Masuhiro Takahashi

Niigata University, Niahi-niigata, Niigata, Japan

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Publications (88)289.38 Total impact

  • Cytotherapy 06/2015; 17(6):S18. DOI:10.1016/j.jcyt.2015.03.363 · 3.29 Impact Factor
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    ABSTRACT: The aim of the present study was to enhance the efficiency of leukemia immunotherapy by increasing the antigen‑specific cytotoxic T lymphocyte‑inducing ability of leukemia cells. The leukemic plasmacytoid dendritic cell line PMDC05 containing the HLA‑A02/24 antigen, which was previously established in our laboratory (Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan), was used in the present study. It exhibited higher expression levels of CD80 following transduction with lentiviruses encoding the CD80 gene. This CD80‑expressing PMDC05 was named PMDC11. In order to establish a more potent antigen‑presenting cell for cellular immunotherapy of tumors or severe infections, PMDC11 cells were transduced with a constitutively active (ca) toll‑like receptor 4 (TLR4) gene using the Tet‑On system (caTLR4‑PMDC11). CD8+ T cells from healthy donors with HLA‑A02 were co‑cultured with mutant WT1 peptide‑pulsed PMDC11, lipopolysaccharide (LPS)‑stimulated PMDC11 or caTLR4‑PMDC11 cells. Interleukin (IL)‑2 (50 IU/ml) and IL‑7 (10 ng/ml) were added on day three of culture. Priming with mutant WT1 peptide‑pulsed PMDC11, LPS‑stimulated PMDC11 or caTLR4‑PMDC11 cells was conducted once per week and two thirds of the IL‑2/IL‑7 containing medium was replenished every 3‑4 days. Immediately prior to the priming with these various PMDC11 cells, the cultured cells were analyzed for the secretion of interferon (IFN)‑γ in addition to the percentage and number of CD8+/WT1 tetramer+ T cells using flow cytometry. caTLR4‑PMDC11 cells were observed to possess greater antigen‑presenting abilities compared with those of PMDC11 or LPS‑stimulated PMDC11 cells in a mixed leukocyte culture. CD8 T cells positive for the WT1 tetramer were generated following 3‑4 weeks of culture and CD8+/WT1 tetramer+ T cells were markedly increased in caTLR4‑PMDC11‑primed CD8+ T cell culture compared with PMDC11 or LPS‑stimulated PMDC11‑primed CD8+ T cell culture. These CD8+ T cells co‑cultured with caTLR4‑PMDC11 cells were demonstrated to secrete IFN‑γ and to be cytotoxic to WT1‑expressing target cells. These data suggested that the antigen‑specific cytotoxic T lymphocyte (CTL)‑inducing ability of PMDC11 was potentiated via transduction of the caTLR4 gene. The present study also suggested that caTLR4‑PMDC11 cells may be applied as potent antigen‑presenting cells for generating antigen‑specific CTLs in adoptive cellular immunotherapy against tumors and severe viral infections.
    Molecular Medicine Reports 04/2015; 12(2). DOI:10.3892/mmr.2015.3685 · 1.55 Impact Factor
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    ABSTRACT: Patients with advanced stage of squamous cell carcinoma of esophagus have a poor prognosis with a lethal outcome. In order to explore the feasibility and effectiveness of dendritic cell (DC)‑based immunotherapy for squamous cell carcinoma of esophagus, we performed a phase Ⅰ/Ⅱ clinical trial of monocyte‑derived dendritic cells (moDCs) pulsed with SART1 peptide in seven patients with advanced stage of this disease. Although the feasibility of this therapy was definite, the effectiveness was not clearly confirmed in advanced stage of squamous cell carcinoma of esophagus. However, in vitro study revealed that moDCs generated for this therapy possessed a potent ability of inducing SART1 peptide‑specific cytotoxic T lymphocytes (CTLs). In addition, these moDCs were demonstrated to be able to produce exosomes with an antigen presenting ability for inducing SART1 peptide‑specific CTLs. ELISPOT assay using cryopreserved patient's lymphocytes demonstrated that IFN‑γ ELISPOTs were increased after four times of SART1 peptide‑pulsed moDC vaccinations compared with before the vaccination in a patient. The present study demonstrated that moDCs prepared from advanced stage of squamous cell carcinoma of esophagus possess a good immune function and in vivo immune responses (detected by ELISPOT assay) were evoked by the infusion of these moDCs. These findings suggest that DC‑based immunotherapy could be one of the modalities applicable for squamous cell carcinoma of esophagus.
    International Journal of Oncology 01/2015; 46(4). DOI:10.3892/ijo.2015.2846 · 3.03 Impact Factor
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    ABSTRACT: Background: Ustekinumab is currently used for the treatment of psoriasis with remarkable efficiency. However, worries about the development of malignancies in ustekinumab-treated patients have not been completely resolved because of the major role of IL-12 and IL-23 in tumor immunity. In the present study, we tried to elucidate the effects of ustekinumab on antigen-specific tumor immunity. Methods: After approval by the institutional ethical committee, a 56-year-old male volunteer with psoriasis was administered with 20 doses of WT1 peptide. WT1-specific cytotoxic T lymphocytes (CTLs) were evaluated by WT1 tetramer assay after mixed lymphocyte peptide culture. Results: WT1 tetramer+ T cells with cytotoxic ability appeared in the blood after peptide administration and the frequency of WT1 tetramer+ T cells increased to more than 15 in 10(6) CD8+ T cells. Thirty months after stopping WT1 administration, the patient commenced treatment with ustekinumab for psoriasis at weeks 0 and 4, and every 12 weeks thereafter. Psoriasis plaques were almost cleared up and the response to ustekinumab has so far lasted for 30 months. The frequency of WT1 tetramer+ T cells has not changed since the initiation of ustekinumab treatment. The effects of ustekinumab on the antigen-presenting and CTL-inducing abilities of dendritic cells were explored in vitro, revealing limited effects on both immune functions. Conclusions: These in vivo/vitro findings imply that ustekinumab improves psoriasis without suppressing tumor antigen-specific CTLs and support the data of recent clinical trials showing no increased incidence of malignancies with ustekinumab treatment.
    International Archives of Allergy and Immunology 10/2014; 165(1):52-60. DOI:10.1159/000366503 · 2.67 Impact Factor
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    ABSTRACT: Background/aim: Indoleamine-2,3-dioxygenase (IDO) is a rate-limiting enzyme for tryptophan metabolism and plays an immunosuppressive role. Antigen-presenting cells, when activated, increase the expression of IDO, which results in the suppression of subsequent immune reaction. A novel IDO inhibitor, Toho-1, was explored for its applicability to immunotherapy. Materials and methods: We investigated the effects of Toho-1 on antigen presentation and antigen-specific cytotoxic T-lymphocyte-inducing ability of leukemia plasmacytoid dendritic cell line PMDC05, which was established in our laboratory. Results: While antigen presentation-associated molecules in PMDC05 cells were increased by stimulation with lipopolysaccharide and interferon-γ, IDO mRNA and protein expression were also enhanced. Such treatment of PMDC05 cells in combination with Toho-1 enhanced the antigen-presenting and CTL-inducing ability of PMDC05 cells. Conclusion: These findings suggest the ability of Toho-1 to potentiate antigen-presenting cells and its applicability in immunotherapy of cancer.
    Anticancer research 08/2014; 34(8):4021-8. · 1.83 Impact Factor
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    ABSTRACT: tRNase-ZL-utilizing efficacious (TRUE) gene silencing is an RNA-mediated gene expression control technology that has therapeutic potential. This technology is based on the property of tRNase ZL that it can cleave any target RNA at any desired site under the direction of an appropriate artificial small guide RNA (sgRNA). To search for novel potential therapeutic sgRNAs for hematological malignancies, we screened a library composed of 156 sgRNAs, and found that 20 sgRNAs can efficiently induce apoptosis in leukemia and/or myeloma cells. Furthermore, we demonstrated that 4 of the 20 sgRNAs can reduce growth rates of HL60 cells in mouse xenograft models.
    Leukemia research 07/2014; 38(7). DOI:10.1016/j.leukres.2014.03.021 · 2.35 Impact Factor
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    ABSTRACT: Lymphocytosis predominantly due to natural killer (NK) cells has been reported in nearly a half of chronic myelogenous leukemia (CML) patients who were being treated with dasatinib. Besides, dasatinib-treated patients with lymphocytosis have a better prognosis than patients without lymphocytosis. In order to elucidate the effects of dasatinib on the proliferation of lymphocyte subset, dasatinib was added to the culture of peripheral blood mononuclear cells with IL-2 (lymphokine-activated killer culture) or a low dose of IL-2 with zoledronate (γδ T-cell culture). In both culture conditions, NK cells were increased in both percentage and absolute number in the culture with dasatinib compared with control culture without dasatinib. The increase of NK cells was dose dependent of dasatinib in the range of 2-25 nM. NK cell cytotoxicity of cultured cells with dasatinib was demonstrated to be superior to control cells without dasatinib in cytotoxicity assay using EGFP-transfected K562 cells as target cells. The present study suggested that lymphocytosis in dasatinib-treated CML patients is at least partly associated with a direct effect of dasatinib to stimulate the proliferation of NK cells. Favourable prognosis in patients with dasatinib-induced lymphocytosis might be associated with the effects of dasatinib to potentiate NK cytotoxicity in vivo. Copyright © 2012 John Wiley & Sons, Ltd.
    Hematological Oncology 09/2013; 31(3). DOI:10.1002/hon.2034 · 3.08 Impact Factor
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    ABSTRACT: TRUE gene silencing is a technology to eliminate specific cellular RNAs by using tRNase Z(L) and small guide RNA (sgRNA). Here we investigated how WT1-mRNA-targeting sgRNAs affect leukemic cells. We showed that sgRNA can be easily taken up by cells without any transfection reagents, and that the naked sgRNAs targeting the WT1 mRNA can reduce its mRNA levels and WT1 protein amounts in the WT1-expressing leukemic cells. Concomitantly, these sgRNAs efficiently induced apoptosis in these cells but not in WT1-nonexpressing cells. We also demonstrated that the reduction in the WT1 mRNA level is caused by its cleavage by tRNase Z(L).
    Leukemia research 02/2013; 37(5). DOI:10.1016/j.leukres.2013.01.015 · 2.35 Impact Factor
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    ABSTRACT: Quantification of tumor-associated mRNA extracted from blood cells/tissues containing tumor cells is used for evaluation of treatment efficacy or residual tumor cell burden in tumors including leukemia. However, this method using tumor cell-containing blood/tissue is difficult to evaluate the whole tumor cell burden in the body. In order to establish an efficient method to evaluate the whole tumor cell burden in the body, we tried to quantify tumor-associated mRNA existing in plasma/serum instead of leukemia cell-containing blood cells in patients with chronic myelogenous leukemia (CML) and compared the levels of BCR-ABL mRNA between plasma/serum and peripheral blood cells. mRNA of BCR-ABL, WT1 or GAPDH (control molecule) was detected by real-time RT-PCR using RNA extracted from plasma/serum of almost all the patients with CML. Copy numbers of BCR-ABL mRNA were significantly correlated between plasma/serum and peripheral blood cells. However, levels of BCR-ABL mRNA extracted from serum were low compared with those extracted with peripheral blood cells. The present findings suggest that although real-time RT-PCR of mRNA existing in plasma/serum could be used for evaluating the whole tumor cell burden in the body, it's required to establish an efficient method to quantify plasma/serum mRNA by nature without degrading during the procedure.
    International journal of medical sciences 11/2012; 9(10):901-8. DOI:10.7150/ijms.4655 · 2.00 Impact Factor
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    ABSTRACT: tRNase Z(L)-utilizing efficacious gene silencing is a gene control technology, which is based on the property that tRNase Z(L) can cleave any target RNA under the direction of an appropriate small guide RNA (sgRNA). To find therapeutic sgRNAs to cure hematological malignancies, we investigated behavior of heptamer-type sgRNA. We demonstrated that a heptamer, mh1(Bcl-2), which targets the human Bcl-2 mRNA, can be taken up by cells without any transfection reagents and that it can induce apoptosis of the leukemia cells. Mouse xenograft experiments showed that a median survival of the mh1(Bcl-2)-treated mice was longer than that of the control mice.
    Cancer letters 10/2012; 328(2). DOI:10.1016/j.canlet.2012.10.016 · 5.62 Impact Factor
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    ABSTRACT: PMDC05, a leukemic plasmacytoid dendritic cell (pDC) line which was established in our laboratory, showed a capacity of generating antigen-specific cytotoxic T lymphocytes (CTLs). In order to enhance an antigen presenting ability of PMDC05, PMDC05 was transduced with CD80 gene by lentiviral vector, which was named as PMDC11. PMDC11 displayed a strong antigen presenting ability even without any stimulation, and by culturing with stimulators such as calcium ionophore PMDC11 gained a more potent antigen presenting ability. Our data suggested PMDC11 could be applied as antigen presenting cells more efficiently in adoptive cellular immunotherapy for tumors and severe infections in comparison with PMDC05.
    Leukemia research 10/2012; 36(12). DOI:10.1016/j.leukres.2012.09.002 · 2.35 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease caused by selective loss of motor neurons. In the ALS motor neurons, TAR DNA-binding protein of 43 kDa (TDP-43) is dislocated from the nucleus to cytoplasm and forms inclusions, suggesting that loss of a nuclear function of TDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism include regulation of transcription, mRNA stability, and alternative splicing of pre-mRNA. However, a function of TDP-43 in tissue affected with ALS has not been elucidated. We sought to identify the molecular indicators reflecting on a TDP-43 function. Using exon array analysis, we observed a remarkable alteration of splicing in the polymerase delta interacting protein 3 (POLDIP3) as a result of the depletion of TDP-43 expression in two types of cultured cells. In the cells treated with TDP-43 siRNA, wild-type POLDIP3 (variant-1) decreased and POLDIP3 lacking exon 3 (variant-2) increased. The RNA binding ability of TDP-43 was necessary for inclusion of POLDIP3 exon 3. Moreover, we found an increment of POLDIP3 variant-2 mRNA in motor cortex, spinal cord and spinal motor neurons collected by laser capture microdissection with ALS. Our results suggest a loss of TDP-43 function in tissues affected with ALS, supporting the hypothesis that a loss of function of TDP-43 underlies the pathogenesis of ALS.
    PLoS ONE 08/2012; 7(8):e43120. DOI:10.1371/journal.pone.0043120 · 3.23 Impact Factor
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    ABSTRACT: Establishment of a leukemia plasmacytoid dendritic cell line (PMDC05) and intra-lineage transformation from pDCs to mDCs in PMDC05 has been reported. In this paper, we show the applicability of PMDC05 for cellular immunotherapy. By stimulation with LPS, PMDC05 showed enhancement in expression of antigen presentation-associated surface molecules and production of cytokines (IL-12p70 and TNF-α). The antigen presenting ability was markedly increased in PMDC05 stimulated with LPS. By co-culturing of CD8(+) T cells with LPS-stimulated and WT1/CMVpp65 peptide-pulsed PMDC05, WT1/CMVpp65 tetramer(+) cytotoxic T lymphocytes were efficiently generated. These findings reveal the applicability of PMDC05 in cellular immunotherapy for tumor and severe viral infections.
    Leukemia research 06/2011; 35(6):793-9. DOI:10.1016/j.leukres.2010.12.003 · 2.35 Impact Factor
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    ABSTRACT: Although antigen-specific immune responses including cytotoxic T cells (CTLs) against antigen peptide could be enhanced after tumor antigen peptide vaccinations, the immune responses do not necessarily result in a decrease or eradication of tumor cells in the vaccination trials. We focused on whether antigen-specific CTLs could be damaged by the repeated stimulation of antigenic peptide and whether regulatory T (Treg) cells would be increased by the administration of WT1 peptide. We administered WT1 peptide 22 times over 18 months in a CML patient who was being treated with imatinib. Although WT1 peptide administration every 2 weeks did not show any beneficial effects on the minimal residual disease (copies of bcr-abl transcripts), the transcripts remarkably decreased to the level of major molecular response after changing the administration interval of WT1 peptide from 2 to 4 weeks. An ex vivo study demonstrated that re-stimulation with WT1 peptide made WT1-specific T cells less reactive to WT1 tetramers and the impaired reactivity of CTLs lasted at least for 1 week. In addition, the cytotoxicity of the T cells was hampered by re-stimulation. Treg cells increased up to more than fivefold at the end of the WT1 administration period. The present findings suggested that the administration of the peptide every 4 weeks is superior to every 2 weeks. In addition, the findings that Treg cells increased gradually in accordance with the duration of WT1 peptide administration revealed the significance of manipulating Treg cells for establishing an efficient tumor antigen peptide vaccination.
    Medical Oncology 03/2011; 28(1):219-30. DOI:10.1007/s12032-010-9425-3 · 2.63 Impact Factor
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    ABSTRACT: This retrospective analysis investigated the prognostic value of monitoring the response to imatinib using peripheral blood (PB) samples and the impact of the response on outcome in 133 patients with chronic myeloid leukemia (CML). We divided the response into 3 categories according to the results of neutrophil (N)-FISH and BCR-ABL transcript levels in PB; more than a 3-log reduction [major molecular response (MMR)], between a 2-log and 3-log reduction or negative with N-FISH [complete cytogenetic response equivalent (CCyRe)], N-FISH positive or less than a 2-log reduction (non-CCyRe). The median follow-up was 5.46 years. At 5 years, the overall survival (OS) rate and progression-free survival (PFS) rate were 94.4 and 92.0%, respectively. The estimated rate of the CCyRe and MMR were 81.7 and 67.1%, respectively. 106 patients achieving the CCyRe had significantly better OS and PFS than 27 patients without achieving the CCyRe. Patients with MMR had significantly better survival free from death, progression, imatinib withdrawal and a loss of the CCyRe, than patients whose response level remained in the CCyRe without achieving MMR until 18 months. Our observation suggests that the response level of the CCyRe on PB serve as a prognostic indicator, and achieving MMR provides stable long-term survival.
    International journal of hematology 02/2011; 93(3):336-43. DOI:10.1007/s12185-011-0774-2 · 1.92 Impact Factor
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    ABSTRACT: How to treat CML patients who are resistant to inhibitors of BCR-ABL tyrosine kinase such as Imatinib is a very important and urgent issue in clinical hematology. Here, we report a case of Imatinib-treated CML in which intradermally administered WT1 peptide vaccine elicited WT1-specific immune responses and the resultant reduction in the persistent residual disease in co-administration of Imatinib. BCR-ABL mRNA levels were being maintained under the detection limit for 8 months since week 77 of vaccination. No adverse effects except local erythema at the injection sites were observed. The tetramer assay revealed that the decrease in BCR-ABL mRNA levels was associated with the increase in frequency of WT1-specific cytotoxic T lymphocytes, notably effector-memory type of that, in the patient's peripheral blood. The case presented here indicates that WT1 peptide vaccine may become a safe and cure-oriented therapy for CML patients who have residual disease regardless of the treatment with Imatinib.
    European Journal Of Haematology 10/2010; 85(4):358-60. DOI:10.1111/j.1600-0609.2010.01497.x · 2.07 Impact Factor
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    ABSTRACT: Pharmacological study is predictably effective in establishing an optimal monitoring strategy for the usage of cyclosporine A (CsA) to prevent graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation recipients. Pharmacokinetic profiling of 33 recipients administered CsA twice daily by 3-h intravenous infusion revealed that levels peaked 2-3 h after the start of infusion, and an exponential decline of CsA concentrations after the termination of infusion was observed. The correlation between the area under the curve (AUC(0-12)) and CsA concentration at various time points after infusion revealed that C (2) and C (3) correlated best with AUC(0-12) (r (2) = 0.725), while the trough concentration correlated poorly. Ex vivo T cell stimulation followed by intracellular cytokine detection with flow cytometry revealed that the capacity of T cells to produce cytokines upon stimulation was inversely proportional to the CsA concentration, and reached a minimum at about 700 ng/mL with a marginal decrease above this concentration. Extrapolation using the regression equations of this study and the data from our retrospective study leads to the assumption that the dose adjustment of CsA based on maintaining the C (3) concentration above 800 ng/mL may effectively prevent acute GVHD. To confirm this assumption, a prospective clinical study is required.
    International journal of hematology 07/2010; 92(1):144-51. DOI:10.1007/s12185-010-0610-0 · 1.92 Impact Factor
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    ABSTRACT: Although tyrosine kinase inhibitors is effective for dramatically reducing CML cells, it might be difficult to eradicate completely the CML stem cells. We aimed to clarify the safety and effects of WT1 peptide vaccination in combination with imatinib therapy for a CML patient. A 51 year-old male with CML in CP, who showed a resistance against imatinib therapy for 2.5 years, began to be treated with 9 mer modified-type WT1 peptides in combination with standard dose of imatinib. Although every 2-week-administration of WT1 peptides for 22 weeks did not show definite effects on the quantification of bcr-abl transcripts, by changing the administration from every 2 weeks to 4 weeks bcr-abl transcripts decreased remarkably. After 11 months of every 4-week-administration of the peptides and 12 months post cessation of the peptides bcr-abl transcripts achieved to the level below detection by RQ/RT-PCR (complete molecular response). WT1/MHC tetramer(+)CD8(+) CTLs, which appeared after the second administration of WT1 peptides and remained more than 15 in number among 10(6) CD8(+) T cells throughout the administration of WT1 peptides, are still present in the blood on 14th month post cessation of the peptides. An in vitro study as to the cytotoxicity of lymphocytes induced by mixed lymphocyte peptide culture demonstrated that cultured lymphocytes possessed cytotoxicity against WT1 expressing leukemia cells and the cytotoxicity was WT1-specific and MHC class I restricted. The present study showed that WT1 peptide vaccination in combination with TKI is feasible and effective in the therapy for imatinib-resistant CML.
    International journal of medical sciences 04/2010; 7(2):72-81. · 2.00 Impact Factor
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    ABSTRACT: Angiogenesis therapy by bone marrow-mononuclear cell implantation (BMI) has been utilized. We found that erythroid cells played an essential role in angiogenesis by BMI. We then tried to establish a novel cell therapy by implantation of ex vivo expanded immature erythroblasts cultured from hematopoietic stem/precursor cells. Immature to mature erythroblasts were purified from human bone marrow, and mRNA expression were analyzed. Strongly expressed VEGF and PLGF in immature erythroid cells decreased according to erythroid maturation. To expand very immature erythroid cells, we established a two-step culturing system, i.e., bone marrow cells were cultured in the presence of Flt-3L, SCF and TPO for 7 days, and the cells were further cultured in the presence of SCF, IGF-I and EPO for an additional 7 days. The in vivo angiogenic effects of implantation of the ex vivo expanded cells were stronger than that of BMI in mouse limb ischemia model. Three patients with severe chronic lower limb ischemia accompanied by Burger's disease or collagen arteritis were enrolled in a pilot clinical trial of the novel cell therapy by transplantation of ex-vivo expanded immature erythroid cells. In the clinical trial, most clinical symptoms such as rest pain and skin ulcers improved in 4 weeks, and did not recur in the one-year follow-up. No adverse events were observed in any of the patients. Moreover this novel cell therapy required only a small amount of bone marrow collection. Further enrollment of patients with chronic severe lower limb ischemia is necessary to confirm the efficacy and safety of this novel cell therapy, and to estimate the necessary amount of bone marrow aspirate.
    Journal of Molecular and Cellular Cardiology 04/2010; 49(3):347-53. DOI:10.1016/j.yjmcc.2010.04.001 · 4.66 Impact Factor
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    ABSTRACT: We investigated the transformation from pDCs to mDCs in a pDC line (PMDC05) which was established from a patient with pDC leukemia in our laboratory. PMDC05 cells were separated into two fractions according to the expression of BDCA1 and CD123. BDCA1(-)CD123(+) cells were found to be pDC-like cells by their morphology, surface phenotypes, mRNA expression and the function. In addition, BDCA1(-)CD123(+) cells were demonstrated to have a proliferating capacity and revealed the ability to transform to BDCA1(+)CD123(-) cells which showed mDC-like properties. Our data demonstrated the possibility of transformation from pDCs to mDCs in human DC lineage.
    Leukemia research 03/2010; 34(11):1517-24. DOI:10.1016/j.leukres.2010.03.002 · 2.35 Impact Factor

Publication Stats

991 Citations
289.38 Total Impact Points


  • 1991–2015
    • Niigata University
      • • Graduate School of Health Sciences
      • • Graduate School of Medical and Dental Sciences
      • • School of Health Sciences
      • • Department of Medical Technology
      • • School of Medicine
      Niahi-niigata, Niigata, Japan