Identification of auto-antigens which trigger the development of immune-mediated bone marrow failure

• Project/Area Number: 21390291
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Kanazawa University
• Principal Investigator: NAKAO Shinji 金沢大学, 医学系, 教授 (70217660)
• Co-Investigator(Renkei-kenkyūsha): YAMAZAKI Hirohito 金沢大学, 大学病院, 講師 (50361994) ; KONDO Yukio 金沢大学, 大学病院, 助教 (10322116) ; ISHIYAMA Ken 金沢大学, 医学系, 協力研究員 (60377380) ; TAKAMATSU Hiroyuki 金沢大学, 医学系, 助教 (70401932)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2011: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2010: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2009: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
• Keywords: 再生不良性貧血 / 6pUPD / HLA / 細胞傷害性T細胞 / 自己抗原 / GPIアンカー膜蛋白 / PNH / TGF-β / CD109 / 骨髄不全 / 自己抗体 / PNH型血球 / GPI-アンカー膜蛋白 / 13q- / RB遺伝子

Research Abstract

Genomic analyses of patients with acquired aplastic anemia(AA) revealed the presence of leukocytes lacking an HLA haplotype as a result of uniparental disomy of chromosome 6p in 13% of patients. The missing HLA haplotypes were strongly biased to HLA-A^* 02 : 01, A^* 02 : 06, A^* 31 : 01, and B^* 40 : 02, which were over-represented in Japanese AA cases. Cytotoxic T lymphocytes specific to hematopoietic stem cell-derived auto-antigens presented by the particular HLAs was thought to trigger the development of AA.

Research Products

• [Journal Article] Aplastic anemia successfully treated with rituximab : the possible role of aplastic anemia-associated autoantibodies as a marker for response (2011)
  • Author(s): Takamatsu, H., Yagasaki, H., Takahashi, Y., Hama, A., Saikawa, Y., Yachie, A., Koizumi, S., Kojima, S., N akao, S.
  • Journal Title: Eur J Haematol Volume: 86 Pages: 541-545
  • NAID: 120003141908
  • Peer Reviewed
• [Journal Article] Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia (2011)
  • Author(s): Katagiri, T., Sato-Otsubo, A., Kashiwase, K., Morishima, S., Sato, Y., Mori, Y., Kato, M., Sanada, M., Morishima, Y., Hosokawa, K., Sasaki, Y., Ohtake, S., Ogawa, S., Nakao, S.
  • Journal Title: Blood Volume: 118 Pages: 6601-6609
  • NAID: 120003752541
  • Peer Reviewed
• [Journal Article] An Epstein-Barr virus-associated leukemic lymphoma in a patient treated with rabbit antithymocyte globulin and cyclosporine for hepatitis-associated aplastic anemia (2011)
  • Author(s): Ohata, K., Iwaki, N., Kotani, T., Kondo, Y., Yamazaki, H., Nakao, S.
  • Journal Title: Acta Haematol Volume: 127 Pages: 96-99
  • NAID: 120003752533
  • Peer Reviewed
• [Journal Article] Aplastic anemia successfully treated with rituximab : The possible role of aplastic anemia-associated autoantibodies as a marker for response (2011)
  • Author(s): Takamatsu, H., Yagasaki, H., Takahashi, Y., Hama, A., Saikawa, Y., Yachie, A., Koizumi, S., Kojima, S., Nakao, S.
  • Journal Title: Eur J Haematol Volume: 86 Pages: 541-5
  • NAID: 120003141908
  • Peer Reviewed
• [Journal Article] GPI-anch ored protein-deficient T cells in patients with aplastic anemia and low-risk myelodysplastic syndrome : implications for the immunopathophysiology of bone marrow failure (2011)
  • Author(s): Katagiri, T., Qi, Z., Ohtake, S., Nakao, S.
  • Journal Title: Eur J Haematol Volume: 86 Pages: 226-36
  • Peer Reviewed
• [Journal Article] Autoantibodies specific to hnRNP K : a new diagnostic marker for immune pathophysiology in aplastic anemia (2010)
  • Author(s): Qi, Z., Takamatsu, H., Espinoza, J, L., Lu, X., Sugimori, N., Yamazaki, H., Okawa, K., Nakao, S.
  • Journal Title: Ann Hematol Volume: 89 Pages: 1255-63
  • Peer Reviewed
• [Journal Article] Autoantibodies specific to hnRNP K : a new diagnostic marker for immune pathophysiology in aplastic anemia. (2010)
  • Author(s): Qi Z, Takamatsu H, Esninoza JL, et al.
  • Journal Title: Ann Hematol Volume: 89 Pages: 1255-1263
  • Peer Reviewed
• [Journal Article] GPI-anchored protein-deficient T cells in patients with aplastic anemia and low-risk myelodysplastic syndrome : implications for the immunopat hophysiology of bone marrow failure. (2010)
  • Author(s): Katagiri T, Qi Z, Ohtake S, et al.
  • Journal Title: Eur J Haematol Volume: 86 Pages: 226-236
  • Peer Reviewed
• [Journal Article] Aplastic anemia successfully treated with rituximab : The possible role of aplastic anemia-associated autoantibodies as a marker for response. (2010)
  • Author(s): Takamatsu H, Yagasaki H, Taka hashi Y, et al.
  • Journal Title: Eur J Haematol Volume: (In press)
  • NAID: 120003141908
  • Peer Reviewed
• [Journal Article] Anti-moesin antibodies in the serum of patients with aplastic anemia stimulate peripheral blood mononuclear cells to secrete TNF-alpha and IFN-gamma (2009)
  • Author(s): Takamatsu, H., Espinoza, J, L., Lu, X., Qi, Z., Okawa, K., Nakao, S.
  • Journal Title: J Immunol Volume: 182 Pages: 703-710
  • Peer Reviewed
• [Journal Article] Anti-moesin antibodies derived from patients with aplastic anemia stimulate monocytic cells to secrete TNF-alpha through an ERK1/2-dependent pathway (2009)
  • Author(s): Espinoza, J, L., Takamatsu, H., Lu, X., Qi, Z., Nakao, S.
  • Journal Title: Int Immunol Volume: 21 Pages: 913-923
  • Peer Reviewed
• [Journal Article] Origin and fate of blood cells deficient in glycosylphosphatidylinositol-anchored protein among patients with bone marrow failure (2009)
  • Author(s): Sugimori, C., Mochizuki, K., Qi, Z., Sugimori, N., Ishiyama, K., Kondo, Y., Yamazaki, H., Takami, A., Okumura, H., Nakao, S.
  • Journal Title: Br J Haematol Volume: 147 Pages: 102-112
  • Peer Reviewed
• [Journal Article] Origin and fate of blood cells deficient in glycosylphosphatidylino sitol-anchored protein among patients with bone marrow failure. (2009)
  • Author(s): Sugimori C, Mochizuki K, Qi Z, Sugimori N, Ishiyama K, Kondo Y, Yamazaki H, Takami A, Okumura H, Nakao S
  • Journal Title: Br J Haematol 147 Pages: 102-112
  • Peer Reviewed
• [Journal Article] Anti-moesin antibodies derived from patients with aplastic anemia stimulate monocytic cells to secrete TNF-alpha through an ERK1/2-dependent pathway. (2009)
  • Author(s): Espinoza JL, Takamatsu H, Lu X, Qi Z, Nakao S
  • Journal Title: Int Immunol 21 Pages: 913-923
  • Peer Reviewed
• [Journal Article] Anti-moesin antibodies in the serum of patients with aplastic anemia stimulate peripheral blood mononuclear cells to secrete TN F-alpha and IFN-gamma. (2009)
  • Author(s): Takamatsu H, Espinoza JL, Lu X, Qi Z, Okawa K, Nakao S
  • Journal Title: J Immunol 182 Pages: 703-710
  • Peer Reviewed
• [Presentation] Bone marrow failure with 13q deletion : A distinct clinicopathological entity with immune pathophysiology (2011)
  • Author(s): Hosokawa, K., Katagir, T., Sugimori, N., Ishiyama, K., Sasaki, Y., Seiki, Y., Sato-Otsubo, A., Sanad a, M., MD, Ogawa, S., Nakao, S.
  • Organizer: The American Society of Hematology 53rd Annual Meeting
  • Place of Presentation: San Diego Convention Center(California, USA.)
  • Year and Date: 2011-12-12
• [Presentation] Bone marrow failure with 13q deletion : A distinct clinicopat hological entity with immune pathophysiology (2011)
  • Author(s): Kohei Hosokawa, Takamasa Katagir, Naomi Sugimori, Ken Ishiyama, Yumi Sasaki, Yu Seiki, Aiko Sato-Otsubo, Masashi Sanada, MD, Seishi Ogawa, Shinji Nakao
  • Organizer: The American Society of Hematology 53rd Annual Meeting
  • Place of Presentation: San Diego Convention Center, California, USA
  • Year and Date: 2011-12-12
• [Presentation] A Functional variation in the NKG2D gene regulates NKG2D receptor expression and is associated with better transplant outcomes after fully-HLA-macthed unrelated bone marrow transplantation (2010)
  • Author(s): J, Luis, Espinoza., Takami, A., Yoshioka, K., Nakata, K., Nakao, S.
  • Organizer: The American Society of Hematology 52th Annual Meeting
  • Place of Presentation: ORANGECOUNTY CONVENTION CENTER(USA)
  • Year and Date: 2010-12-06
• [Presentation] Immunologically-Selected Hematopoiesis Caused by HLA Allelic Loss In Patients with Aplastic Anemia (2010)
  • Author(s): Katagiri, T., Matsubara, A., Kashiwase, K., Kato, M., Morishima, Y., Hosokawa, K., Ohtake, S., Ogawa, S., Nakao, S.
  • Organizer: The American Society of Hematology 52th Annual Meeting
  • Place of Presentation: ORANGE COUNTY CONVENTION CENTER(USA)
  • Year and Date: 2010-12-06
• [Presentation] Immunologically-Selected Hematopoiesis Caused by HLA Allelic Loss In Patients with Aplastic Anemia. (2010)
  • Author(s): Katagiri T, Matsubara A, Kashiwase K, Kato M, Morishima Y, Hosokaw a K, Ohtake S, Ogawa S, Nakao S
  • Organizer: 第52回米国血液学会
  • Place of Presentation: アメリカ/ORANGE COUNTY CO INVENTION CENTER
  • Year and Date: 2010-12-06
• [Presentation] A Functional variation in the NKG2D gene regulates NKG2D receptor expression and is associated with better transplant outcomes after fully-HLA-macthed un related bone marrow transplantation. (2010)
  • Author(s): J.Luis Espinoza, Takami A, Yoshiok a K, Nakata K, Nakao S
  • Organizer: 第52回米国面血液学会
  • Place of Presentation: アメリカ/ORANGE COUNTY CONVENTION CENTERS
  • Year and Date: 2010-12-06
• [Presentation] GPI-AP deficient cells detected exclusively in T cells in patients with aplastic anemia : Evidence against an escape mechanism for the initial proliferation of PIGA mutant hematopoietic stem cells (2009)
  • Author(s): Katagiri, T., Qi, Z., Seiki, Y., Sugimori, N., Espinoza, J, L., Takami, A., Ohtake, S., Nakao, S.
  • Organizer: The American Society of Hematology 51th Annual Meeting
  • Place of Presentation: Ernest N. Morial Convention Center.(New Orleans, LA America.)
  • Year and Date: 2009-12-09
• [Presentation] GPI-AP deficient cells detected exclusively in T cells in patients with aplastic anemia : Evidence against an escape mechanism for the initia 1 proliferation of PIGA mutant hematopoietic stem cells (2009)
  • Author(s): Takamasa K, Qi Z, Seiki Y, Sugimori N, Espinoza JL, Takami A, Ohtake S, Nakao S
  • Organizer: The American Society of Hematology 51th Annual Meeting
  • Place of Presentation: Ernest N.Morial Convention Center New Orleans, LA America
  • Year and Date: 2009-12-09
• [Patent(Industrial Property Rights)] PNH型白血球の検出方法 (2010)
  • Inventor(s): 中尾眞二、杉盛千春、片桐孝和、清木ゆう、杉森尚美、山崎宏人、細川晃平
  • Industrial Property Rights Holder: 中尾眞二、杉盛千春、片桐孝和、清木ゆう、杉森尚美、山崎宏人、細川晃平
  • Filing Date: 2010-12-10