Shigeru Chiba

Tokyo Medical University, Edo, Tōkyō, Japan

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Publications (390)

  • [Show abstract] [Hide abstract] ABSTRACT: CD4(+)Foxp3(+) regulatory T cells (Treg) are a subpopulation of T cells, which regulate the immune system and enhance immune tolerance after transplantation. Donor-derived Treg prevent the development of lethal acute graft versus host disease (GVHD) in murine models of allogeneic hematopoietic stem cell transplantation (HCT). We recently demonstrated that a single treatment of the agonistic antibody to DR3 (Death receptor 3, αDR3) to donor mice resulted in the expansion of donor derived Treg and prevented acute GVHD, although the precise role of DR3 signaling in GVHD has not been elucidated. In this study, we comprehensively analyzed the immunophenotype of Treg after DR3 signal activation, demonstrating that DR3 activated Treg (DR3-Treg) had an activated/mature phenotype. Furthermore, the CD25(+)Foxp3(+) subpopulation in DR3-Treg showed stronger suppressive effects in vivo. Prophylactic treatment of αDR3 to recipient mice expanded recipient derived Treg and reduced the severity of GVHD, whereas DR3 activation in mice with ongoing GVHD further promoted donor T cell activation/proliferation. These data suggest that the function of DR3 signaling was highly dependent on the activation status of the T cells. In conclusion, our data demonstrated that DR3 signaling affects the function of Treg and T cell activation after alloantigen exposure in a time-dependent manner. These observations provide important information for future clinical testing using human DR3 signal modulation and highlight the critical impact of the state of T cell activation on clinical outcomes following activation of DR3.
    Article · Oct 2016 · Blood
  • Article · Oct 2016 · Immunobiology
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    Full-text available · Article · Sep 2016 · Oncology Reports
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    Dataset: HBV
    S Goyama · Y Kanda · Y Nannya · [...] · H Hirai
    File available · Dataset · Jul 2016
  • Haruhiko Ninomiya · Naoshi Obara · Shigeru Chiba · [...] · Yuzuru Kanakura
    [Show abstract] [Hide abstract] ABSTRACT: Data characterizing the safety and effectiveness of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) are limited. We describe the safety and effectiveness of eculizumab in PNH patients enrolled in a post-marketing surveillance study. Types and frequencies of observed adverse events were similar to those reported in previous clinical trials and no meningococcal infection was reported. Effectiveness outcomes included the reduction of intravascular hemolysis, the change in hemoglobin (Hb) level, the withdrawal of transfusion and corticosteroids, the change of renal function, and overall survival. The effect of eculizumab on intravascular hemolysis was demonstrated by a reduction in lactate dehydrogenase levels at all measurements after baseline. Significant increases in Hb levels from baseline were also observed after 1 month's treatment with eculizumab (p < 0.01). Of those who were transfusion-dependent at baseline, the median number of transfusions decreased significantly from 18 to 0 unit/year after 1 year of treatment with eculizumab (p < 0.001). An increase in Hb and a high rate of transfusion independence were observed, especially in patients with platelet count ≥150 × 10(9)/L. Approximately 97 % of patients showed maintenance or improvement of renal function. Overall survival rate was about 90 % (median follow-up 1.9 years). These results suggest an acceptable safety profile and favorable prognosis after eculizumab intervention.
    Article · Jul 2016 · International Journal of Hematology
  • Article · May 2016 · British Journal of Haematology
  • [Show abstract] [Hide abstract] ABSTRACT: Angioimmunoblastic T-cell lymphoma (AITL) is an infrequent subtype of peripheral T-cell lymphoma derived from follicular helper T cells. Recently, a somatic G17V RHOA gene mutation has been reported. In this article, we examined the RHOA G17V mutation in 18 cases of AITL by 3 different techniques of Sanger sequencing, fully automated SNP genotyping, and deep sequencing, using routine diagnostic formalin-fixed paraffin-embedded tissue. The RHOA G17V mutation was detected in 10 cases (56%). Among the 10 mutated cases, 8 cases were detected by all 3 methods. The status of RHOA mutation was subsequently compared with the clinicopathologic characteristics of AITL. RHOA-mutated AITL (10 cases) was clinically characterized by high serum IL-2R and a poor ECOG performance status. By immunohistochemistry, expression of CD10, PD-1, CXCL13, and CCR4 and a wide distribution of CD21(+) follicular dendritic cells were observed in RHOA-mutated cases. Among these, CCR4 expression and the CD21(+) network in RHOA-mutated AITL cases were more extensive than in the RHOA mutation-negative AITL cases (P<0.05). Thus, RHOA-mutated AITL cases are more characteristic of follicular helper T cells, and the presence of such a mutation is an important marker for AITL.
    Article · May 2016 · The American journal of surgical pathology
  • Mamiko Sakata-Yanagimoto · Yasuhisa Yokoyama · Hideharu Muto · [...] · Shigeru Chiba
    Dataset · Feb 2016
  • Mamiko Sakata-Yanagimoto · Yasuhisa Yokoyama · Hideharu Muto · [...] · Shigeru Chiba
    Article · Feb 2016 · Annals of Hematology
  • Mamiko Sakata-Yanagimoto · Yasuhisa Yokoyama · Hideharu Muto · [...] · Shigeru Chiba
    Dataset · Feb 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Adult T-cell leukemia/lymphoma (ATLL) is a distinct form of peripheral T-cell lymphoma (PTCL) with poor prognosis which is caused by human T-lymphotropic virus type 1 (HTLV-1). In contrast to the unequivocal importance of HTLV-1 infection in the pathogenesis of ATLL, the role of acquired mutations in HTLV-1 infected T-cells has not been fully elucidated with a handful of genes known to be recurrently mutated. In this study, we identified unique RHOA mutations in ATLL through whole genome sequencing of an index case, followed by deep sequencing of 203 ATLL samples. RHOA mutations showed distinct distribution and function from those found in other cancers. Involving 15% (30/203) of ATLL cases, RHOA mutations were widely distributed across the entire coding sequence but almost invariably located at the GTP-binding pocket, with Cys16Arg being most frequently observed. Unexpectedly, depending on mutation types and positions, these RHOA mutants showed different or even opposite functional consequences in terms of GTP/GDP-binding kinetics, regulation of actin fibers, and transcriptional activation. The Gly17Val mutant did not bind GTP/GDP and act as a dominant negative molecule, whereas other mutants (Cys16Arg and Ala161Pro) showed fast GTP/GDP cycling with enhanced transcriptional activation. These findings suggest that both loss- and gain-of-RHOA functions could be involved in ATLL leukemogenesis. In summary, our study not only provides a novel insight into the molecular pathogenesis of ATLL but also highlights a unique role of variegation of heterologous RHOA mutations in human cancers.
    Article · Nov 2015 · Blood
  • [Show abstract] [Hide abstract] ABSTRACT: We have previously shown the clinical usefulness of Wilms' tumor 1 gene (WT1) mRNA expression in peripheral blood (PB) as a minimal residual disease (MRD) monitoring marker in 191 acute myeloid leukemia (AML) patients using the WT1 mRNA assay kit "Otsuka" (Otsuka Pharmaceutical Co., Ltd.; "former kit"). In contrast, the usefulness of WT1 mRNA expression in bone marrow (BM) has been investigated in only a limited number of subjects using former kit. Following that previous study, a next-generation kit, WT1 mRNA assay kit II "Otsuka" (Otsuka Pharmaceutical Co., Ltd.; "new kit") has been newly developed. In the present study, we aimed to evaluate the performance of the new kit and to investigate the clinical usefulness of WT1 mRNA expression in BM. The PB and BM were collected on the same day from 164 blood disease patients, including 118 AML patients. WT1 mRNA expression was determined using the new and former kits and the values obtained were compared. The performance of new kit was shown to be equivalent to that of former kit. As reported in PB, WT1 mRNA expression in BM was found to be a useful marker for monitoring disease status as well as for a diagnosis of early stage relapse in AML patients.
    Article · Nov 2015 · International journal of hematology
  • Shigeru Chiba
    Article · Oct 2015 · International journal of hematology
  • [Show abstract] [Hide abstract] ABSTRACT: Acute graft-versus-host disease (aGVHD) represents one of the major complications in allogeneic stem cell transplantation and is primarily caused by genetic disparity between the donor and recipient. In human leukocyte antigen (HLA)-matched transplants, the disparity is thought to be determined by loci encoding minor histocompatibility antigens (minor H antigens), which are presented by specific HLA molecules. We performed a genome-wide association study (GWAS) to identify minor H antigen loci associated with aGVHD. A total of 500,568 single nucleotide polymorphisms (SNPs) were genotyped for donors and recipients from 1,589 unrelated bone marrow transplants matched for HLA-A, B, C, DRB1, and DQB1, followed by the imputation of unobserved SNPs. We interrogated SNPs whose disparity between the donor and recipient was significantly associated with aGVHD development. Without assuming HLA unrestriction, we successfully captured a known association of HLA-DPB1 disparity (P = 4.50 × 10(-9)) with grade II-IV aGVHD development, providing a proof of the concept of the GWAS design aimed at discovering genetic disparity associated with aGVHD. In HLA-restricted analyses, where association tests were confined to major subgroups sharing common HLA alleles to identify putative minor H antigen loci, we identified three novel loci significantly associated with grade III-IV aGVHD. Among these, rs17473423 (P = 1.20 × 10(-11)) at 12p12.1 within the KRAS locus showed the most significant association in the subgroup sharing HLA DQB1*06:01. Our result suggested that GWAS can be successfully applied to identify allele mismatch associated with aGVHD development, contributing to the understanding of the genetic basis of aGVHD.
    Article · Oct 2015 · Blood
  • Mamiko Sakata-Yanagimoto · Shigeru Chiba
    [Show abstract] [Hide abstract] ABSTRACT: Understanding the molecular pathogenesis of peripheral T cell lymphomas (PTCLs) has lagged behind that of B cell lymphomas due to disease rarity. However, novel approaches are gradually clarifying these mechanisms, and gene profiling has identified specific signaling pathways governing PTCL cell survival and growth. For example, genetic alterations have been discovered, including signal transducer and activator of transcription (STAT)3 and STAT5b mutations in several PTCLs, disease-specific ras homolog family member A (RHOA) mutations in angioimmunoblastic T cell lymphoma (AITL), and recurrent translocations at the dual specificity phosphatase 22 (DUSP22) locus in anaplastic lymphoma receptor tyrosine kinase (ALK)-negative anaplastic large cell lymphomas (ALCLs). Intriguingly, some PTCL-relevant mutations are seen in apparently normal blood cells as well as tumor cells, while others are confined to tumor cells. These data have dramatically changed our understanding of PTCL origins: once considered to originate from mature T lymphocytes, some PTCLs are now believed to emerge from immature hematopoietic progenitor cells.
    Article · Oct 2015 · Current Hematologic Malignancy Reports
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    File available · Dataset · Sep 2015
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    File available · Dataset · Sep 2015
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    [Show abstract] [Hide abstract] ABSTRACT: Narcolepsy without cataplexy (NA w/o CA) (narcolepsy type 2) is a lifelong disorder characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep abnormalities, but no cataplexy. In the present study, we examined the human leukocyte antigen HLA-DQB1 in 160 Japanese patients with NA w/o CA and 1,418 control subjects. Frequencies of DQB1*06:02 were significantly higher in patients with NA w/o CA compared with controls (allele frequency: 16.6 vs. 7.8%, P=1.1×10−7, odds ratio (OR)=2.36; carrier frequency: 31.3 vs. 14.7%, P=7.6×10−8, OR=2.64). Distributions of HLA-DQB1 alleles other than DQB1*06:02 were compared between NA w/o CA and narcolepsy with cataplexy (NA-CA) to assess whether the genetic backgrounds of the two diseases have similarities. The distribution of the HLA-DQB1 alleles in DQB1*06:02-negative NA w/o CA was significantly different from that in NA-CA (P=5.8×10−7). On the other hand, the patterns of the HLA-DQB1 alleles were similar between DQB1*06:02-positive NA w/o CA and NA-CA. HLA-DQB1 analysis was also performed in 186 Japanese patients with idiopathic hypersomnia (IHS) with/without long sleep time, but no significant associations were observed.
    Full-text available · Article · Sep 2015
  • Naoshi Obara · Shigeru Chiba · Takayasu Kato · [...] · Yuichi Hasegawa
    Article · Sep 2015 · Experimental Hematology
  • [Show abstract] [Hide abstract] ABSTRACT: TET (Ten Eleven Translocation) family proteins are dioxygenases that convert methylcytosine to hydroxymethylcytosine, and play an important role in the DNA demethylation process. Most notably, TET2 mutations have frequently been identified in myeloid malignancies, such as myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia, and acute myeloid leukemias, as well as angioimmunoblastic T-cell lymphoma and a proportion of peripheral T-cell lymphomas. To date, various types of Tet2 knockout/knockdown mice have been generated. Tet2 mutations induce enhanced self-renewal ability and competitive repopulation capacity in hematopoietic stem cells, and various MPN/MDS-like diseases and T-cell lymphoma consequently develop in model mice. These findings appear to have a strong correlation with the recently identified TET2 mutations in a significant proportion of healthy elderly people, and suggest that TET2 mutations lead to a pre-cancer state in hematopoietic stem/progenitor cells. In conclusion, TET2 might play a major role as a gate keeper for hematopoietic stem/progenitor cells preventing them from developing into various hematologic malignancies by acquiring additional disease-specific gene mutations.
    Article · Aug 2015 · [Rinshō ketsueki] The Japanese journal of clinical hematology

Publication Stats

11k Citations


  • 2009-2013
    • Tokyo Medical University
      • Division of Hematology
      Edo, Tōkyō, Japan
  • 2008-2011
    • Sharp Corporation
      Ōsaka, Ōsaka, Japan
  • 2006
    • Saiseikai Maebashi Hospital
      Edo, Tōkyō, Japan
  • 2004-2006
    • Tohoku University
      • Graduate School of Engineering
      Miyagi, Japan
  • 2005
    • University of Groningen
      • Department of Stem Cell Biology
      Groningen, Groningen, Netherlands
  • 1989
    • The University of Tokyo
      • Division of Internal Medicine
      Tokyo, Tokyo-to, Japan