Publications (23)172.54 Total impact
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Article: Conditional ablation of CD205+ conventional dendritic cells impacts the regulation of T-cell immunity and homeostasis in vivo.
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ABSTRACT: Dendritic cells (DCs) are composed of multiple subsets that play a dual role in inducing immunity and tolerance. However, it is unclear how CD205(+) conventional DCs (cDCs) control immune responses in vivo. Here we generated knock-in mice with the selective conditional ablation of CD205(+) cDCs. CD205(+) cDCs contributed to antigen-specific priming of CD4(+) T cells under steady-state conditions, whereas they were dispensable for antigen-specific CD4(+) T-cell responses under inflammatory conditions. In contrast, CD205(+) cDCs were required for antigen-specific priming of CD8(+) T cells to generate cytotoxic T lymphocytes (CTLs) mediated through cross-presentation. Although CD205(+) cDCs were involved in the thymic generation of CD4(+) regulatory T cells (Tregs), they maintained the homeostasis of CD4(+) Tregs and CD4(+) effector T cells in peripheral and mucosal tissues. On the other hand, CD205(+) cDCs were involved in the inflammation triggered by Toll-like receptor ligand as well as bacterial and viral infections. Upon microbial infections, CD205(+) cDCs contributed to the cross-priming of CD8(+) T cells for generating antimicrobial CTLs to efficiently eliminate pathogens, whereas they suppressed antimicrobial CD4(+) T-cell responses. Thus, these findings reveal a critical role for CD205(+) cDCs in the regulation of T-cell immunity and homeostasis in vivo.Proceedings of the National Academy of Sciences 06/2012; 109(28):11288-93. · 9.68 Impact Factor -
Article: Plasmacytoid dendritic cells are crucial for the initiation of inflammation and T cell immunity in vivo.
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ABSTRACT: Plasmacytoid dendritic cells (pDCs) are characterized as type I interferon-producing cells that engage endosomal toll-like receptors (TLRs) and exclusively express sialic acid binding Ig-like lectin (Siglec)-H. However, their role in vivo remains unclear. Here we report a critical role for pDCs in the regulation of inflammation and T cell immunity in vivo by using gene-targeted mice with a deficiency of Siglec-H and conditional ablation of pDCs. pDCs were required for inflammation triggered by a TLR ligand as well as by bacterial and viral infections. pDCs controlled homeostasis of effector and regulatory CD4(+) T cells. Upon antigenic stimulation and microbial infection, pDCs suppressed the induction of CD4(+) T cell responses and participated in the initiation of CD8(+) T cell responses. Furthermore, Siglec-H appeared to modulate the function of pDCs in vivo. Thus, our findings highlight previously unidentified roles of pDCs and the regulation of their function for the control of innate and adaptive immunity.Immunity 12/2011; 35(6):958-71. · 21.64 Impact Factor -
Article: DCs in immune tolerance in steady-state conditions.
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ABSTRACT: Dendritic cells (DCs) are antigen-presenting cells (APCs) characterized by a unique capacity to stimulate naïve T cells and initiate primary immune responses. Recent studies suggest that DCs are also involved in the induction of immunological tolerance in peripheral tissues under steady-state conditions by maintaining the homeostasis of self-reactive CD4(+)Foxp3(+)naturally occurring thymic-derived regulatory T cells (nT(regs)) and de novo generation of antigen-specific CD4(+)Foxp3(+)inducible regulatory T cells (iT(regs)). We demonstrate here the impact of CD11(+)DCs on the antigen-specific differentiation of CD4(+)Foxp3(+)iT(regs) from CD4(+)Foxp3(-)T cells under steady-state and inflammatory conditions. CD11c(+)DCs promoted the transforming growth factor (TGF)-β1-mediated conversion of CD4(+)Foxp3(-)T cells into CD4(+)Foxp3(+)iT(regs) in vitro, while stimulation of CD11c(+)DCs with CpG oligodeoxynucleotide (ODN) abrogated this conversion. Furthermore, antigen-specific generation of CD4(+)Foxp3(+)iT(regs) required the function of CD11(+)DCs under steady-state conditions, whereas such conversion was severely abolished under inflammatory conditions. Thus, these results suggest the crucial role of DCs in the antigen-specific de novo conversion of CD4(+)Foxp3(-)T cells into CD4(+)Foxp3(+)iT(regs) under steady-state conditions, thereby leading to the establishment of peripheral immune tolerance.Methods in molecular biology (Clifton, N.J.) 01/2011; 677:113-26. -
Article: Crucial roles of B7-H1 and B7-DC expressed on mesenteric lymph node dendritic cells in the generation of antigen-specific CD4+Foxp3+ regulatory T cells in the establishment of oral tolerance.
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ABSTRACT: Oral tolerance is a key feature of intestinal immunity, generating systemic tolerance to fed antigens. However, the molecular mechanism mediating oral tolerance remains unclear. In this study, we examined the role of the B7 family members of costimulatory molecules in the establishment of oral tolerance. Deficiencies of B7-H1 and B7-DC abrogated the oral tolerance, accompanied by enhanced antigen-specific CD4(+) T-cell response and IgG(1) production. Mesenteric lymph node (MLN) dendritic cells (DCs) displayed higher levels of B7-H1 and B7-DC than systemic DCs, whereas they showed similar levels of CD80, CD86, and B7-H2. MLN DCs enhanced the antigen-specific generation of CD4(+)Foxp3(+) inducible regulatory T cells (iT(regs)) from CD4(+)Foxp3(-) T cells rather than CD4(+) effector T cells (T(eff)) relative to systemic DCs, owing to the dominant expression of B7-H1 and B7-DC. Furthermore, the antigen-specific conversion of CD4(+)Foxp3(-) T cells into CD4(+)Foxp3(+) iT(regs) occurred in MLNs greater than in peripheral organs during oral tolerance under steady-state conditions, and such conversion required B7-H1 and B7-DC more than other B7 family members, whereas it was severely impaired under inflammatory conditions. In conclusion, our findings suggest that B7-H1 and B7-DC expressed on MLN DCs are essential for establishing oral tolerance through the de novo generation of antigen-specific CD4(+)Foxp3(+) iT(regs).Blood 09/2010; 116(13):2266-76. · 9.90 Impact Factor -
Article: Naturally occurring regulatory dendritic cells regulate murine cutaneous chronic graft-versus-host disease.
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ABSTRACT: Chronic graft-versus-host disease (cGVHD) is a limiting factor in allogeneic hematopoietic stem cell transplantation (alloHSCT) for the treatment of leukemia and other malignancies. Relative to the process that initiates and promotes cGVHD, the regulation is poorly understood. In this study, we examined the role of naturally occurring regulatory dendritic cells (DC(regs)) in murine major histocompatibility complex (MHC)-compatible and multiple minor histocompatibility antigen (miHAg)-incompatible model of cGVHD in alloHSCT. DC(regs) generated from bone marrow in vitro (BM-DC(regs)) exclusively expressed CD200 receptor 3 (CD200R3), which exerted a suppressive function in the Ag-specific CD4(+) T-cell response. CD49(+)CD200R3(+) cells showed similarities in phenotype and function to BM-DC(regs), which formally distinguishes them from other leukocytes, suggesting that they are the natural counterpart of BM-DC(regs). Treatment of the recipient mice after alloHSCT with the recipient-type CD49(+)CD200R3(+) cells as well as BM-DC(regs) protected against cGVHD, and the protection was associated with the generation of Ag-specific anergic CD4(+) T cells as well as CD4(+)CD25(+)Foxp3(+) regulatory T cells (T(regs)) from donor-derived alloreactive CD4(+)CD25(-)Foxp3(-) T cells. In addition, the depletion of CD49(+)CD200R3(+) cells before alloHSCT enhanced the progression of cGVHD. In conclusion, CD49(+)CD200R3(+) cells act as naturally occurring DC(regs) to regulate the pathogenesis of cGVHD in alloHSCT mediated through the control of the transplanted alloreactive CD4(+) T cells.Blood 03/2009; 113(19):4780-9. · 9.90 Impact Factor -
Article: Regulatory dendritic cells protect against allergic airway inflammation in a murine asthmatic model.
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ABSTRACT: Dendritic cells (DCs) are crucial for the induction of immunity and tolerance. Despite an improved understanding of the DC-mediated control of T(H)1-biased immunity, little is known about how DCs regulate T(H)2-mediated immunity. The effects of immunostimulatory mature DCs (maDCs) and regulatory DCs (DCregs) on T(H)2-driven allergic immunity involving IgE production were examined. A murine model of airway hyperresponsiveness; the adoptive transfer of maDCs, DCregs, and T cells; and T-cell function were studied. Antigen-pulsed maDCs inhibited antigen-specific IgE production but enhanced the production of antigen-specific IgG1 and IgG2a. Analysis of Ifng-/- mice and Il21r-/- mice revealed that the inhibitory effect of antigen-pulsed maDCs on antigen-specific IgE production involved IL-21-producing T follicular helper cells but not IFN-gamma-producing T(H)1 cells. In contrast, antigen-pulsed DCregs impaired the production of antigen-specific IgE, IgG1, and IgG2a. In vivo blockade experiments showed that antigen-specific CD4+CD25+Foxp3+ regulatory T cells mainly mediated the suppressive effect of antigen-pulsed DCregs on the production of antigen-specific IgE. Antigen-pulsed maDCs promoted airway inflammation, whereas antigen-pulsed DCregs markedly suppressed the pathogenesis. DCregs abolish T(H)2-mediated IgE production and allergic inflammation based on antigen-specific dominant tolerance, whereas maDCs exacerbate the pathogenesis despite inhibiting the IgE response through the activation of diverse types of T(H) cell responses.The Journal of allergy and clinical immunology 02/2008; 121(1):95-104.e7. · 9.17 Impact Factor -
Article: Regulatory dendritic cells protect against cutaneous chronic graft-versus-host disease mediated through CD4+CD25+Foxp3+ regulatory T cells.
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ABSTRACT: Chronic graft-versus-host disease (cGVHD) is a common cause of morbidity and mortality in allogeneic bone marrow transplantation (alloBMT). However, effective strategies for the treatment of cGVHD have not been established. In this study, we examined the therapeutic utility of modified dendritic cells (DCs) with a greater capacity to regulate immune responses than previously known tolerogenic DCs, regulatory DCs (DC(regs)), in the major histocompatibility complex-compatible, and multiple minor histocompatibility antigen-incompatible model of cGVHD in alloBMT. Treatment of the recipient mice after alloBMT with the recipient-type DC(regs) led to greater suppression of the incidence and severity of cutaneous cGVHD than rapamycin, whereas treatment with the recipient-type mature DCs promoted the pathogenesis. Analysis of the recipient mice suggested that the protective effect of the recipient-type DC(regs) involved the peripheral generation of alloreactive CD4(+)CD25(+)Foxp3(+)regulatory T (T(R)) cells from donor-derived CD4(+)CD25(-)Foxp3(-) T cells. Thus, immunotherapy with DC(regs) is a promising strategy for the treatment of cGVHD in alloBMT mediated through the induction of a dominant tolerance involving CD4(+)CD25(+)Foxp3(+) T(R) cells.Blood 12/2007; 110(10):3793-803. · 9.90 Impact Factor -
Article: Construction of an open-access database that integrates cross-reference information from the transcriptome and proteome of immune cells.
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ABSTRACT: Although a huge amount of mammalian genomic data does become publicly available, there are still hurdles for biologists to overcome before such data can be fully exploited. One of the challenges for gaining biological insight from genomic data has been the inability to cross-reference transcriptomic and proteomic data using a single informational platform. To address this, we constructed an open-access database that enabled us to cross-reference transcriptomic and proteomic data obtained from immune cells. The database, named RefDIC (Reference genomics Database of Immune Cells), currently contains: (i) quantitative mRNA profiles for human and mouse immune cells/tissues obtained using Affymetrix GeneChip technology; (ii) quantitative protein profiles for mouse immune cells obtained using two-dimensional gel electrophoresis (2-DE) followed by image analysis and mass spectrometry and (iii) various visualization tools to cross-reference the mRNA and protein profiles of immune cells. RefDIC is the first open-access database for immunogenomics and serves as an important information-sharing platform, enabling a focused genomic approach in immunology. All raw data and information can be accessed from http://refdic.rcai.riken.jp/. The microarray data is also available at http://cibex.nig.ac.jp/ under CIBEX accession no. CBX19, and http://www.ebi.ac.uk/pride/ under PRIDE accession numbers 2354-2378 and 2414.Bioinformatics 12/2007; 23(21):2934-41. · 5.47 Impact Factor -
Article: Dendritic cells: nature and classification.
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ABSTRACT: Dendritic cells (DCs) are antigen (Ag)-presenting cells (APCs) characterized by a unique capacity to stimulate naive T cells and initiate primary immune responses. Recent studies suggest that DCs also play critical roles in the induction of central and peripheral immunological tolerance, regulate the types of T cell immune responses, and function as sentinels in innate immunity against microbes. The diverse functions of DCs in immune regulation depend on the heterogeneity of DC subsets and their functional plasticity. Here we review recent progress in our understanding of the nature and classification of DCs.Allergology International 10/2007; 56(3):183-91. -
Article: Targeting of antigen to dendritic cells with poly(gamma-glutamic acid) nanoparticles induces antigen-specific humoral and cellular immunity.
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ABSTRACT: Nanoparticles are considered to be efficient tools for inducing potent immune responses by an Ag carrier. In this study, we examined the effect of Ag-carrying biodegradable poly(gamma-glutamic acid) (gamma-PGA) nanoparticles (NPs) on the induction of immune responses in mice. The NPs were efficiently taken up by dendritic cells (DCs) and subsequently localized in the lysosomal compartments. gamma-PGA NPs strongly induced cytokine production, up-regulation of costimulatory molecules, and the enhancement of T cell stimulatory capacity in DCs. These maturational changes of DCs involved the MyD88-mediated NF-kappaB signaling pathway. In vivo, gamma-PGA NPs were preferentially internalized by APCs (DCs and macrophages) and induced the production of IL-12p40 and IL-6. The immunization of mice with OVA-carrying NPs induced Ag-specific CTL activity and Ag-specific production of IFN-gamma in splenocytes as well as potent production of Ag-specific IgG1 and IgG2a Abs in serum. Furthermore, immunization with NPs carrying a CD8(+) T cell epitope peptide of Listeria monocytogenes significantly protected the infected mice from death. These results suggest that Ag-carrying gamma-PGA NPs are capable of inducing strong cellular and humoral immune responses and might be potentially useful as effective vaccine adjuvants for the therapy of infectious diseases.The Journal of Immunology 04/2007; 178(5):2979-86. · 5.79 Impact Factor -
Article: Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response.
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ABSTRACT: Bacterial infection triggers host inflammation through the activation of immune cells, leading to the elimination of bacteria. However, the regulatory mechanisms of the host inflammatory response remain unknown. Here we report that a subset of potent tolerogenic dendritic cells (DCs), regulatory DCs (DC(regs)), control the systemic inflammatory response. Unlike normal DCs, which produced proinflammatory cytokines in response to bacterial lipopolysaccharide (LPS), DC(regs) produced fewer proinflammatory cytokines and instead preferentially produced interleukin-10 (IL-10), and these events involved the expression of IkappaBNS and Bcl-3 as well as cyclic AMP (cAMP)-mediated activation of protein kinase A (PKA). In addition, DC(regs) not only suppressed LPS-induced production of proinflammatory cytokines in macrophages, but also reduced their serum levels in mice. Furthermore, DC(regs) protected mice against the lethality induced by experimental endotoxemia and bacterial peritonitis. The inhibitory effect of DC(regs) against inflammatory responses involved the production of IL-10. On the other hand, naturally existing tolerogenic DC subsets producing IL-10, CD11c(low)CD45RB(high) DCs, also suppressed LPS-induced host inflammatory responses. Thus, a subset of tolerogenic DCs act as potential regulators of the host inflammatory response, and they might have preventive and therapeutic potential for the treatment of systemic as well as local inflammatory diseases.Blood 06/2006; 107(9):3656-64. · 9.90 Impact Factor -
Article: Role of CCL21 and CCL19 in allergic inflammation in the ovalbumin-specific murine asthmatic model.
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ABSTRACT: Dendritic cells are the most powerful of the antigen-presenting cells and are known to play important roles in sensitization and inflammation in allergen-specific asthma. Various cytokines and chemokines are involved in the maturation and activation of dendritic cells. Among them is CC chemokine ligand (CCL)21, a key chemokine in the entry of naive T cells and antigen-stimulated dendritic cells into the T-cell zones of secondary lymphoid organs, which is a critical process in antigen-specific T-cell activation. We studied the role of CCL21 in airway inflammation in asthma by using BALB/c-plt/plt (plt) mice, which possess genetic defects in expression of both CCL21 and CCL19. Plt and control BALB/c mice were immunized with ovalbumin and alum 4 times and thereafter were subjected to a 2-week regimen of ovalbumin inhalation. In plt mice, ovalbumin-specific IgE response was delayed compared with control BALB/c mice, but they had the same level of response after final immunization. Although airway inflammation and response to acetylcholine were significantly reduced compared with BALB/c mice, significant eosinophilic inflammation and hyperresponsiveness were also observed in plt mice after 2 weeks of inhalation. Four weeks after cessation of inhalation, airway inflammation and hyperresponsiveness in plt mice were greater than in BALB/c mice. At the time of resolution of airway inflammation, IL-10 production was enhanced in BALB/c mice but not in plt mice. The chemokines CCL21 and CCL19 were critical for resolution of airway inflammation. The findings about the chemokines for induction and resolution of inflammation are key to establishing a new strategy for asthma immunotherapy.Journal of Allergy and Clinical Immunology 06/2006; 117(5):1040-6. · 11.00 Impact Factor -
Article: Carbonic anhydrase II is a tumor vessel endothelium-associated antigen targeted by dendritic cell therapy.
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ABSTRACT: Tumor-associated antigens are promising candidates as target molecules for immunotherapy and a wide variety of tumor-associated antigens have been discovered through the presence of serum antibodies in cancer patients. We previously conducted dendritic cell therapy on 10 malignant melanoma patients and shrinkage or disappearance of metastatic tumors with massive necrosis occurred in two patients. In this study, we found a 29-kDa protein against which antibody was elicited by dendritic cell therapy in one of the two patients. Matrix-assisted laser desorption ionization-time of flight/mass spectrometry analysis of the protein isolated by two-dimensional electrophoresis combined with Western blots revealed that the 29-kDa protein was carbonic anhydrase II (CA-II). Immunohistochemistry of the tumors and normal tissues showed that CA-II was expressed in the tumor vessel but not in normal vessel endothelium. CA-II expression in tumor endothelium was observed as well in other cancers including esophageal, renal, and lung cancers. In an in vitro angiogenesis model, CA-II expression of normal human vein endothelial cells was significantly up-regulated when cells were cultured in the acidic and hypoxic conditions indicative of a tumor environment. These findings suggest that CA-II is a tumor vessel endothelium-associated antigen in melanoma and other cancers, and elicitation of serum anti-CA-II antibody by dendritic cell therapy may be associated with good clinical outcome including tumor reduction.Clinical Cancer Research 12/2005; 11(22):8201-7. · 7.74 Impact Factor -
Article: Effectiveness of anti-folate receptor beta antibody conjugated with truncated Pseudomonas exotoxin in the targeting of rheumatoid arthritis synovial macrophages.
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ABSTRACT: To define the distribution of folate receptor beta (FRbeta)-expressing cells in various tissues, including rheumatoid arthritis (RA) synovial tissues, and to verify the effects of an immunotoxin composed of an anti-FRbeta monoclonal antibody (mAb) and truncated Pseudomonas exotoxin A (PEA) on apoptosis and tumor necrosis factor alpha (TNFalpha) production by adherent synovial mononuclear cells from RA patients. Anti-FRbeta mAb were produced by immunizing mice with FRbeta-transfected murine pre-B cells. The distribution of the FRbeta antigen was examined by immunohistochemical analysis using anti-FRbeta mAb and macrophage-specific anti-CD163 mAb. Anti-FRbeta mAb was chemically crosslinked with truncated PEA. FRbeta-expressing macrophages were produced by the transfection of adenovirus vector containing the FRbeta gene. Apoptotic cells were detected by staining with propidium iodide. TNFalpha was measured by enzyme-linked immunosorbent assay. FRbeta-expressing cells were not present in peripheral blood leukocytes and their activated cells. In all of the tissues examined, most FRbeta-expressing cells were CD163+. The immunotoxin significantly induced the apoptosis of FRbeta-transfected macrophages and adherent RA synovial mononuclear cells and inhibited TNFalpha production by adherent RA synovial mononuclear cells. We demonstrated the limited distribution of FRbeta-expressing cells in various tissues. The immunotoxin targeting FRbeta-expressing cells will provide a therapeutic tool for rheumatoid synovitis.Arthritis & Rheumatism 10/2005; 52(9):2666-75. · 7.87 Impact Factor -
Article: Induction of dendritic cell-mediated immune responses against HIV-1 by antigen-capturing nanospheres in mice.
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ABSTRACT: Prophylactic vaccines, designed to elicit potent humoral and cellular immune responses to human immunodeficiency virus type 1 (HIV-1) antigens in mucosa, are the important approach to the protection of individuals against HIV-1 infection, since HIV-1 transmission is largely a result of sexual contact. In this study, a novel strategy has been developed to induce HIV-1-specific immune responses, which involves inactivated HIV-1-caputring concanavalin A (Con A)-immobilized nanospheres (HIV-NS) and their interaction with bone marrow (BM)-derived dendritic cells. HIV-NS were taken up by dendritic cells via cytoskeleton-dependent but mannose-binding site-independent phagocytosis. Serial stimulations to unprimed T-cells with HIV-1 gp120-capturing NS-pulsed dendritic cells could induce antigen-specific T-cell response. Intranasal administration of fluorescein isothiocyanate-labeled nanospheres (NS) in mice proved that the particles were taken up into pulmonary dendritic cells. Analysis of mice receiving intranasal immunizations with HIV-NS revealed that the mice efficiently induced the antibodies against HIV-1 in the genital tract and specific cytotoxic T-cells in the spleen. These results suggest that the use of HIV-1-NS may provide a novel and promising approach for the induction of humoral and cellular immune responses to HIV-1.Journal of Medical Virology 06/2005; 76(1):7-15. · 2.82 Impact Factor -
Article: TRAIL-transduced dendritic cells protect mice from acute graft-versus-host disease and leukemia relapse.
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ABSTRACT: TRAIL preferentially induces apoptotic cell death in a wide variety of transformed cells, whereas it induces no apoptosis, but inhibits activation of Ag-specific T cells via blockade of cell cycle progression. Although accumulating results suggest that TRAIL is involved in the maintenance of immunological homeostasis under steady state conditions as well as in the initiation and progression of immunopathologies, the potential regulatory effect of TRAIL on immune responses and its therapeutic potential in immunological diseases remains unclear. We report in this study the potential usefulness of TRAIL-transduced dendritic cells (DCs) for the treatment of lethal acute graft-vs-host disease (GVHD) and leukemia relapse. DCs genetically modified to express TRAIL showed potent cytotoxicity against both alloreactive T cells and leukemic cells through the induction of apoptosis. In addition, treatment with genetically modified DCs expressing TRAIL of allogeneic BM transplants recipients with leukemia was effective for protection against acute GVHD and leukemia relapse. Thus, gene transfer of TRAIL to DCs is a novel modality for the treatment of acute GVHD and leukemia relapse by selective targeting of pathogenic T cells and leukemic cells.The Journal of Immunology 05/2005; 174(7):4025-33. · 5.79 Impact Factor -
Article: Potent activation of antigen-specific T cells by antigen-loaded nanospheres.
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ABSTRACT: Polystyrene nanospheres (NS) were found to be efficiently taken up by murine antigen-presenting cells (APC), especially bone marrow-derived dendritic cells (DC), in vitro and in vivo. The efficiency of NS uptake was not affected by the maturation state of DC. Both immature and mature DC had similar ability to take up NS in a dose- and time-dependent manner. Uptake and intracellular localization of NS was clearly demonstrated by confocal laser microscopy, using NS with fluorescence. DC could efficiently take up ovalbumin (OVA), when loaded on the surface of NS (OVA-NS). Consequently, OVA-NS-pulsed DC activated antigen-specific interferon (IFN)-gamma-producing T cells much more strongly than OVA-pulsed DC in vitro. These results suggest that NS can be used as an efficient antigen delivery system to DC for a variety of vaccines, such as an anti-human immunodeficiency virus type 1 vaccine.Immunology Letters 05/2005; 98(1):123-30. · 2.53 Impact Factor -
Article: Thyroglobulin-pulsed human monocyte-derived dendritic cells induce CD4+ T cell activation.
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ABSTRACT: Although thyroglobulin (Tg) would be expected to act as a tumor-associated antigen that might be exploitable by immunotherapy against thyroid cancers, it remains unclear how to effectively enhance the immune response to Tg in human since it is a self-component glycoprotein. We therefore tested whether and how human peripheral blood (PB) monocyte-derived dendritic cells (DCs) pulsed with human (h)Tg would induce activation of hTg-specific T cells. We found that immature DCs (iDCs) exhibited a higher endocytic capacity for fluorescein isothiocyanate-conjugated hTg than did mature DCs (mDCs). Although freshly isolated T cells responded poorly to mDCs, hTg-primed T cells responded much more strongly to hTg pulsed mDCs, which selectively induced IFN-gamma-secreting T cells. These results suggest that hTg-pulsed mDCs enhance the responses of Tg-specific T cells, raising the possibility that vaccination with hTg-pulsed mDCs may be an effective approach as immunotherapy to potentiate thyroid cancer specific therapy.International Journal of Molecular Medicine 02/2004; 13(1):33-9. · 1.98 Impact Factor -
Article: Results of a phase I clinical study using autologous tumour lysate-pulsed monocyte-derived mature dendritic cell vaccinations for stage IV malignant melanoma patients combined with low dose interleukin-2.
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ABSTRACT: We conducted a pilot study to assess the feasibility and efficacy of immunotherapy for stage IV malignant melanoma patients resistant to conventional therapies involving vaccination with mature dendritic cells (mDCs) combined with administration of low dose interleukin-2. Autologous monocytes were harvested from a single apheresis and cultured for 7 days with granulocyte-macrophage colony-stimulating factor and interleukin-4, yielding immature dendritic cells (iDCs), which were then cryopreserved until use. For 4 days prior to vaccination, iDCs were exposed to autologous tumour lysate combined with tumour necrosis factor-alpha to induce terminal differentiation into mDCs. Patients were then vaccinated weekly with 107 mDCs for 10 weeks and given 350-700 kIU of interleukin-2 three times per week. Of the 10 patients in the study, one showed stable disease, seven showed progressive disease, and two showed mixed responses, including partial tumour regression, and were therefore given 20 additional injections. Only minimal adverse events were noted, including localized skin reactions and mild fever (NIH-CTC grade 0-1). Median survival from the first vaccination was 240 days (range 31-735 days). In vitro, melanoma patient-derived dendritic cells (DCs) showed reduced cell surface expression of CD1a antigen on iDCs and reduced CD86 and HLA-DR expression on mDCs. In addition, antigen uptake, chemotaxis and antigen presentation were all attenuated in DCs from the patients. In summary, although improvement of clinical efficacy will require further research, autologous tumour lysate-pulsed monocyte-derived mDCs could be safely harvested, cryopreserved and administrated to patients without obvious complications.Melanoma Research 11/2003; 13(5):521-30. · 2.19 Impact Factor -
Article: Modified myeloid dendritic cells act as regulatory dendritic cells to induce anergic and regulatory T cells.
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ABSTRACT: To exploit a novel strategy to regulate T cell-mediated immunity, we established human and murine modified dendritic cells (DCs) with potent immunoregulatory properties (designed as regulatory DCs), which displayed moderately high expression levels of major histocompatibility complex (MHC) molecules and extremely low levels of costimulatory molecules compared with their normal counterparts. Unlike human normal DCs, which caused the activation of allogeneic CD4(+) and CD8(+) T cells, human regulatory DCs not only induced their anergic state but also generated CD4(+) or CD8(+) regulatory T (Tr) cells from their respective naive subsets in vitro. Although murine normal DCs activated human xenoreactive T cells in vitro, murine regulatory DCs induced their hyporesponsiveness. Furthermore, transplantation of the primed human T cells with murine normal DCs into severe combined immunodeficient (SCID) mice enhanced the lethality caused by xenogeneic graft-versus-host disease (XGVHD), whereas transplantation of the primed human T cells with murine regulatory DCs impaired their ability to cause XGVHD. In addition, a single injection of murine regulatory DCs following xenogeneic or allogeneic transplantation protected the recipients from the lethality caused by XGVHD as well as allogeneic acute GVHD. Thus, the modulation of T cell-mediated immunity by regulatory DCs provides a novel therapeutic approach for immunopathogenic diseases.Blood 06/2003; 101(9):3581-9. · 9.90 Impact Factor
Top co-authors
Top Journals
- Blood (3)
- The Journal of Immunology (3)
- Blood (2)
- Arthritis & Rheumatism (1)
- Cellular Immunology (1)
Institutions
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2005–2007
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RIKEN
Wako, Saitama-ken, Japan
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2003–2005
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The University of Tokyo
- • Institute of Medical Science
- • Department of Medical Science
Tokyo, Tokyo-to, Japan
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2002–2005
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Kagoshima University
- • Graduate School of Medical and Dental Sciences
- • Division of Human Retroviruses
- • School of Medicine
Kagoshima-shi, Kagoshima-ken, Japan
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