ヒト白血球抗原半合致移植の成立機序の解析

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24591434
• Research Institution: Hyogo Medical University
• Principal Investigator: 小川 啓恭 兵庫医科大学, 医学部, 教授 (80194447)
• Co-Investigator(Kenkyū-buntansha): 岡田 昌也 兵庫医科大学, 医学部, 講師 (00309452) ; 海田 勝仁 兵庫医科大学, 医学部, 助教 (00441254) ; 池亀 和博 兵庫医科大学, 医学部, 講師 (20372609) ; 井上 貴之 兵庫医科大学, 医学部, 助教 (20441256)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: HLA半合致移植 / 移植片対宿主病 / 制御性T細胞 / 白血病 / 移植片対白血病効果

Outline of Annual Research Achievements

1.HLA半合致ミニ移植の多施設共同研究：厚労省の班研究として、多施設共同前方向の形で、当科が考案したHLA半合致ミニ移植の臨床研究(第I/II相試験)を行った。第I相試験(10例)の主要評価項目はドナー生着であり、第II相試験のそれは100日生存であった。当科を含む5施設から34例の症例登録があった。第I相試験では、10例全例で生着が得られ、第II相試験に進んだ。第II相試験の100日生存は88.2%であり、本治療法の安全性、有効性が証明できた(Int J Hematol, in press)。
2.HLA半合致移植の腸管GVHDの病態生理の解析：大腸ファイバーや生検といった侵襲的検査に関して、症状の重い患者の承諾が取りにくかったこともあって、現在までのところ、目標の症例数に達することができず、病理学的検査も進行中である。HHV-6、CMVのPCR検査は、順次結果を得ており、GVHD症例の中に、多くのHHV-6腸炎、CMV腸炎の例が認められた。また、GVHDとの合併例も散見された。今後、引き続き症例の蓄積を行いたい。
3.マウスのMHC半合致移植モデルでのGVL効果発現機序の解析：前処置の強度を変えることで、致死的なGVHD発症に至るものと、ドナー生着を得るが重症のGVHDを起こさないものの2つのMHC半合致移植のマウスモデルを独自に樹立した。両群間でGVL効果の強さに変わりはなく、むしろ前処置を軽減したグループで、GVHDが軽減することが判明した。その機序として、host由来のTregが残存し、重症のGVHDの発症を制御していることが判った(Journal of Immunol, submitted)。

Remarks

兵庫医科大学　血液内科　研究内容
http://www.hyo-med.ac.jp/department/hmt/kenkyuu.html

Research Products

• [Journal Article] Unmanipulated haploidentical RIST using fludarabine, busulfan, low-dose ATG and steroid for patients in non-CR or at high risk of relapse: a prospective multicenter phase I/II study in Japan (2015)
  • Author(s): Ikegame K, Yoshida T, Yoshihara S, T Daimon, Shimizu H, Maeda Y, Ueda Y, Kaida K, Ishii S, Taniguchi K, Okada M, Tamaki H, Okumura H, Kaya H, Kurokawa T, Kodera Y, Taniguchi S, Kanda Y, Ogawa H.
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 未定 Pages: 未定
  • DOI: 10.1016/j.bbmt.2015.04.012.
  • Peer Reviewed
• [Journal Article] Pretransplant diabetes mellitus is a risk factor for infection-related mortality, after allogeneic hematopoietic stem cell transplantation. (2015)
  • Author(s): Fuji S, Takano K, Uchida N, Ogawa H, Ohashi K, Eto T, Sakamaki H, Morishima Y, Kato K, Suzuki R, Fukuda T
  • Journal Title: Bone Marrow Transplantation Volume: 50 Pages: 553-558
  • DOI: 10.1038/bmt.2014.315.
  • Peer Reviewed
• [Journal Article] Prospectively isolated human bone marrow cell-derived MSCs support primitive human CD34-negative hematopoietic stem cells. (2015)
  • Author(s): Matsuoka Y, Nakatsuka R, Sumide K, Kawamura H, Takahashi M, Fujioka T, Uemura Y, Asano H, Sasaki Y, Inoue M, Ogawa H, Takahashi T, Hino M, Sonoda Y
  • Journal Title: Stem Cells Volume: 33 Pages: 1554-1565
  • DOI: 10.1002/stem.1941
  • Peer Reviewed
• [Journal Article] Fatal reactivation of hepatitis B virus infection in a patient with adult T-cell leukemia-lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab (2015)
  • Author(s): Ifuku H, Kusumoto S, Tanaka Y, Totani H, Ishida T, Okada M, Murakami S, Mizokami M, Ueda R, Iida S
  • Journal Title: Hepatology Research Volume: 未定 Pages: 未定
  • DOI: 10.1111/hepr.12513
  • Peer Reviewed
• [Journal Article] A phase 1/2 study of bosutinib in Japanese adults with Philadelphia chromosome-positive chronic myeloid leukemia (2015)
  • Author(s): Nakaseko C, Takahashi N, Ishizawa K, Kobayashi Y, Ohashi K, Nakagawa Y, Yamamoto K, Miyamura K, Taniwaki M, Okada M, Kawaguchi T, Shibata A, Fujii Y, Ono C, Ohnishi K
  • Journal Title: International Journal of Hematology Volume: 101 Pages: 154-164
  • DOI: 10.1007/s12185-014-1722-8
  • Peer Reviewed
• [Journal Article] A Single high-resolution HLA mismatch has a similar adverse impact on the outcome of related hematopoietic stem cell transplantation as a single low-resolution HLA mismatch (2015)
  • Author(s): Fuji S, Kanda J, Kato S, Ikegame K, Morishima S, Miyamoto T, Hidaka M, Kubo K, Miyamura K, Tsudo M, Kobayashi H, Maesako Y, Eto T, Adachi S, Ichinohe T, Atsuta Y, Kanda Y
  • Journal Title: American Journal of Hematology Volume: 未定 Pages: 未定
  • DOI: 10.1002/ajh.24028
  • Peer Reviewed
• [Journal Article] Soluble interleukin-2 receptor level on day 7 as a predictor of graft-versus-host disease after HLA-haploidentical stem cell transplantation using reduced intensity conditioning. (2014)
  • Author(s): Kaida K, Ikegame K, Ikemoto J, Murata R, Irie R, Yoshihara S, Ishii S, Okada M, Inoue T, Tamaki H, Soma T, Fujimori Y, Kai S, Ogawa H.
  • Journal Title: International Journal of Hematology Volume: 99 Pages: 463-470
  • DOI: 10.1007/s12185-014-1542-x
  • Peer Reviewed
• [Journal Article] Risk factors and organ involvement of chronic graft-versus-host disease in Japan (2014)
  • Author(s): Kanda J, Nakasone H, Atsuta Y, Toubai T, Yokoyama H, Fukuda T, Taniguchi S, Ohashi K, Ogawa H, Eto T, Miyamura K, Morishima Y,Nagamura-Inoue T, Sakamaki H, Murata M.
  • Journal Title: Bone Marrow Transplantation Volume: 49 Pages: 228-235
  • DOI: 10.1038/bmt.2013.151
  • Peer Reviewed
• [Journal Article] Allogeneic transplantation for primary myelofibrosis with bone marrow, peripheral blood, or umbilical cord blood: An analysis of the JSHCT. (2014)
  • Author(s): Murata, M, Nishida T, Taniguchi S, Ohashi K, Ogawa H, Fukuda T, Mori T, Kobayashi H, Nakaseko C, Yamagata N, Morishima Y, Nagamura-Inoue T, Sakamaki H, Atsuta Y, Suzuki R, Naoe T.
  • Journal Title: Bone Marrow Transplantation Volume: 49 Pages: 355-360
  • DOI: 10.1038/bmt.2013.180
  • Peer Reviewed
• [Journal Article] Comparison of angiogenic, cytoprotective, and immunosuppressive properties of human amnion- and chorion-derived mesenchymal stem cells. (2014)
  • Author(s): Yamahara K, Harada K, Ohshima M, Ishikane S, Ohnishi S, Tsuda H, Otani K, Taguchi A, Soma T, Ogawa H, Katsuragi S, Yoshimatsu J, Harada-Shiba M, Kangawa K, Ikeda T
  • Journal Title: PLos One Volume: 9 Pages: e88319
  • DOI: 10.1371/journal.pone.0088319
  • Peer Reviewed
• [Journal Article] Recombinant human soluble thrombomodulin attenuates FK506-induced endothelial dysfunction through prevention of Akt inactivation (2014)
  • Author(s): Eguchi R, Fujimori Y, Okada M, Tamaki H, Wakabayashi I, Ogawa H.
  • Journal Title: Experimental Cell Research Volume: 323 Pages: 112-117
  • DOI: 10.1016/j.yexcr.2014.02.023.
  • Peer Reviewed
• [Journal Article] Outcome of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with central nervous system involvement. (2014)
  • Author(s): Aoki J, Ishiyama K, Taniguchi S, Fukuda T, Ohashi K, Ogawa H, Kanamori H, Eto T, Iwato K, Sakamaki H, Morishima Y, Nagamura T, Atsuta Y, Takami A
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 20 Pages: 2029-2033
  • DOI: 10.1016/j.bbmt.2014.09.001.
  • Peer Reviewed
• [Journal Article] Granulocyte colony-stimulating factor combined regimen in cord blood transplantation for acute myeloid leukemia: a nationwide retrospective analysis in Japan (2014)
  • Author(s): Konuma T, Ooi J, Uchida N, Ogawa H, Ohashi K, Kanamori H, Aotsuka N, Onishi Y, Yamaguchi H, Kozai Y, Nagamura-Inoue T, Kato K, Suzuki R, Atsuta Y, Kato S, Asano S, Takahashi S
  • Journal Title: Haematologica Volume: 99 Pages: e264-268
  • DOI: 10.3324/haematol.2014.114504
  • Peer Reviewed
• [Journal Article] The preventative effects of recombinant thrombomodulin on transplantation- associated coagulopathy after allogeneic hematopoietic stem cell transplantation (2014)
  • Author(s): Nomura S, Ishii K, Maeda Y, Katayama Y, Yagi H, Fujishima N, Ota S, Seki M, Okada M, Ikezoe T, Hayashi K, Fujita S, Satake A, Ito T, Kyo T, Ishida Y, Chiba S, Ogawa H, Tanimoto M, Sawada K
  • Journal Title: Journal of Stem Cell Research & Therapy Volume: 4 Pages: 247
  • DOI: 10.1007/s12185-014-1696-6
  • Peer Reviewed
• [Journal Article] Impact of HLA allele mismatch on the clinical outcome in serologically matched related hematopoietic SCT. (2014)
  • Author(s): Fuji S, Kanda J, Kato S, Ikegame K, Morishima S, Miyamoto T, Hidaka M, Kubo K, Miyamura K, Ohashi K, Kobayashi H, Maesako Y, Adachi S, Ichinohe T, Atsuta Y, Kanda Y
  • Journal Title: Bone Marrow Transplant Volume: 49 Pages: 1187-1192
  • DOI: 10.1038/bmt.2014.141.
  • Peer Reviewed
• [Presentation] 進行期血液腫瘍に対する、低用量ATGとステロイドを用いたUnmanipulated haploidentical RIST (2015)
  • Author(s): 小川啓恭
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 神戸ポートピアホテル 神戸
  • Year and Date: 2015-03-06 – 2015-03-06
  • Invited
• [Presentation] 複数臍帯血/骨髄内臍帯血移植 (2015)
  • Author(s): 岡田昌也
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 神戸国際会議場 神戸
  • Year and Date: 2015-03-06 – 2015-03-06
  • Invited
• [Presentation] 胎児付属物由来MSCを使いたGVHD治療法の開発 (2015)
  • Author(s): 相馬俊裕 山原研一 田口明彦 池上武史 黒田将子 藤盛好啓 田浦明映 柴原浩章 田中宏幸 小川啓恭
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 神戸国際会議場 神戸
  • Year and Date: 2015-03-06 – 2015-03-06
• [Presentation] 樹状細胞の成熟はホスト由来制御性T細胞により抑制される:GVHD発症における重要な役割について (2015)
  • Author(s): 井上貴之 池亀和博 海田勝仁 岡田昌也 玉置広哉 相馬俊裕 小川啓恭
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 神戸国際会議場 神戸
  • Year and Date: 2015-03-06 – 2015-03-06
• [Presentation] ハプロタイプを共用しない血縁ドナーからの造血幹細胞移植 (2015)
  • Author(s): 海田勝仁 池亀和博 井上貴之 岡田昌也 玉置広哉 相馬俊裕 小川啓恭
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 神戸国際会議場 神戸
  • Year and Date: 2015-03-06 – 2015-03-06
• [Presentation] 同種造血幹細胞移植の適応とドナーの選択：成人 (2015)
  • Author(s): 池亀和博
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 神戸国際会議場 神戸
  • Year and Date: 2015-03-05 – 2015-03-05
• [Presentation] Based on haplo, beyond haplo (2015)
  • Author(s): 池亀和博
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 神戸ポートピアホテル 神戸
  • Year and Date: 2015-03-05 – 2015-03-05
  • Invited
• [Presentation] Spousal hematopoietic stem cell transplantation for post-transplant relapse/rejection. (2015)
  • Author(s): Ikegame K, Kaida K, Ishii S, Yoshihara S, Taniguchi K, Inoue T, Tamaki H, Okada M, Soma T, Ogawa H
  • Organizer: 2015 BMT Tandem Tandem Meetings
  • Place of Presentation: SanDiego, USA
  • Year and Date: 2015-02-11 – 2015-02-15
• [Presentation] The impact of HLA mismatch only in the host-versus-graft direction on the outcome of related hematopoietic stem cell transplantation for patients with HLA-homozygous Haplotypes: A Retrospective Analysis of the JSHCT HLA working group study (2015)
  • Author(s): Kanda J, Ikegame K, Fuji S, Fukuda T, Kurokawa M, Ogawa H, Ohashi K, Ishikawa J, Inoue M, Ichinohe T, Atsuta Y, Kanda Y
  • Organizer: 2015 BMT Tandem Tandem Meetings
  • Place of Presentation: San diego, USA
  • Year and Date: 2015-02-11 – 2015-02-15
• [Presentation] Low incidence of human herpesvirus 6 reactivation in unmanipulated HLA-haploidentical related stem cell transplantation with corticosteroid as graft-versus-host disesase prophylaxis (2015)
  • Author(s): Tamaki H, Ikegame K, Yoshihara S, Kaida K, Inoue T, Okada M, Soma T, Ogawa H
  • Organizer: 2015 BMT Tandem Tandem Meetings
  • Place of Presentation: San diego, USA
  • Year and Date: 2015-02-11 – 2015-02-15
• [Presentation] Soluble Interleukin-2 receptor level on day 7 as a predictor of GVHD after HLA-Haploidentical RIST (2014)
  • Author(s): Kaida K, Ikegame K, Ikemoto J, Murata R, Irie R, Yoshihara S, Ishii S, Okada M, Inoue T, Tamaki H, Soma T, Fujimori Y, Kai S, Ogawa H
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場 大阪
  • Year and Date: 2014-11-02 – 2014-11-02
• [Presentation] Analysis for HBV reactivation in CML treated with TKIs (2014)
  • Author(s): Okada M, Fujimori Y, Ifuku H, Takatsuka H, Asada T, Ooe Y, Toda A, Okamoto T, Shimizu Y, Mori A, Misawa M, Inoue T, Tokugawa T, Kaida K, Sawada A, Ikegame K, Tamaki H, Higasa S, Soma T, Ogawa H
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場 大阪
  • Year and Date: 2014-11-02 – 2014-11-02
• [Presentation] Haploidentical transplantation and further (2014)
  • Author(s): Ikegame K
  • Organizer: 2nd International Conference on Hematology & Blood Disorders
  • Place of Presentation: Baltimore, USA
  • Year and Date: 2014-09-29 – 2014-10-01
  • Invited
• [Presentation] Clinical usefulness of WT1 mRNA expression in bone marrow detected using a new WT1 mRNA assay kit for monitoring acute myeloid leukemia: A comparison with peripheral blood WT1 mRNA expressions (2014)
  • Author(s): Ishiyama K, Miyawaki S, Kitamura K, Suzuki K, Ishikawa J, Ogawa H, Imai K, Naoe T, Chiba S, Miyazaki Y, Hatta Y, Kurokawa M, Ueda Y, Koga D, Sugiyama H, Takaku F
  • Organizer: The 19 th European Hematology Association
  • Place of Presentation: Milan, Italy
  • Year and Date: 2014-06-12 – 2014-06-15