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Koji Kato,
Toshihiro Miyamoto,
Akihiko Numata,
Takashi Nakaike,
Hideyo Oka,
Ayano Yurino, Takuro Kuriyama,
Yasuo Mori,
Satoshi Yamasaki,
Tsuyoshi Muta,
Katsuto Takenaka,
Hiromi Iwasaki,
Takanori Teshima,
Koichi Akashi
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ABSTRACT: We present the case of a 62-year-old Japanese woman with relapsed adult T-cell leukemia/lymphoma (ATLL) who was treated with humanized anti-CCR4 monoclonal antibody (KW-0761). Although this antibody was highly effective against refractory ATLL, 6 months after the final KW-0761 infusion, the patient complained of hypoxia due to diffuse panbronchiolitis. Physicians should remain vigilant to the possibility of such previously unreported late-onset adverse effects associated with KW-0761 therapy.
International journal of hematology 02/2013; · 1.17 Impact Factor
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Takuro Kuriyama,
Katsuto Takenaka,
Kentaro Kohno,
Takuji Yamauchi,
Shinya Daitoku,
Goichi Yoshimoto,
Yoshikane Kikushige,
Junji Kishimoto,
Yasunobu Abe,
Naoki Harada,
Toshihiro Miyamoto,
Hiromi Iwasaki,
Takanori Teshima,
Koichi Akashi
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ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated engulfment of hematopoietic cells by bone marrow macrophages activated presumably by systemic inflammatory hypercytokinemia. We here show that the pathogenesis of HLH involves impairment of the anti-phagocytic system operated by interaction of surface CD47 and signal regulatory protein alpha (SIRPA). In HLH patients, the changes of expression levels, or HLH-specific polymorphism of SIRPA were not found. In contrast, the expression of surface CD47 was down-regulated specifically in HSCs in association with exacerbation of HLH, but not in healthy individuals. The number of bone marrow HSCs in HLH patients was reduced to ~20% of normal controls, and macrophages from normal donors aggressively engulfed HSCs purified from HLH patients but not those from normal controls in vitro. Furthermore, in response to inflammatory cytokines, normal HSCs, but not progenitors or mature blood cells, down-regulated CD47 sufficient to be engulfed by macrophages. The expression of pro-phagocytic calreticulin was kept suppressed at the HSC stage in both HLH and normal controls, even in the presence of inflammatory cytokines. These data suggest that the CD47-SIRPA anti-phagocytic system plays a key role in maintenance of HSCs, and that its disruption by HSC-specific CD47 down-regulation might be critical for HLH development.
Blood 09/2012; · 9.90 Impact Factor
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Yasuo Mori,
Toshihiro Miyamoto,
Koji Kato,
Kenjiro Kamezaki, Takuro Kuriyama,
Seido Oku,
Katsuto Takenaka,
Hiromi Iwasaki,
Naoki Harada,
Motoaki Shiratsuchi,
Yasunobu Abe,
Koji Nagafuji,
Takanori Teshima,
Koichi Akashi
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ABSTRACT: Virus-associated hemorrhagic cystitis (HC) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Although numerous studies have attempted to identify factors that predispose patients to viral HC, its causes remain controversial. We analyzed retrospectively the results of 266 allogeneic HSCTs to identify factors associated with HC. Of this group, 42 patients (15.8%) were diagnosed with viral HC, because of either adenovirus (ADV; n = 26; 9.8%) or BK virus (BKV; n = 16; 6.0%). ADV-HC was frequently associated with T cell purging, and was less common in patients with acute graft-versus-host-disease (GVHD). Conversely, BKV-HC was more frequently observed in patients with excessive immune reactions such as GVHD, preengraftment immune reaction, and hemophagocytic syndrome. These observations indicate that ADV- and BKV-HC may differ significantly in their risk factors and pathogenesis. Profound immune deficiency is more likely to be associated with ADV-HC, whereas immune hyperactivity might play a key role in BKV-HC.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2011; 18(3):458-65. · 3.15 Impact Factor
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Seido Oku,
Katsuto Takenaka, Takuro Kuriyama,
Kotaro Shide,
Takashi Kumano,
Yoshikane Kikushige,
Shingo Urata,
Takuji Yamauchi,
Chika Iwamoto,
Haruko K Shimoda,
Toshihiro Miyamoto,
Koji Nagafuji,
Junji Kishimoto,
Kazuya Shimoda,
Koichi Akashi
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ABSTRACT: The acquired JAK2 V617F mutation is observed in the majority of patients with BCR-ABL1 negative chronic myeloproliferative neoplasms (MPN). BCR-ABL1 negative MPN displays myeloproliferation with an elevated leucocyte alkaline phosphatase (LAP) activity, a neutrophil activation marker. We tried to separate the downstream signalling of JAK2 V617F to stimulate myeloproliferation and LAP activity. NB4, a myeloid lineage cell line, was transduced with Jak2 V617F mutation or wild-type Jak2. We found that Jak2 V617F mutation, but not wild-type Jak2 enhanced LAP expression in NB4-derived neutrophils and proliferation of NB4 cells. JAK2 V617F induces constitutive phosphorylation of STAT3 and STAT5, and uses signalling targets such as Ras/MEK/ERK and PI3K/Akt pathways. By using MEK1/2 inhibitor U0126, PI3K inhibitor LY294002, and STAT3 or STAT5 siRNAs, JAK2 V617F was found to specifically use the STAT3 pathway to enhance LAP expression, while STAT5, Ras/MEK/ERK and PI3K/Akt, but not STAT3 pathways, were able to stimulate cell proliferation. These data strongly suggest that JAK2 V617F uses distinct signalling pathways to induce typical pathological features of MPN, such as high LAP activity and enhanced cell proliferation.
British Journal of Haematology 08/2010; 150(3):334-44. · 4.94 Impact Factor
