HLA haplotype effects in allogeneic hematopoietic stem cell transplantation

• Project/Area Number: 26461455
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: University of the Ryukyus (2016); Fujita Health University (2014-2015)
• Principal Investigator: MORISHIMA Satoko 琉球大学, 医学(系)研究科(研究院), 准教授 (40463195)
• Co-Investigator(Kenkyū-buntansha): 森島 泰雄 愛知県がんセンター(研究所), その他部局等, 研究員 (20220056)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 同種造血幹細胞移植 / HLA / HLAハプロタイプ / 急性GVHD / 造血幹細胞移植

Outline of Final Research Achievements

We demonstrated the structure of Japanese common HLA haplotypes using multi-SNP data in HLA region of 1500 patient-donor unrelated bone marrow transplantation (UR-BMT) pairs.
We also identified high-risk HLA alleles and haplotypes for severe acute graft-versus-host disease (aGVHD) using database of 6967 UR-BMT pairs from the Japan Marrow Donor Program. The patient and/or donor HLA-B*51:01 and patient HLA-C*14:02 were significantly associated with an increased risk of severe aGVHD. Furthermore, patient mismatched HLA-C*14:02 showed the highest risk of severe aGVHD and overall mortality among all patient mismatched HLA-C alleles. KIR2DL-ligand mismatch has been considered as high-risk HLA-C mismatch in Japanese UR-BMT, however our data demonstrated that the effect of KIR2DL-ligand mismatch was attributable to patient HLA-C*14:02 and donor HLA-C*15:02 mismatch combination. Patient mismatched HLA-C*14:02 should be considered a non-permissive HLA-C mismatch in donor selection for UR-BMT.

Research Products

• [Journal Article] High-risk HLA alleles for severe acute graft-versus-host disease and mortality in unrelated donor bone marrow transplantation. (2016)
  • Author(s): Morishima S, Kashiwase K, Matsuo K, Azuma F, Yabe T, Sato-Otsubo A, Ogawa S, Shiina T, Satake M, Saji H, Kato S, Kodera Y, Sasazuki T, Morishima Y.
  • Journal Title: Haematologica. Volume: 101 Pages: 491-498
  • DOI: 10.3324/haematol.2015.136903
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Gene Map of the HLA Region, Graves' Disease and Hashimoto Thyroiditis, and Hematopoietic Stem Cell Transplantation. (2016)
  • Author(s): Sasazuki T, Inoko H, Morishima S, Morishima Y.
  • Journal Title: Adv Immunol Volume: 129 Pages: 175-249
  • DOI: 10.1016/bs.ai.2015.08.003
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 非血縁同種造血幹細胞移植におけるHLA-DPB1ミスマッチと急性移植片対宿主病（GVHD） (2016)
  • Author(s): 森島聡子
  • Journal Title: 血液内科 Volume: 72 Pages: 344-350
• [Journal Article] Genome-wide surveillance of mismatched alleles for graft-versus-host disease in stem cell transplantation. (2015)
  • Author(s): A. Sato-Otsubo, Y. Nannya, K. Kashiwase, M. Onizuka, F. Azuma, Y. Akatsuka, Y. Ogino, M. Satake, M. Sanada, S. Chiba, H. Saji, H. Inoko, G. C. Kennedy, K. Yamamoto, S. Morishima, Y. Morishima, Y. Kodera, T. Sasazuki, and S. Ogawa
  • Journal Title: Blood Volume: 126 Pages: 2752-2763
  • DOI: 10.1182/blood-2015-03-630707
  • Peer Reviewed
• [Journal Article] Cost-efficient multiplex PCR for routine genotyping of up to nine classical HLA loci in a single analytical run of multiple samples by next generation sequencing. (2015)
  • Author(s): Ozaki Y, Suzuki S, Kashiwase K, Shigenari A, Okudaira Y, Ito S, Masuya A, Azuma F, Yabe T, Morishima S, Mitsunaga S, Satake M, Ota M, Morishima Y, Kulski JK, Saito K, Inoko H, Shiina T.
  • Journal Title: BMC Genomics Volume: 16 Pages: 318-318
  • DOI: 10.1186/s12864-015-1514-4
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Increased T-cell responses to Epstein-Barr virus with high viral load in patients with Epstein-Barr virus-positive diffuse large B-cell lymphoma. (2015)
  • Author(s): Morishima S, Nakamura S, Yamamoto K, Miyauchi H, Kagami Y, Kinoshita T, Onoda H, Yatabe Y, Ito M, Miyamura K, Nagai H, Moritani S, Sugiura I, Tsushita K, Mihara H, Ohbayashi K, Iba S, Emi N, Okamoto M, Iwata S, Kimura H, Kuzushima K, Morishima Y.
  • Journal Title: Leuk Lymphoma. Volume: 56 Pages: 1072-1078
  • DOI: 10.3109/10428194.2014.938326
  • Peer Reviewed
• [Journal Article] Biological significance of HLA locus matching in unrelated donor bone marrow transplantation. (2015)
  • Author(s): Morishima Y, Kashiwase K, Matsuo K, Azuma F, Morishima S, Onizuka M, Yabe T, Murata M, Doki N, Eto T, Mori T, Miyamura K, Sao H, Ichinohe T, Saji H, Kato S, Atsuta Y, Kawa K, Kodera Y, Sasazuki T; Japan Marrow Donor Program.
  • Journal Title: Blood Volume: 125 Pages: 1189-1197
  • DOI: 10.1182/blood-2014-10-604785
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 急性GVHD発症に関与する系統樹に基づくHLA-DP2/DP5 groupの同定とHLA-DPB1 T-cell-epitope matchingとの関連 (2016)
  • Author(s): 森島聡子、椎名隆、小川誠司、鈴木進悟、柏瀬貢一、東史啓、屋部登志雄、佐治博夫、笹月健彦、森島泰雄
  • Organizer: 第25回日本組織適合性学会大会
  • Place of Presentation: 北海道大学（北海道札幌市）
  • Year and Date: 2016-10-22
• [Presentation] Evolutionary basis of HLA alleles affects acute GVHD in unrelated donor stem cell transplantation (2016)
  • Author(s): Morishima S, Shiina T, Ogawa S, Suzuki S, Sato-Otsubo A, Kashiwase K, Azuma F, Yabe T, Matsuo K, Saji H, Kodera Y, Sasazuki T, Morishima Y
  • 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: 2016-10-13
• [Presentation] 非血縁者間骨髄移植において重症急性GVHDのリスクが高いHLAアリルの同定 (2016)
  • Author(s): 森島聡子、柏瀬貢一、松尾恵太郎、東史啓、屋部登志雄、佐藤亜以子、小川誠司、椎名隆、佐竹正博、佐治博夫、加藤俊一、小寺良尚、笹月健彦、森島泰雄
  • Organizer: 第38回日本造血細胞移植学会総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2016-03-03
• [Presentation] High risk HLA allele for severe acute graft-versus-host disease and mortality in unrelated donor hematopoietic stem cell transplantation. (2016)
  • Author(s): Morishima S, Kashiwase K, Matsuo K, Azuma F, Yabe T, Sato-Otsubo A, Ogawa S, Shiina T, Satake M, Saji H, Kato S, Kodera Y, Sasazuki T, Morishima Y.
  • Organizer: BMT Tandem Meetings 2016
  • Place of Presentation: Honolulu, USA
  • Year and Date: 2016-02-18
  • Int'l Joint Research
• [Presentation] Effect of HLA-DPB1 T-cell-epitope matching in unrelated donor bone marrow transplantation: The Japan Marrow Donor Program analysis. (2015)
  • Author(s): Morishima S, Kashiwase K, Azuma F, Yabe T, Sasazuki T, Kodera Y, Morishima Y.
  • Organizer: The 20th Annual Congress of Asia-Pacific Blood and Marrow Transplantation Group
  • Place of Presentation: Okinawa, JAPAN
  • Year and Date: 2015-10-30
  • Int'l Joint Research
• [Presentation] 日本骨髄バンクの非血縁者間骨髄移植におけるHLA-DPB1 T-cell epitope matchingの影響 (2015)
  • Author(s): 森島聡子、柏瀬貢一、東史啓、屋部登志雄、笹月健彦、森島泰雄
  • Organizer: 第24回日本組織適合性学会大会
  • Place of Presentation: ホテルレイクビュー水戸
  • Year and Date: 2015-09-10