Masatoshi Nakazawa

Yokohama City University, Yokohama, Kanagawa, Japan

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Publications (39)115.32 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: BCR-ABL tyrosine kinase inhibitors (TKI) have dramatically improved therapy for chronic myelogenous leukemia (CML). However, several problems leading to TKI resistance still impede a complete cure of this disease. IFN regulatory factor-8 (IRF8) is a transcription factor essential for the development and functions of immune cells, including dendritic cells. Irf8−/− mice develop a CML-like disease and IRF8 expression is downregulated in patients with CML, suggesting that IRF8 is involved in the pathogenesis of CML. In this study, by using a murine CML model, we show that BCR-ABL strongly inhibits a generation of dendritic cells from an early stage of their differentiation in vivo, concomitant with suppression of Irf8 expression. Forced expression of IRF8 overrode BCR-ABL (both wild-type and T315I-mutated) to rescue dendritic cell development in vitro, indicating that the suppression of Irf8 causes dendritic cell deficiency. Gene expression profiling revealed that IRF8 restored the expression of a significant portion of BCR-ABL–dysregulated genes and predicted that BCR-ABL has immune-stimulatory potential. Indeed, IRF8-rescued BCR-ABL–expressing dendritic cells were capable of inducing CTLs more efficiently than control dendritic cells. Altogether, our findings suggest that IRF8 is an attractive target in next-generation therapies for CML.
    Cancer Research 11/2013; 73(22):6642-6653. · 8.65 Impact Factor
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    ABSTRACT: BCR-ABL tyrosine kinase inhibitors (TKI) have dramatically improved therapy for chronic myelogenous leukemia (CML). However, several problems leading to TKI resistance still impede a complete cure of this disease. IFN regulatory factor-8 (IRF8) is a transcription factor essential for the development and functions of immune cells, including dendritic cells. Irf8(-/-) mice develop a CML-like disease and IRF8 expression is downregulated in patients with CML, suggesting that IRF8 is involved in the pathogenesis of CML. In this study, by using a murine CML model, we show that BCR-ABL strongly inhibits a generation of dendritic cells from an early stage of their differentiation in vivo, concomitant with suppression of Irf8 expression. Forced expression of IRF8 overrode BCR-ABL (both wild-type and T315I-mutated) to rescue dendritic cell development in vitro, indicating that the suppression of Irf8 causes dendritic cell deficiency. Gene expression profiling revealed that IRF8 restored the expression of a significant portion of BCR-ABL-dysregulated genes and predicted that BCR-ABL has immune-stimulatory potential. Indeed, IRF8-rescued BCR-ABL-expressing dendritic cells were capable of inducing CTLs more efficiently than control dendritic cells. Altogether, our findings suggest that IRF8 is an attractive target in next-generation therapies for CML. Cancer Res; 73(22); 6642-53. ©2013 AACR.
    Cancer Research 11/2013; 73(22):6642-53. · 8.65 Impact Factor
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    ABSTRACT: Monocytes regulate host defenses, inflammation and tissue homeostasis. The transcription factor (TF) Interferon Regulatory Factor-8 (IRF8) stimulates monocyte/macrophage differentiation, yet genome-wide understanding of the differentiation program initiated by IRF8 is lacking. By combining chromatin immunoprecipitation-sequencing with gene expression profiling, we show here that during IRF8-dependent monocyte differentiation, IRF8 binding occurs at both promoter-proximal and distal regions together with the TF PU.1 and is associated with gene induction. Many of the promoter-distal IRF8 binding sites show an increase in histone H3 lysine 4 monomethylation, a signature for enhancers. However, about half of IRF8-induced genes were not bound by IRF8, suggesting the involvement of downstream TFs. Analysis of DNA motifs in cis-regulatory elements of these indirect IRF8 target genes predicted that Krüppel-like factor-4 (KLF4), which is essential for Ly6C(+) monocyte development, is one such factor. Indeed, monocyte development in Irf8(-/-) mice is as defective as that in Klf4(-/-) chimeric mice. Moreover, Irf8(-/-) monocyte-dendritic cell progenitors do not express Klf4 mRNA. Introduction of KLF4 into an Irf8(-/-) myeloid progenitor cell line induced a subset of IRF8 target genes and caused partial monocyte differentiation. Taken together, our present results uncover genome-wide behavior of IRF8 and identify an IRF8-KLF4 axis that operates during monocyte differentiation.
    Blood 01/2013; · 9.06 Impact Factor
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    ABSTRACT: Sneezing and persistent itching of the nasal mucosa are distressing symptoms of allergic rhinitis (AR). Recent studies have revealed that hyperinnervation of sensory neurons in the nasal turbinate is one of the underlying causes of sneezing and itching. Since Semaphorin-3A (Sema3A) has been previously shown to restrict innervation of sensory neurons, it is presumed that reduced Sema3A expression in the nasal mucosa might contribute to the hypersensitivity. Analysis of the mouse model of ovalbumin-sensitized AR demonstrated a decreased expression of Sema3A in the nasal epithelium, which was accompanied by an increased nerve fiber density in the lamina propria of the turbinate. In rescue experiments, intranasal administration of recombinant Sema3A in the AR model mice alleviated sneezing and nasal rubbing symptoms. In addition, histological examinations also revealed that nerve fiber density was decreased in the lamina propria of the Sema3A-treated nasal turbinate. These results suggest that the nasal hypersensitivity of AR may be attributed to reduction of Sema3A expression and intranasal administration of Sema3A may provide a novel approach to alleviate the allergic symptoms for AR treatment.
    Journal of Pharmacological Sciences 08/2011; 117(1):34-44. · 2.15 Impact Factor
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    ABSTRACT: Interferon regulatory factor (IRF) 8 and IRF4 are structurally-related, hematopoietic cell-specific transcription factors that cooperatively regulate the differentiation of dendritic cells and B cells. Whilst in myeloid cells IRF8 is known to modulate growth and differentiation, the role of IRF4 is poorly understood. In this study, we show that IRF4 has activities similar to IRF8 in regulating myeloid cell development. The ectopic expression of IRF4 in myeloid progenitor cells in vitro inhibits cell growth, promotes macrophages, but hinders granulocytic cell differentiation. We also show that IRF4 binds to and activates transcription through the IRF-Ets composite sequence (IECS). Furthermore, we demonstrate that Irf8⁻/⁻Irf4⁻/⁻ mice exhibit a more severe chronic myeloid leukemia (CML)-like disease than Irf8⁻/⁻ mice, involving a disproportionate expansion of granulocytes at the expense of monocytes/macrophages. Irf4⁻/⁻ mice, however, display no obvious abnormality in myeloid cell development, presumably because IRF4 is expressed at a much lower level than IRF8 in granulocyte-macrophage progenitors. Our results also suggest that IRF8 and IRF4 have not only common but also specific activities in myeloid cells. Since the expression of both the IRF8 and IRF4 genes is downregulated in CML patients, these results may add to our understanding of CML pathogenesis.
    PLoS ONE 01/2011; 6(10):e25812. · 3.73 Impact Factor
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    ABSTRACT: Influenza A viral infection is concerned with induction of asthma. CD11c+ pulmonary antigen presenting cells (APCs) play a central role in sensitization with inhaled antigens during the acute phase of influenza A viral infection and also reside on bronchial epithelium for the long term after sensitization. To investigate the role of CD11c+ pulmonary APCs in the inhaled antigen sensitization during the acute phase of influenza A viral infection, we analyzed their function. Mice were infected with influenza A virus and were sensitized intranasally with BSA/alum during the acute phase of influenza A viral infection. Expression of surface antigens on CD11c+ pulmonary APCs was analyzed by FACS. Cytokine production from CD11c+ pulmonary APCs, and interaction between CD11c+ pulmonary APCs and naïve CD4+ T cells was assessed by ELISA. Ability of antigen presentation by CD11c+ pulmonary APCs was measured by proliferation assay. BSA antigen sensitization during the acute phase of influenza A viral infection induced eosinophil recruitment into the lungs after BSA antigen challenge and moderately increased expression of MHC class II molecules on CD11c+ pulmonary APCs. The interaction between the CD11c+ pulmonary APCs and naïve CD4+ T cells secreted large amounts of IL-10. BSA antigen sensitization during the acute phase of influenza A viral infection enhanced IL-10 production from naïve CD4+ T cell interaction with CD11c+ pulmonary APCs. The IL-10 secretion evoked Th2 responses in the lungs with downregulation of Th1 responses and was important for the eosinophil recruitment into the lungs after BSA antigen challenge.
    Allergology International 08/2009; 58(3):445-54.
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    ABSTRACT: Background:  Respiratory viral infections are known to be a risk factor for the exacerbation of asthma. In a model of asthma with influenza A virus infection, dendritic cells play an important role during antigen sensitization and antigen challenge. However, the role of T cells in the asthma−influenza A model was unclear. The aim of the present study was to assess the roles of T cells during antigen sensitization and antigen challenge in the asthmatic model.Methods:  C57BL/6 mice were infected with influenza A virus and were sensitized with inhaled antigen during the acute phase of the virus infection. Anti-CD4 or anti-CD8 monoclonal antibodies were administered during antigen sensitization or antigen challenge to evaluate the role of CD4+ or CD8+ T cells in this murine model of asthma. The onset of asthma was determined by eosinophil recruitment into the lung.Results:  During antigen sensitization, depletion of either CD4+ or CD8+ T cells resulted in an absence of eosinophil infiltration into the lung after antigen challenge. However, during antigen challenge, depletion of CD4+ T cells did cause such an absence of eosinophil infiltration.Conclusions:  During antigen sensitization, both CD4+ and CD8+ T cells were required in C57BL/6 mice for exacerbation of asthma. During antigen challenge, CD4+ T cells were important for the onset of asthma, whereas CD8+ T cells do not affect eosinophil recruitment into the lung.
    Allergology International 06/2008; 53(2):159 - 167.
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    ABSTRACT: Glycolipid-reactive Valpha24(+) invariant natural killer T (iNKT) cells have been implicated in regulating a variety of immune responses and in the induction of immunologic tolerance. Activation of iNKT cells requires interaction with professional antigen-presenting cells, such as dendritic cells (DCs). We have investigated the capacity of distinct DC subsets to modulate iNKT cell functions. We demonstrate that tolerogenic DCs (tolDCs), generated by treatment of monocyte-derived DC with interleukin (IL)-10, induced regulatory functions in human iNKT cells. tolDCs, compared with immunogenic DCs, had reduced capacity to induce iNKT-cell proliferation, but these cells produced large amounts of IL-10 and acquired an anergic phenotype. These anergic Valpha24(+) iNKT cells were able to potently inhibit allogeneic CD4(+) T-cell proliferation in vitro. Furthermore, the anergic Valpha24(+) iNKT cells could suppress DC maturation in vitro. We conclude that the interaction of iNKT cells with tolDCs plays an important role in the immune regulatory network, which might be exploited for therapeutic purposes.
    Blood 05/2008; 111(8):4254-63. · 9.06 Impact Factor
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    ABSTRACT: Zinc is one of the essential dietary factors and zinc deficiency diminishes the immune system. However, the mechanisms by which zinc deficiency affects the immune system are not fully understood. We analyzed the mechanisms of zinc deficiency affecting the allergic response using a DS-Nh mouse model of atopic dermatitis. Male DS-Nh mice were fed a zinc deficient diet for 4 weeks. We measured transepidermal water loss (TEWL) and epidermal moisture level, assessed the skin eruption score, and examined the frequency of lymphocyte subpopulation in spleen and thymus by flow cytometry. The suppressive effect of CD25+CD4+ T cells was analyzed in vitro. The amount of cytokines produced by the spleen cells and the serum IgE levels were measured by ELISA. In DS-Nh mice fed the zinc deficient diet, skin eruptions were exacerbated and serum IgE levels and number of S. aureus on the skin surface was increased. IFN-gamma and IL-13 production by spleen cells was increased. The number of CD25+CD4+ T cells in spleen was significantly decreased, while the percentage of Foxp3 positive cells in the CD25+CD4+ T cells was comparable to those of the controls. CD25+CD4+ T cells from mice fed the zinc deficient diet maintained a suppressive function compared with those from the controls. These findings indicate that zinc deficiency influences the skin barrier system and immune system, and suggests that zinc deficiency acts as an exacerbation factor of atopic dermatitis.
    Journal of Dermatological Science 05/2008; 50(1):31-9. · 3.52 Impact Factor
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    ABSTRACT: This paper describes the fabrication and performance of CMOS transistors featuring flash lamp annealing (FLA) for 45 nm node. We show, for the first time, applying FLA prior to spike RTA as S/D annealing is effective to enhance the channel stress in PFET with epitaxially grown SiGe (eSiGe) S/D. In NFET, FLA recovers the damaged layer in S/D extension caused by implantation and suppresses the transient enhanced diffusion (TED). These improvements result in 11% and 8% higher saturation drive current, and IDSAT=750muA/mum and 1160muA/mum for IOFF=100 nAmum at Vdd=lV in PFET and NFET, respectively. We also report the pattern density dependence of performance gain from FLA technique.
    Electron Devices Meeting, 2007. IEDM 2007. IEEE International; 01/2008
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    ABSTRACT: A number of studies have investigated the role of tumor-infiltrating lymphocytes in cancer, yet the local immune response to hepatic colorectal cancer metastasis remains unclear. As the tumor doubling time (DT) of hepatic colorectal cancer metastases is a good index of tumor growth, we examined the correlation between tumor DT and the local immune response by phenotype in hepatic colorectal cancer metastases. Tumor DT and local immune response were examined in 20 patients with hepatic colorectal cancer metastases by analyzing tumor-infiltrating lymphocytes using flow cytometry or immunohistochemical studies. Tumor proliferative activity was also investigated by determining the expression levels of Ki-67 and proliferating cell nuclear antigen (PCNA). Locally abundant populations of CD83(+) dendritic cells (DCs) and CD8(+) T cells were positively related to longer tumor DT (P < 0.05), as were abundant CD8(+) T cells having interferon-gamma-producing potentials (P < 0.05). There was no significant correlation between tumor cell expression levels of Ki-67 or PCNA and tumor DT. Longer DT tumors have increased local populations of CD8(+) T cells and CD83(+) DCs even in hepatic colorectal cancer metastases.
    Journal of Surgical Oncology 11/2007; 96(6):525-33. · 2.64 Impact Factor
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    ABSTRACT: The effect of stress memorization technique (SMT) in performance and power reduction is maximized by choosing the appropriate stressor with large stress change by spike RTA. 30% mobility enhancement and 60% reduction of gate leakage have been achieved simultaneously. Stress distribution in channel region for SMT is confirmed to be uniform, hence layout dependency is minimized and performance is maximized in aggressively scaled CMOS with dense gate pitch rule (190 nm) in 45 nm technology node.
    VLSI Technology, 2007 IEEE Symposium on; 07/2007
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    ABSTRACT: To regulate the expression of the apoptotic gene, we constructed bicistronic DNA vaccines that encode for HIV env and caspase-3 mutant (casp 3m) that are expressed via the encephalomyocarditis virus internal ribosomal entry site (IRES) or cytomegalovirus (CMV) promoter-dependent translations. While IRES-casp 3m induced weak apoptosis and caused little reduction in antigen expression, CMV-casp 3m elicited strong apoptosis and led to a marked decrease in the antigen expression. Therefore, IRES-casp 3m augmented HIV-specific immune responses, and IRES-casp 3m induced significant protection against the vaccinia-HIV chimeric virus. These results suggest that the appropriate level of apoptosis is important for DNA vaccine development.
    Vaccine 02/2007; 25(3):438-45. · 3.49 Impact Factor
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    ABSTRACT: We present the state-of-the-art 45nm high performance bulk logic platform technology which utilizes, for the first time in the industry, ultra high NA (1.07) immersion lithography to realize highly down-scaled chip size. Fully renovated MOSFET integration scheme which features reversed extension and SD diffusion formation is established to meet Vt roll-off requirement with excellent transistor performance of Ion=1100muA/mum for nFET and Ion=700muA/mum for pFET at Ioff=100nA/mum. Also, we achieved excellent BEOL reliability and manufacturability by implementing hybrid dual-damascene (DD) structure with porous low-k film (keff=2.7)
    Electron Devices Meeting, 2006. IEDM '06. International; 01/2007
  • Journal of Allergy and Clinical Immunology - J ALLERG CLIN IMMUNOL. 01/2007; 119(1).
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    ABSTRACT: Alymphoplasia (aly/aly) mice are from a naturally occurring strain with a mutation in nuclear factor-kappa B inducing kinase (NIK). The NIK mutation causes disruption of the architecture of the thymus and spleen and aly/aly mice show decreased numbers of CD25+CD4+T cells in the spleen. For the expansion of CD25+CD4+T cells, interactions between dendritic cells (DCs) and CD25+CD4+ regulatory T cells are necessary. We investigated the ability of DCs to induce expansion of CD25+CD4+T cells. We found that DCs are reduced in the spleen of aly/aly mice, and showed low expressions of CD80, CD86 and MHC class II molecules on the surface. DCs from aly/aly mice showed decreased ability to present ovalbumin (OVA) to T cells from OVA specific TCR transgenic mice, and a decreased ability for alloantigen presentation. Further, DCs showed a decreased ability to induce expansion of CD25+CD4+T cells in vitro. Our results suggested that the impairment of DCs in aly/aly mice is responsible, at least in part, for the decreased numbers of CD25+CD4+T cells in the periphery of aly/aly mice.
    Autoimmunity 10/2006; 39(6):445-53. · 2.77 Impact Factor
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    ABSTRACT: In the last few decades, numerous chemical compounds have been produced as a result of industrial development. At the same time, the number of atopic dermatitis (AD) patients has been increasing. It has been reported that tributyltin (TBT) compounds have effects not only on the reproductive system but also on the immune system. To investigate whether TBT has an effect on AD, we fed a diet containing TBT to DS-Nh mice, which spontaneously developed dermatitis under conventional conditions. DS-Nh mice fed TBT or a control diet were examined for skin changes, number of Staphylococcus aureus on the skin and serum IgE levels. To determine Th1/Th2 cytokine production by lymphocytes, lymphocytes of DS-Nh mice fed TBT and of controls were cultured with staphylococcal enterotoxin B and cytokine levels in the supernatants were measured by ELISA. We observed not only spontaneous dermatitis but also dermatitis induced by sensitization with 2,4,6-trinitrochlorobenzene (TNCB). The AD-like lesions induced by TNCB sensitization were more severe in the mice fed TBT than in those fed the control diet. A greater increase in S. aureus on the skin was observed in the mice fed TBT than in the mice fed the control diet. A decrease in IFN-gamma production and an increase in IL-5 and IL-13 production were observed in the mice fed the TBT diet and treated with TNCB. These findings suggest that the increase in S. aureus and the enhancement of Th2 response induced by TBT exacerbate the AD-like lesions in mice treated with TNCB.
    International Archives of Allergy and Immunology 02/2006; 141(4):337-45. · 2.25 Impact Factor
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    ABSTRACT: Dendritic cells (DCs) are the only antigen-presenting cell population having a cross-presentation capacity. For cross-presentation, however, the intracellular antigen-processing pathway and its regulatory mechanism have not been defined. Here we report the differences in cross-presentation ability among murine bone marrow-derived immature DC, early immature day8-DC and late immature day10-DC, and fully mature day10 + lipopolysaccharide DC. Day8-DCs and day10-DCs show an immature phenotypic profile but are different in morphology. Day8-DCs can internalize an abundant volume of exogenous soluble ovalbumin (OVA) and result in cross-presentation. In contrast, day10-DCs are not able to cross-present, although they maintain efficient macropinocytosis. Exogenously internalized OVA antigens are stored in the endocytic compartments. The endocytic compartments are temporarily maintained at mildly acidic pH in day8-DCs and are rapidly acidified in day10-DCs after uptake of antigens. We show that OVA antigens accumulated in the endocytic compartments move into the cytosol in day8-DCs but do not in day10-DCs. NH(4)Cl-treatment, which neutralizes the acidic endocytic compartments and/or delays endosomal maturation, restores day10-DCs for transport the stored OVA antigens from the endocytic compartments into the cytosol. Diphenyleneiodonium chloride-treatment, which acidifies the endocytic compartments, decreases an amount of transported OVA antigen into the cytosol in day8-DCs. These data indicate that only the early immature stage of DC interferes with endosomal maturation, even after uptake of exogenous antigens, and then transports the antigens into the cytosol.
    Immunology 02/2006; 117(1):97-107. · 3.71 Impact Factor
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    ABSTRACT: Adjuvants in vaccines are immune stimulants that play an important role in the induction of effective and appropriate immune responses to vaccine component(s). Diphtheria-tetanus-pertussis (DPT) vaccine contains not only aluminum hydrate (alum) to enhance the immune response to the vaccine ingredients, but also, both for that purpose and as a principal ingredient, pertussis toxin (PT). However, both adjuvants strongly promote T helper (Th) 2 type immune responses. Th1 and Th2 type immune responses are counterbalanced in vivo, and a Th2-prone immune response is not effective against intracellular infections but promotes IgE production, which is related to allergic disease. In this study, we used the CpG motif contained in oligodeoxynucleotide (CpG-ODN), which has an adjuvant effect and also induces the Th1 response, as an adjuvant to this vaccine, and we investigated its adjuvanticity and its potential to modulate immune responses to DPT vaccine. Administration of DPT vaccine with CpG-ODN (DPT-alum/ODN) to mice significantly reduced the total IgE levels and increased the anti-PT specific IgG2a titer in serum, in comparison with ordinary DPT vaccine (DPT-alum). Moreover, we investigated the antibody response to orally administrated ovalbumin (OVA) after vaccine administration. In the DPT-alum/ODN-administered group, the OVA specific IgE production in serum greatly decreased in comparison with that in the DPT-alum-administered group. These data indicate that CpG-ODN was not useful only as an efficient vaccine adjuvant but also shifted the immune responses substantially toward Th1 and modulated the Th1/Th2 immune response in DPT vaccine. These data suggested new applications of CpG-ODN as adjuvants in DPT vaccine.
    Vaccine 12/2005; 23(46-47):5450-6. · 3.49 Impact Factor
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    ABSTRACT: It is well known that cyclophosphamide (Cy) treatment before sensitization paradoxically enhances rather than suppresses contact hypersensitivity (CH) reactions. In fact, Cy-treated mice developed a significant (p < 0.05) increase of the CH reactions to 2,4,6-trinitro-1-chrolobenzene (TNCB) in comparison with untreated mice. In order to examine whether the target cells of Cy in the immuno-augmentative effect are CD25(+) CD4(+) regulatory T cells or not, we investigated effect of Cy treatment on CD25(+) CD4(+) T cells. We examined Cy-treated CD25(+) CD4(+) T cells by flow cytometer and by inhibition assay on proliferation of CD25(-) CD4(+) T cells. Cy treatment remarkably reduced the number and percentage of CD25(+) CD4(+) T cells in the spleen and lymph nodes 3 and 5 days later. Moreover, CD25(+) CD4(+) T cells taken from the Cy-treated mice 3 days later showed the lower suppressive activity on proliferation of CD25(-) CD4(+) T cells, as compared to that from the untreated mice. Furthermore, transfer of CD25(+) CD4(+) T cells from untreated mice resulted in a significant decrease (p < 0.05) of the CH reactions enhanced by Cy treatment. These results indicate that enhancement of the CH reactions to TNCB by Cy treatment is attributed to the decrease in the number, percentage and the function of CD25(+) CD4(+) regulatory T cells.
    Journal of Dermatological Science 08/2005; 39(2):105-12. · 3.52 Impact Factor

Publication Stats

555 Citations
115.32 Total Impact Points

Institutions

  • 1996–2013
    • Yokohama City University
      • • Department of Hematology
      • • Department of Medicine
      Yokohama, Kanagawa, Japan
  • 2007–2008
    • Toshiba Corporation
      Edo, Tōkyō, Japan
  • 1997
    • Centers for Disease Control and Prevention
      Atlanta, Michigan, United States