Journal Title: Mod Rheumatol Volume: 15 Issue: 5 Pages: 1-6
  • DOI: 10.1080/14397595.2016.1259602
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Proposed diagnostic criteria, disease severity classification and treatment strategy for TAFRO syndrome, 2015 version. (2016)
  • Author(s): Masaki Y, Kawabata H, Takai K, Kojima M, Tsukamoto N, Ishigaki Y, Kurose N, Ide M, Murakami J, Nara K, Yamamoto H, Ozawa Y, Takahashi H, Miura K, Miyauchi T, Yoshida S, Momoi A, Awano N, Ikushima S, Ohta Y, Furuta N, Fujimoto S, Kawanami H, Sakai T, Kawanami T, Fujita Y, Fukushima T, Nakamura S, Kinoshita T, Aoki S.
  • Journal Title: Int J Hematol. Volume: in press Issue: 6 Pages: 686-92
  • DOI: 10.1007/s12185-016-1979-1
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] <b>CD14</b>^<b>+</b><b> follicular dendritic cells in lymphoid follicles may play a role in the pathogenesis of IgG4-related </b><b>disease </b> (2015)
  • Author(s): Tomomi Satoh-Nakamura, Nozomu Kurose, Takafumi Kawanami, Takuji Nakamura, Haruka Iwao-Kawanami, Akio Nakajima, Miyuki Miki, Tomoyuki Sakai, Yoshimasa Fujita, Masao Tanaka, Toshihiro Fukushima, and Yasufumi Masaki
  • Journal Title: Biomedical Research Volume: 36 Issue: 2 Pages: 143-153
  • DOI: 10.2220/biomedres.36.143
  • NAID: 130005065277
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Decreased Expression of Innate Immunity-Related Genes in Peripheral Blood Mononuclear Cells from Patients with IgG4-Related Disease (2015)
  • Author(s): Nakajima A, Masaki Y, Nakamura T,et al.
  • Journal Title: Pros One Volume: １０ Issue: 5 Pages: e0126582-e0126582
  • DOI: 10.1371/journal.pone.0126582
  • Peer Reviewed / Open Access
• [Journal Article] International consensus guidance statement on the management and treatment of IgG4-related disease (2015)
  • Author(s): Khosroshahi A, Wallace ZS, Crowe JL, Kawa S, Stone JH.et al.
  • Journal Title: Arthritis Rheumatol. Volume: 67 Issue: 7 Pages: 1688
  • DOI: 10.1002/art.39132
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IgG4関連疾患の診断と治療～IgG4関連皮膚病変も含めて～. (2015)
  • Author(s): 正木康史、清水啓智、中村（佐藤）智美、中村拓路、中島章夫、河南（岩男）悠、河南崇典、山田和徳、濱口儒人、川野充弘、福島俊洋.
  • Journal Title: 日本皮膚アレルギー接触性皮膚炎学会雑誌 Volume: 9(4) Serial No.42 Pages: 212-217
  • NAID: 40020643274
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 多クローン性高ガンマグロブリン血症を呈する疾患の鑑別～IgG4関連疾患、多中心性Castleman病など～ (2018)
  • Author(s): 正木康史
  • Organizer: 第 57回日本臨床検査医学会東海・北陸支部総会、第 336回日本臨床化学会東海・北陸支部例会 連合大会
  • Invited
• [Presentation] 多クローン性高ガンマグロブリン血症を呈する疾患の鑑別～IgG4関連疾患、多中心性Castleman病など～ (2018)
  • Author(s): 正木康史
  • Organizer: 第 57回日本臨床検査医学会東海・北陸支部総会、第 336回日本臨床化学会東海・北陸支部例会 連合大会.
  • Invited
• [Presentation] Clinicopathologic manifestations of multi centric Cattleman disease or TAFRO syndrome. (2017)
  • Author(s): Masaki Y.
  • Organizer: Korean Society of Experimental Hematology (KSEH).
  • Int'l Joint Research / Invited
• [Presentation] Castleman病とTAFRO症候群． (2017)
  • Author(s): 正木康史．
  • Organizer: 日本内科学会 北陸支部第72回生涯教育講演会
  • Int'l Joint Research / Invited
• [Presentation] 世界の診断基準とスタンダード治療．「IgG4関連疾患の世界トップレベル」 (2016)
  • Author(s): 正木康史.
  • Organizer: 第31回日本臨床リウマチ学会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-10-30
  • Invited
• [Presentation] 新たな疾患概念ーTAFRO症候群ー (2016)
  • Author(s): 正木康史.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-14
  • Invited
• [Presentation] TAFRO症候群の診断基準・診療ガイドラインの作成． (2016)
  • Author(s): 正木康史.
  • Organizer: 第56回日本リンパ網内系学会総会
  • Place of Presentation: ホテル日航熊本（熊本県熊本市）
  • Year and Date: 2016-09-03
• [Presentation] IgG4関連疾患に対する前方視的多施設共同治療研究～病理中央診断後の解析～ (2016)
  • Author(s): 正木康史
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-04-22
  • Int'l Joint Research
• [Presentation] IgG4関連疾患に対する前方視的多施設共同治療研究 (2015)
  • Author(s): 正木康史、松井祥子、佐伯敬子、坪井洋人、平田信太郎、宮下賜一郎、折口智樹、藤川敬太、森本尚敬、黒瀬 望
  • Organizer: 第24回 日本シェーグレン症候群学会
  • Place of Presentation: 京王プラザホテル（東京）
  • Year and Date: 2015-09-19
• [Presentation] IgG4関連疾患に対する 第II相多施設共同前方視的治療研究 (2015)
  • Author(s): 正木康史、清水啓智、佐藤智美、中村拓路、岩男 悠、河南崇典、 中島章夫、黒瀬 望、佐藤康晴、小島 勝、中村栄男、吉野 正
  • Organizer: 第55回 日本リンパ網内系学会総会
  • Place of Presentation: 岡山コンベンションセンター（岡山）
  • Year and Date: 2015-07-11
• [Presentation] A multicenter phase II prospective clinical trial of glucocorticoid treatment for patients with untreated IgG4-related disease. (2015)
  • Author(s): Yasufumi Masaki & All Japan IgG4-RD Research Group
  • Organizer: 13th International Sjogren's syndrome symposium
  • Place of Presentation: Radisson Blu Royal Hotel, Bryggen Bergen, Norway
  • Year and Date: 2015-05-19
  • Int'l Joint Research
• [Book] 改訂第3版ステロイドの選び方・使い方ハンドブック；血液疾患 (2018)
  • Author(s): 正木康史
  • Total Pages: 374
  • Publisher: 羊土社
• [Book] 内科学 第11版：白血球減少症、白血球増加症 (2017)
  • Author(s): 正木康史.
  • Total Pages: 2822
  • Publisher: 朝倉書店
• [Book] 臨床医必読最新 IgG4関連疾患. 岡崎和一、川 茂幸編集主幹 (2015)
  • Author(s): 正木康史
  • Publisher: 診断と治療社
• [Book] Modern Physician 11 特集 全身疾患としてのIgG4関連疾患 (2015)
  • Author(s): 正木康史
  • Total Pages: 7
  • Publisher: 新興医学出版社
• [Patent(Industrial Property Rights)] IgG4関連疾患診断用マーカー及びその利用 (2019)
  • Inventor(s): 正木康史、石垣靖人
  • Industrial Property Rights Holder: 正木康史、石垣靖人
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Acquisition Date: 2019