Therapeutic strategy and biological characterization of Epstein-Barr virus (EBV) infected cells in chronic active EBV infection

• Project/Area Number: 19591255
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kyushu University
• Principal Investigator: OHGA Shouichi Kyushu University, 大学病院, 准教授 (60233053)
• Co-Investigator(Kenkyū-buntansha): MIYAMOTO Toshihiro 九州大学, 大学病院, 講師 (70343324) ; TANAKA Tamami 九州大学, 医学研究院, 学術研究員 (60423547)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2007: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 小児感染症学 / EBウイルス / リンパ増殖性疾患 / 感染細胞 / 免疫不全症

Research Abstract

慢性活動性EB ウイルス感染症(Chronic active Epstein-Barr virus infection : CAEBV)の治療法確立をめざして、EBV持続感染細胞(T/NK細胞)の特性と患児の治療成績について解析した。造血幹細胞移植が唯一の根治療法である本症の3大合併症は、神経、心血管および腸管病変である。患者のEBV 感染細胞特性(T型、NK型、clonality、活性化マーカーなどについて高発現遺伝子を中心に網羅的に解析したが、病勢の進行と予後を予測することは困難であった。神経合併症については、神経症状のない時期から脳脊髄液にEBV 量が上昇している例があり、末梢血より脳脊髄液でEBV量の多い例も確認できた。患児の髄液に細胞増多のみられたものはなく、cell free EBV DNA が 中枢神経におけるEBV再活性化と感染細胞の浸潤を予測する可能性が示唆された。心合併症については、心血管病変の合併が60%と高く、このうち冠動脈病変が最も多いこと 、そしてこれが予後不良因子であることが示された。さらに造血幹細胞移植後、感染細胞が排除された症例では冠動脈病変が消失することも確認した。EBV 関連性血球貪食症候群とCAEBV の移植成績を文献報告し、骨髄非破壊的移植と非血縁臍帯血移植をうまく選択することが治療成績向上に結びつくことを報告した。今回の結果から、CAEBV 患者は、発熱と血球減少に注意しながら観察し、中枢神経および心血管合併症が出現する前に速やかに造血幹細胞移植を行うことが重要であることが示唆された。移植源に応じた前処置の方法を今後の前向き調査により明らかにすることが必要である。

Research Products

• [Journal Article] Characteristics of hemophagocytic lymphohistiocytosis in neonates : a nationwide survey in Japan (2009)
  • Author(s): Suzuki N, Morimoto A, Ohga S, Kudo K, Ishida Y, Ishii E
  • Journal Title: J Pediatr (in press)
  • Peer Reviewed
• [Journal Article] Cardiovascular complications associated with chronic active Epstein-Barr virus infection (2009)
  • Author(s): Muneuchi J, Ohga S, Ishimura M, Ikeda K, Yamaguchi K, Nomura A, Takada H, Abe Y, Hara T
  • Journal Title: Pediatr Cardiol (in press)
  • Peer Reviewed
• [Journal Article] Neonatal onset hemophagocytic lymphohistiocytosis in a premature infant (2009)
  • Author(s): Katsuragi S, Ohga S, Horiuchi H, Hara T, Terao K, Ikeda T
  • Journal Title: Pediatr Blood Cancer (in press)
  • Peer Reviewed
• [Journal Article] Characteristics of hemophagocytic lymphohistiocytosis in neonates : a nationwide survey in Japan (2009)
  • Author(s): Suzuki N, Morimoto A, Ohga S, Kudo K, Ishida Y, Ishii E
  • Journal Title: J Pediatr (未定)(in press)
  • Peer Reviewed
• [Journal Article] Cardiovascular complications associated with chronic active Epstein-Barr virus infection (2009)
  • Author(s): Muneuchi J, Ohga S, Ishimura M, Ikeda K, Yamaguchi K, Nomura A, Takada H, Abe Y, Hara T
  • Journal Title: Pediatr Cardiol (未定)(in press)
  • Peer Reviewed
• [Journal Article] Fulminant sepsis/meningitis in a protein C-deficient heterozygote treated with activated protein C therapy (2009)
  • Author(s): Ishimura M, Saito M, Ohga S, Hoshina T, Baba H, Urata M, Kira R, Takada H, Kusuhara K, Kane D, Hara T
  • Journal Title: Eur J Pediatr (未定)(in press)
  • Peer Reviewed
• [Journal Article] Neonatal onset hemophagocytic lymphohistiocytosis in a premature infant (2009)
  • Author(s): Katsuragi S, Ohga S, Horiuchi H, Hara T, Terao K, Ikeda T
  • Journal Title: Pediatr Blood Cancer (未定)(in press)
  • Peer Reviewed
• [Journal Article] Disseminated Bacillus Calmette-Guerin lymphadenitis in a patient with gp91phox-chronic granulomatous disease 25 years after vaccination (2009)
  • Author(s): Kusuhara K, Ohga S, Hoshina T, Saito M, Sasaki Y, Ishimura M, Takada H, Fujita M, Hara T
  • Journal Title: Eur J Pediatr (未定)(in press)
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus load in cerebrospinal fluid of patients with chronic active Epstein-Barr virus infection (2008)
  • Author(s): Ohga S, Sanefuji M, Ishimura M, Nomura A, Torisu H, Kira R, Takada H, Mizuno Y, Kazuyama Y, Hara T
  • Journal Title: Pediatr Infect Dis J 27 Pages: 1027-1030
  • Peer Reviewed
• [Journal Article] Prospective multicenter trial comparing repeated immunosuppressive therapy with stem cell transplantation from an alternative donor as second-line treatment for children with severe and very severe aplastic anemia (2008)
  • Author(s): Kosaka Y, Yagasaki H, Sano K, Kobayashi R, Ayukawa H, Kaneko T, Yabe H, Tsuchida M, Mugishima H, Ohara A, Morimoto A, Otsuka Y, Ohga S, Bessho F, Nakahata T, Tsukimoto I, Kojima S
  • Journal Title: Blood 111 Pages: 1054-1059
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide-induced monocytic cell death for the diagnosis of mild neonatal-onset multisystem inflammatory disease (2008)
  • Author(s): Takada H, Ishimura M, Inada H, Ohga S, Kusuhara K, Moroi Y, Furue M, Hara T
  • Journal Title: J Pediatr 152 Pages: 885-887
  • Peer Reviewed
• [Journal Article] Insulin-like growth factor-II : a novel autocrine growth factor modulating the apoptosis and maturation of umbilical cord blood erythroid progenitors (2008)
  • Author(s): Nagatomo T, Muta K, Ohga S, Ochiai M, Ohshima K, Hara T
  • Journal Title: Exp Hematol 36 Pages: 401-411
  • Peer Reviewed
• [Journal Article] Thromboembolic complications in splenectomized patients with dominantly inherited beta-thalassemia (2008)
  • Author(s): Ohga S, Ideguchi H, Kato J, Ishimura M, Takada H, Harada N, Kawanaka H, Hattori Y, Kang D, Hamasaki N, Hara T
  • Journal Title: Acta Haematol-Basel 120 Pages: 31-35
  • Peer Reviewed
• [Journal Article] Allogeneic hematopoietic stem cell transplantation for Epstein-Barr virusassociated T/ NK-cell lymphoproliferative disease in Japan (2008)
  • Author(s): Sato E, Ohga S, Kuroda H, Yoshiba F, Nishimura M, Nagasawa M, Inoue M, Kawa K
  • Journal Title: Am J Hematol 83 Pages: 721-727
• [Journal Article] Epstein-Barr virus associated encephalomyelitis : Intrathecal reactivation of the virus in an immunocompetent child (2008)
  • Author(s): Sanefuji M, Ohga S, Kira R, Nomura A, Torisu H, Takada H, Kusuhara K, Hara T
  • Journal Title: J Child Neurol 50 Pages: 723-726
  • Peer Reviewed
• [Journal Article] Early-onset sarcoidosis mimicking refractory cutaneous histiocytosis (2008)
  • Author(s): Ohga S, Ichino K, Urabe K, Ishimura M, Takada H, Nishikomori R, Furue M, Hara T
  • Journal Title: Pediatr Blood Cancer 50 Pages: 723-726
  • Peer Reviewed
• [Journal Article] Sjogren's syndrome-associated meningo-encephalomyelitis : cerebrospinal fluid cytokines levels and therapeutic utility of tacrolimus (2008)
  • Author(s): Hoshina T, Yamaguchi Y, Ohga S, Kira R, Ishimura M, Takada H, Tanaka T, Hara T
  • Journal Title: J Neurol Sci 267 Pages: 182-186
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus load in cerebrospinal fluid of patients with chronic active Epstein-Barr virus infection (2008)
  • Author(s): Ohga S, Sanefuji M, Ishimura M, Nomura A, Torisu H, Kira R, Takada H, Mizuno Y, Kazuyama Y, Hara T
  • Journal Title: Pediatr Infect Dis J 27(11) Pages: 1027-1030
  • Peer Reviewed
• [Journal Article] An effective scoring system of chest CT for assessing the clinical status of neonatal bfonchopulmonary dysplasia (2008)
  • Author(s): Ochiai M, Hikino S, Yabuuchi H, Nakayama H, Sato K, Ohga S, Hara T
  • Journal Title: J Pediatr 152(1) Pages: 90-95
  • Peer Reviewed
• [Journal Article] Prospective multicenter trial comparing repeated immunosuppressive therapy with stem cell transplantation from an alternative donor as second-line treatment for children with severe and very severe aplastic anemia (2008)
  • Author(s): Kosaka Y, Yagasaki H, Sano K, Kobayashi R, Ayukawa H, Kaneko T, Yabe H, Tsuchida M, Mugishima H, Ohara A, Morimoto A, Otsuka Y, Ohga S, Bessho F, Nakahata T, Tsukimoto I, Kojima S
  • Journal Title: Blood 111(3) Pages: 1054-1059
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide-induced monocytic cell death for the diagnosis of mild neonatal-onset multisystem inflammatory disease (2008)
  • Author(s): Takada H, Ishimura M, Inada H, Ohga S, Kusuhara K, Moroi Y, Fume M, Hara T
  • Journal Title: J Pediatr 152(6) Pages: 885-887
  • Peer Reviewed
• [Journal Article] Insulin-like growth factor-II : a novel autocrine growth factor modulating the apoptosis and maturation of umbilical cord blood erythroid progenitors (2008)
  • Author(s): Nagatomo T, Muta K, Ohga S, Ochiai M, Ohshima K, Hara T
  • Journal Title: Exp Hematol 36(4) Pages: 401-411
  • Peer Reviewed
• [Journal Article] Head circumference and long-term outcome in small-for gestational age infants (2008)
  • Author(s): Ochiai M, Nakayama H, Sato K, Iida K, Hikino S, Ohga S, Tsukimori K, Wake N, Masumoto K, Taguchi T, Hara T
  • Journal Title: J Perinat Med 36(4) Pages: 341-347
  • Peer Reviewed
• [Journal Article] Thromboembolic complications in splenectomized patients with dominantly inherited beta-thalassemia (2008)
  • Author(s): Ohga S, Ideguchi H, Kato J, Ishimura M, Takada H, Harada N, Kawanaka H, Hattori Y, Kang D, Hamasaki N, Hara T
  • Journal Title: Acta Haematol-Basel 120(1) Pages: 31-35
  • Peer Reviewed
• [Journal Article] Allogeneic hematopoietic stem cell transplantation for Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disease in Japan (2008)
  • Author(s): Sato E, Ohga S, Kuroda H, Yoshiba F, Nishimura M, Nagasawa M, Inoue M, KawaK
  • Journal Title: Am J Hematol 83(9) Pages: 721-727
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus associated encephalomyelitis : Intrathecal reactivation of the virus in an immunocompetent child (2008)
  • Author(s): Sanefuji M, Ohga S, Kira R, Nomura A, Torisu H, Takada H, Kusuhara K, Hara T
  • Journal Title: J Child Neurol 50(3) Pages: 723-726
  • Peer Reviewed
• [Journal Article] Early-onset sarcoidosis mimicking refractory cutaneous histiocytosis (2008)
  • Author(s): Ohga S, Ichino K, Urabe K, Ishimura M, Takada H, Nishikomori R, Fume M, Hara T
  • Journal Title: Pediatr Blood Cancer 50(3) Pages: 723-726
  • Peer Reviewed
• [Journal Article] Sjogren's syndrome-associated meningoencephalomyelitis : cerebrospinal fluid cytokineslevels and therapeutic utility of tacrolimus (2008)
  • Author(s): Hoshina T, Yamaguchi Y, Ohga S, Kira R, Ishimura M, Takada H, Tanaka T, Hara T
  • Journal Title: J Neurol Sci 267(1-2) Pages: 182-186
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus load in cerebrospinal fluid of patients with chronic active Epstein-Bart virus infection (2008)
  • Author(s): Ohga S, Sanefuji M, Ishimura M, et. al.
  • Journal Title: Pediatr Infect Dis J (in press)
  • Peer Reviewed
• [Journal Article] Prospective multicenter trial comparing repeated immunosuppressive terapy with stem cell transplantation from an alternative donor as second-line treatment for children with severe and very severe aplastic anemia (2008)
  • Author(s): Kosaka Y, Sano K, Kobayashi R, …, Ohga S, et. al.
  • Journal Title: Blood 111 Pages: 1054-1059
  • Peer Reviewed
• [Journal Article] Early-onset sarcoidosis mimicking refractory cutaneous histiocytosis (2008)
  • Author(s): Ohga S, Ichino K, Urabe K, et. al.
  • Journal Title: Pediatr Blood Cancer 50 Pages: 723-726
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus associated encephalomyelitis:Intrathecal reactivation of the virus in an immunocompetent child (2008)
  • Author(s): Sanefuji M, Ohga S, Kira R, et. al.
  • Journal Title: J Child Neurol (in press)
  • Peer Reviewed
• [Journal Article] Perforin gene mutations in hemophagocytic lymphohistiocytosis with late-life onset (2007)
  • Author(s): Nagafuji K, Nonami A, Kumano T, Kikushige Y, Yoshimoto G, Takenaka K, Shimoda K, Ohga S, Yasukawa M, Horiuchi H, Ishii E, Harada
  • Journal Title: Haematologica 92 Pages: 978-981
  • Peer Reviewed
• [Journal Article] Nation-wide survey analysis of hemophagocytic lympho- histiocytosis in Japan (2007)
  • Author(s): Ishii E, Ohga S, Imashuku S, Yasukawa M, Tsuda H, Miura I, Yamamoto K, Horiuchi H, Takada K, Ohshima K, Nakamura S, Kinukawa N, Oshimi K, Kawa K
  • Journal Title: Int J Hematol 86 Pages: 58-65
  • Peer Reviewed
• [Journal Article] Successful prolonged rituximab treatment for post-transplant lymphoproliferative disorder following living donor liver transplantation in a child (2007)
  • Author(s): Hayashida M, Ogita K, Matsuura T, Takahashi Y, Nishimoto Y, Ohga S, Hara T, Soejima Y, Taketomi A, Maehara Y, Kohashi K, Tsuneyoshi M, Taguchi T
  • Journal Title: Pediatr Transplant 11 Pages: 671-675
  • Peer Reviewed
• [Journal Article] Perforin gene mutations in hemophagocytic lymphohistiocytosis with late-life onset (2007)
  • Author(s): Nagafuji K, Nonami A, Kumano T, …, Ohga S, et. al.
  • Journal Title: Haematologica 92 Pages: 978-981
  • Peer Reviewed
• [Journal Article] Hematopoietic stem cell transplantation for Diamond-Blackfan anemia:a report from the Aplastic Anemia Committee of the Japanese Society of Pediatric Hematology (2007)
  • Author(s): Mugishima H, Ohea S, Ohara A, Kojima S, et. al.
  • Journal Title: Pediatric Transplant 11 Pages: 601-607
  • Peer Reviewed
• [Journal Article] Nation-wide survey analysis of hemophagocytic lymphohistiocytosis(HLH)in Japan (2007)
  • Author(s): Ishii E, Ohga S, Imashuku S, et. al.
  • Journal Title: Int J Hematol 86 Pages: 58-65
  • Peer Reviewed
• [Journal Article] Successful prolonged rituximab treatment for post-transplant lyrnphoproliferative disorder following living donor liver transplantation in a child (2007)
  • Author(s): Hayashida M, Ogita K, Matsuura T, …, Ohga S, et. al.
  • Journal Title: Pediatr Transplant 11 Pages: 671-675
  • Peer Reviewed
• [Presentation] Clinical outcomes of stem cell transplantation for childhood hemophagocytic lympho- histiocytosis in Japan (2009)
  • Author(s): Ohga S, Kudo K, Morimoto A, Honjo S, Osugi Y, Inoue M, Tabuchi K, Suzuki N, Ishida Y, Kawa K, Imashuku S, Hara T, Kato S, Ishii E
  • Organizer: The 4th JSPS-NRCT Hematology Workshop by Asian CORE Program
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2009-02-20
• [Presentation] Clinical outcomes of stem cell transplantation for childhood hemophagocytic lymphohistiocytosis (HLH/HPS) in Japan (2009)
  • Author(s): Ohga S, Kudo K, Morimoto A, Honjo S, Osugi Y, Inoue M, Tabuchi K, Suzuki N, Ishida Y, Kawa K, Imashuku S, Hara T, Kato S, Ishii E
  • Organizer: The 4^<th> JSPS-NRCT Hematology Workshop by Asian CORE Program
  • Place of Presentation: Bangkok Thailand
  • Year and Date: 2009-02-20
• [Presentation] Hematopoietic stem cell transplantation for familial hemophagocytic lymphohistiocytosis or Epstein-Barr virus-associated hemophagocytic lympho- histiocytosis in Japan (2008)
  • Author(s): Ohga S, Kudo K, Osugi Y, Sawada A, Tabuchi K, Suzuki N, Morimoto A, Ishida Y, Kato S, Ishii E
  • Organizer: The 24th Annual Meeting of Histiocyte Society
  • Place of Presentation: Berlin, Germany
• [Presentation] Nationwide survey of single system single site Langerhans cell histiocytosis in Japan (2008)
  • Author(s): Morimoto A, Ishii E, Ohga S, Kudou K, Ishida Y, Suzuki N
  • Organizer: The 24th Annual Meeting of Histiocyte Society
  • Place of Presentation: Berlin, Germany
• [Presentation] Hematopoietic stem cell transplantation for familial hemophagocytic lymphohistiocytosis or Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in Japan (2008)
  • Author(s): Ohga S, Kudo K, Osugi Y, Sawada A, Tabuchi K, Suzuki N, Morimoto A, Ishida Y, Kato S, Ishii E
  • Organizer: The 24th Annual Meeting of Histiocyte Society
  • Place of Presentation: Berlin, Germany
• [Presentation] Nationwide survey of single system single site (SS-s)Langerhans cell histiocytosis in Japan. (2008)
  • Author(s): Morimoto A, Ishii E, Ohea S, Kudou K, Ishida Y, Suzuki N
  • Organizer: The 24th Annual Meeting of Histiocyte Society
  • Place of Presentation: Berlin, Germany
• [Presentation] Pathophysiology and treatment of Diamond-Blackfan anemia (2008)
  • Author(s): Ohga S
  • Organizer: The 3^<rd> JSPS-NRCT Hematology Workshop by Asian CORE Program
  • Place of Presentation: Fukuoka, Japan
• [Presentation] Chronic active Epstein-Barr virus infection (CAEBV) : the nationwide survey in Japan (2007)
  • Author(s): Ohga S, Maeda A, Kimura H, Kawa K, and Wakiguchi H
  • Organizer: The 2nd Workshop of Asian Hematology in Bangkok, JSPS Asian CORE program
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2007-10-31
• [Presentation] Chronic active Epstein-Barr virus infection(CAEBV):the nationwide survey in Japan (2007)
  • Author(s): Ohga S, Maeda A, Kimura H, et. al.
  • Organizer: The 2nd Workshop of Asian Hematology in Bangkok, JSPS Asian CORE program
  • Place of Presentation: Bangkok,Thailand
  • Year and Date: 2007-10-31
• [Presentation] Central nervous system reactivation of Epstein-Barr virus (EBV) in chronic active EBV infection and EBV-associated encephalitis (2007)
  • Author(s): Ohga S, Sanefuji M, Ishimura M, Nomura A, Torisu H, Kira R, Takada H, Mizuno Y, Kazuyama Y, Hara T
  • Organizer: The 3rd Congress of Asian Society for Pediatric Research
  • Place of Presentation: Tokyo, Japan
• [Presentation] Clinical outcomes of cardiac complications associated with chronic active Epstein-Barr virus infection (2007)
  • Author(s): Muneuchi J, Ohga S, Ishimura M, Yamawaki K, Kanaya Y, Takada H, Hara T
  • Organizer: The 3rd Congress of Asian Society for Pediatric Research
  • Place of Presentation: Tokyo, Japan
• [Presentation] 慢性活動性EB ウイルス感染症の病態と予後 (2007)
  • Author(s): 大賀正一、前田明彦、木村宏、森尾友宏、今井章介、岡野素彦、金兼弘和、河敬世、土屋滋、森雅亮、森本哲、谷内江昭宏、岡村隆行、脇口宏
  • Organizer: 第14回ヘルペス感染症フォーラム
  • Place of Presentation: 札幌
• [Presentation] Central nervous system reactivation of Epstein-Barr virus(EBV)in chronic active EBV infection and EBV-associated encephalitis (2007)
  • Author(s): Ohga S, Sanefuji M, Ishimura M, et. al.
  • Organizer: The 3rd Congress of Asian Society for Pediatric Research(Oral)
  • Place of Presentation: Tokyo,Japan
• [Presentation] Clinical outcomes of cardiac complications associated with chronic active Epstein-Barr vhus infection (2007)
  • Author(s): Muneuchi J, Ohga S, Ishimura M, et. al.
  • Organizer: The 3rd Congress of Asian Society for Pediatric Research(Oral)
  • Place of Presentation: Tokyo,Japan