Genetically Manipulated Human Embryonic Stem Cell-Derived Dendritic Cells with Immune Regulatory Function

Senju, Satoru; Suemori, Hirofumi; Zembutsu, Hitoshi; Uemura, Yukari; Hirata, Satoshi; Fukuma, Daiki; Matsuyoshi, Hidetake; Shimomura, Manami; Haruta, Miwa; Fukushima, Satoshi; Matsunaga, Yusuke; Katagiri, Toyomasa; Nakamura, Yusuke; Furuya, Masataka; Nakatsuji, Norio; Nishimura, Yasuharu

doi:10.1634/stemcells.2007-0321

Cited by 61 publications

(43 citation statements)

References 36 publications

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“…For these purposes, administration of genetically modified DCs with enhanced immune-regulatory functions may be a promising strategy. Using directed differentiation of embryonic stem cells or induced pluripotent stem cells into DCs, we have developed efficient methods for genetically engineering mouse and human DCs (25,36,37). Among the molecules implicated in immune-regulatory functions, we found that TRAIL was the were stimulated with plate-bound anti-CD3 (3 mg/ml) and anti-CD28 mAb (3 mg/ml) and human IL-2 (20 U/ml) for 72 h. Then, mDR5, mDc-TRAIL-R1, and mDcTRAIL-R2 on each T cell subset were analyzed by flow cytometry.…”

Section: Discussionmentioning

confidence: 99%

Dual Effects of TRAIL in Suppression of Autoimmunity: The Inhibition of Th1 Cells and the Promotion of Regulatory T Cells

Ikeda

Hirata

Fukushima

et al. 2010

The Journal of Immunology

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TRAIL is known to play a pivotal role in the inhibition of autoimmune disease. We previously demonstrated that administration of dendritic cells engineered to express TRAIL and myelin-oligodendrocyte glycoprotein reduced the severity of experimental autoimmune encephalomyelitis and suggested that CD4+CD25+ regulatory T cells (Tregs) were involved in mediating this preventive effect. In the current study, we investigated the effect of TRAIL on Tregs, as well as conventional T cells, using TRAIL-deficient mice. Upon induction of experimental autoimmune encephalomyelitis, TRAIL-deficient mice showed more severe clinical symptoms, a greater frequency of IFN-γ–producing CD4+ T (Th1) cells, and a lower frequency of CD4+Foxp3+ Tregs than did wild-type mice. In vitro, conventional T cells stimulated by bone marrow-derived dendritic cells (BM-DCs) from TRAIL-deficient mice showed a greater magnitude of proliferation than did those stimulated by BM-DCs from wild-type mice. In contrast, TRAIL expressed on the stimulator BM-DCs enhanced the proliferative response of CD4+CD25+ Tregs in the culture. The functional TRAILR, mouse death receptor 5 (mDR5), was expressed in conventional T cells and Tregs upon stimulation. In contrast, the decoy receptor, mDc-TRAILR1, was slightly expressed only on CD4+CD25+ Tregs. Therefore, the distinct effects of TRAIL may be due to differences in the mDc-TRAILR1 expression or the signaling pathways downstream of mouse death receptor 5 between the two T cell subsets. Our data suggest that TRAIL suppresses autoimmunity by two mechanisms: the inhibition of Th1 cells and the promotion of Tregs.

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Section: Discussionmentioning

confidence: 99%

Dual Effects of TRAIL in Suppression of Autoimmunity: The Inhibition of Th1 Cells and the Promotion of Regulatory T Cells

Ikeda

Hirata

Fukushima

et al. 2010

The Journal of Immunology

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“…Several groups have previously established methods to generate APC or DCs from mouse [1,2] and human [3][4][5] embryonic stem (ES) cells (ES-DCs). Genetic engineering of ES-DCs can readily be done by the introduction of transgenes into undifferentiated ES cells and subsequent differentiation of the ES cell clones into ES-DCs.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Dendritic Cells and Macrophages Generated by Directed Differentiation from Mouse Induced Pluripotent Stem Cells

et al. 2009

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Methods have been established to generate dendritic cells (DCs) from mouse and human embryonic stem (ES) cells. We designated them as ES-DCs and mouse models have demonstrated the induction of anti-cancer immunity and prevention of autoimmune disease by in vivo administration of genetically engineered ES-DCs. For the future clinical application of ES-DCs, the histoincompatibility between patients to be treated and available human ES cells and the ethical concerns associated with human ES cells may be serious obstacles. However, recently developed induced pluripotent stem (iPS) cell technology is expected to resolve these issues. This report describes the generation and characterization of DCs derived from mouse iPS cells. The iPS cell-derived DCs (iPS-DCs) possessed the characteristics of DCs including the capacity of T-cell-stimulation, antigen-processing and presentation and cytokine production. DNA microarray analyses revealed the upregulation of genes related to antigen-presenting functions during differentiation into iPS-DCs and similarity in gene expression profile in iPS-DCs and bone marrow cell-derived DCs. Genetically modified iPS-DCs expressing antigenic protein primed T-cells specific to the antigen in vivo and elicited efficient antigen-specific antitumor immunity. In addition, macrophages were generated from iPS cells (iPS-MP). iPS-MP were comparable with bone marrow cell-derived macrophages in the cell surface phenotype, functions, and gene expression profiles.

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“…Considering future clinical application of ES-DC, we also tried to generate ES-DC from human ES cells [12]. Based on experience in the generation of DC from mouse ES cells and also based on the findings in a preliminary study using cynomolgus monkey ES cells [18], feeder cell-co-culture method was adopted for the generation of DC from human ES cells, instead of the EB based method.…”

Section: Generation Of Human Es-dc Based On Op9-co-culturementioning

confidence: 99%

“…KhES-3 differentiation was similar to KhES-1 except that KhES-3 differentiated slightly more quickly than KhES-1, and a first step culture of 14-15 days was sufficient for the differentiation of KhES-3. Generation of ES-DC from nonhuman primate, cynomolgus monkey, ES cells was also achieved by this method [12].…”

Section: Generation Of Human Es-dc Based On Op9-co-culturementioning

confidence: 99%

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Pluripotent stem cells as source of dendritic cells for immune therapy

et al. 2010

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Dendritic cells (DC) are the most potent antigen-presenting cells. In vivo transfer of antigen-bearing DC has proven efficient in priming T cell responses specific to the antigen. DC-based cellular vaccination is now regarded as a powerful means for immunotherapy, especially for anti-cancer immunotherapy. Clinical trials of therapy with DC pulsed with peptide antigens or genetically modified to present antigens are currently carried out in many institutions. In addition, antigen-specific negative regulation of immune response by DC is considered to be a promising approach for treatments of autoimmune diseases and also for regulation of allo-reactive immune response causing graft rejection and GVHD in transplantation medicine. DC for transfer therapy are now generated by in vitro differentiation of peripheral blood monocytes of the patients. However, there is a limitation in the number of available monocytes, and the DC-differentiation potential of monocytes varies depending on the blood donor. Embryonic stem (ES) cells possess both pluripotency and infinite propagation capacity. We consider ES cells to be an ideal source for DC to be used in immunotherapy. Several groups, including us, have developed methods to generate DC from ES cells. This review introduces the studies on generation, characterization, and genetic modification of DC derived from ES cells or induced pluripotent stem (iPS) cells. The issues to be resolved before clinical application of pluripotent stem cell-derived DC will also be discussed.

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Genetically Manipulated Human Embryonic Stem Cell-Derived Dendritic Cells with Immune Regulatory Function

Abstract: STEM CELLS 2007;25:2720 -2729 Disclosure of potential conflicts of interest is found at the end of this article.

Cited by 61 publications

References 36 publications

Dual Effects of TRAIL in Suppression of Autoimmunity: The Inhibition of Th1 Cells and the Promotion of Regulatory T Cells

Dual Effects of TRAIL in Suppression of Autoimmunity: The Inhibition of Th1 Cells and the Promotion of Regulatory T Cells

Characterization of Dendritic Cells and Macrophages Generated by Directed Differentiation from Mouse Induced Pluripotent Stem Cells

Pluripotent stem cells as source of dendritic cells for immune therapy

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