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ABSTRACT: KRN7000 is one of the α-galactosylceramides, which has a 2-hexacosanoylamino-3,4-dihydroxyoctadecyl group. This compound, known as a ligand for the activation of CD1d mediated invariant natural killer T cells (iNKT cells) which release both T helper 1 (Th1) cytokines such as IFNγ and Th2 cytokines such as IL-4, has been anticipated as an antitumor drug, because of its strong secretion of IFNγ. This time, we focused on the hydroxylated analogues of KRN7000 which could be thought of as increasing hydrophilicity and showing bias to Th2 cytokine (IL-4) secretion. Therefore, they may become the drugs for autoimmune diseases for the following reasons: (i) compound OCH, one of the α-galactosylceramide analogues with a shorter sphingosine chain than KRN7000, increases hydrophilicity relative to KRN7000; and (ii) OCH is known to induce much more Th2 cytokines (IL-4) than Th1 cytokines from iNKT cells compared to KRN7000. Naturally, OCH has become one of the candidate drugs for autoimmune diseases. The more hydroxylated derivatives of KRN7000 are anticipated to induce Th2 bias. Therefore, eight analogues with 1-4 excess hydroxyl groups on the lipid chain of KRN7000 were synthesized to examine if they behave in the same way as OCH. As a result, three out of eight compounds biased largely to IL-4 secretion, and their effectiveness for experimental autoimmune encephalomyelitis (EAE) was examined. It was recognized that two compounds RCAI-147/-160 showed good suppression of EAE symptoms.
Carbohydrate research 04/2013; 370:46-66. · 2.03 Impact Factor
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ABSTRACT: We synthesized ten new analogs of 6'-modified KRN7000 (A): RCAI-58, 61, 64, 83, 85-87, 113, 119, and 125. They could be synthesized by α-selective galactosylation of ceramide 9 with the 6-modified d-galactopyranosyl fluorides (8a-8f) or l-arabinopyranosyl fluoride (17), or by etherification of the known alcohol 19. Bioassay of the ten analogs demonstrated that RCAI-61 (1, 6'-O-methylated analog of A) was the most potent immunostimulant among them, and could induce the production of a large amount of IFN-γ even at a low concentration in mice in vivo.
Bioorganic & medicinal chemistry 03/2013; · 2.82 Impact Factor
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Mochamad Ali Sobirin,
Shintaro Kinugawa,
Masashige Takahashi,
Arata Fukushima,
Tsuneaki Homma,
Taisuke Ono,
Kagami Hirabayashi,
Tadashi Suga,
Putri Azalia,
Shingo Takada, Masaru Taniguchi,
Toshinori Nakayama,
Naoki Ishimori,
Kazuya Iwabuchi,
Hiroyuki Tsutsui
[show abstract]
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ABSTRACT: Rationale: Chronic inflammation in the myocardium is involved in the development of left ventricular (LV) remodeling and failure after myocardial infarction (MI). Invariant natural killer T (iNKT) cells have been shown to produce inflammatory cytokines and orchestrate tissue inflammation. However, no previous studies have determined the pathophysiological role of iNKT cells in post-MI LV remodeling. Objective: The purpose of this study was to examine whether the activation of iNKT cells might affect the development of LV remodeling and failure. Methods and Results: After creation of MI, mice received the injection of either α-galactosylceramide (αGC; n=27), the activator of iNKT cells, or phosphate-buffered saline (n=31) 1 and 4 days after surgery, and were followed during 28 days. Survival rate was significantly higher in MI+αGC than MI+PBS (59% versus 32%, P<0.05). LV cavity dilatation and dysfunction were significantly attenuated in MI+αGC, despite comparable infarct size, accompanied by a decrease in myocyte hypertrophy, interstitial fibrosis, and apoptosis. The infiltration of iNKT cells were increased during early phase in noninfarcted LV from MI and αGC further enhanced them. It also enhanced LV interleukin (IL)-10 gene expression at 7 days, which persisted until 28 days. AntienIL-10 receptor antibody abrogated these protective effects of αGC on MI remodeling. The administration of αGC into iNKT cell-deficient Jα18(-/-) mice had no such effects, suggesting that αGC was a specific activator of iNKT cells. Conclusions: iNKT cells play a protective role against post-MI LV remodeling and failure through the enhanced expression of cardioprotective cytokines such as IL-10.
Circulation Research 08/2012; 111(8):1037-47. · 9.49 Impact Factor
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ABSTRACT: RCAI-84, 91, and 105-108 (1-6), the analogs of KRN7000 (A) with a ureido or a thioureido linkage instead of a carboxamido bond, were synthesized to examine their immunostimulatory activity against mouse lymphocytes. According to their bioassay, the ureido analog of KRN7000 [RCAI-105 (1)] and its 6'-O-methylated derivative [RCAI-106 (4)] induced a large amount of IFN-γ in mice in vivo. The hexadecyl ureido analog [RCAI-84 (2)] was comparable to KRN7000 in its bioactivity. The octylureido [RCAI-107 (3)], 5-phenylpentylureido [RCAI-108 (5)], and thioureido [RCAI-91 (6)] analogs were almost inactive.
Bioorganic & medicinal chemistry 06/2012; 20(14):4540-8. · 2.82 Impact Factor
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Arerugī = [Allergy] 06/2012; 61(6):798-804.
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ABSTRACT: Invariant natural killer T (iNKT) cells are characterized by the expression of an invariant Vα14-Jα18 paired with Vβ8/7/2 in mice, and Vα24-Jα18 with Vβ11 in humans, that recognizes glycolipids, such as α-galactosylceramide (α-GalCer), presented on the MHC class I-like molecule, CD1d. iNKT cells act as innate T lymphocytes and serve as a bridge between the innate and acquired immune systems. iNKT cells augment anti-tumor responses by producing IFN-γ, which acts on NK cells to eliminate MHC-non-restricted (MHC(-)) target tumor cells, and on CD8(+) cytotoxic T lymphocytes to directly kill MHC-restricted (MHC(+)) tumor cells. Thus, when iNKT cells are activated by α-GalCer-pulsed dendritic cells, both MHC(-) and MHC(+) tumor cells can be effectively eliminated. Both of these tumor cell types are simultaneously present in cancer patients, and at present iNKT cells are only the cell type capable of eliminating them. Based on these findings, we have developed iNKT cell-targeted adjuvant immunotherapies with strong anti-tumor activity in humans. However, two-thirds of patients were ineligible for this therapy due to the limited numbers of iNKT cells in their bodies. In order to overcome the problem in cancer patients, we successfully established a method to generate iNKT cells with adjuvant activity from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). In this review, we would like to outline the clinical potential for iNKT cells derived from ESCs and iPSCs for cancer immunotherapy, and the technical hurdles that must be overcome if we achieve effective ESC/iPSC-mediated cancer therapies.
International journal of hematology 05/2012; 95(6):624-31. · 1.17 Impact Factor
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Kaoru Nagato,
Shinichiro Motohashi,
Fumihiro Ishibashi,
Kohsuke Okita,
Kazuki Yamasaki,
Yasumitsu Moriya,
Hidehisa Hoshino,
Shigetoshi Yoshida,
Hideki Hanaoka,
Shin-Ichiro Fujii, Masaru Taniguchi,
Ichiro Yoshino,
Toshinori Nakayama
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ABSTRACT: The intravenous administration of α-Galactosylceramide (α-GalCer)-pulsed antigen presenting cells (APCs) is well tolerated and the increased IFN-γ producing cells in the peripheral blood after the treatment appeared to be associated with prolonged survival. An exploratory study protocol was designed with the preoperative administration of α-GalCer-pulsed APCs to clarify the mechanisms of these findings, while especially focusing on the precise tumor site.
Patients with operable advanced lung cancer received an intravenous injection of α-GalCer-pulsed APCs before surgery. The resected lung and tumor infiltrating lymphocytes (TILs) as well as peripheral blood mononuclear cells were collected and the invariant NKT (iNKT) cell-specific immune responses were analyzed.
Four patients completed the study protocol. We observed a significant increase in iNKT cell numbers in the TILs and augmented IFN-γ production by the α-GalCer-stimulated TILs.
The administration of α-GalCer-pulsed APCs successfully induced the dramatic infiltration and activation of iNKT cells in the tumor microenvironment.
Journal of Clinical Immunology 04/2012; 32(5):1071-81. · 3.08 Impact Factor
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Hiroshi Watarai,
Etsuko Sekine-Kondo,
Tomokuni Shigeura,
Yasutaka Motomura,
Takuwa Yasuda,
Rumi Satoh,
Hisahiro Yoshida,
Masato Kubo,
Hiroshi Kawamoto,
Haruhiko Koseki, Masaru Taniguchi
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ABSTRACT: There is heterogeneity in invariant natural killer T (iNKT) cells based on the expression of CD4 and the IL-17 receptor B (IL-17RB), a receptor for IL-25 which is a key factor in T(H)2 immunity. However, the development pathway and precise function of these iNKT cell subtypes remain unknown. IL-17RB⁺iNKT cells are present in the thymic CD44⁺/⁻ NK1.1⁻ population and develop normally even in the absence of IL-15, which is required for maturation and homeostasis of IL-17RB⁻iNKT cells producing IFN-γ. These results suggest that iNKT cells contain at least two subtypes, IL-17RB⁺ and IL-17RB⁻ subsets. The IL-17RB⁺iNKT subtypes can be further divided into two subtypes on the basis of CD4 expression both in the thymus and in the periphery. CD4⁺ IL-17RB⁺iNKT cells produce T(H)2 (IL-13), T(H)9 (IL-9 and IL-10), and T(H)17 (IL-17A and IL-22) cytokines in response to IL-25 in an E4BP4-dependent fashion, whereas CD4⁻ IL-17RB⁺iNKT cells are a retinoic acid receptor-related orphan receptor (ROR)γt⁺ subset producing T(H)17 cytokines upon stimulation with IL-23 in an E4BP4-independent fashion. These IL-17RB⁺iNKT cell subtypes are abundantly present in the lung in the steady state and mediate the pathogenesis in virus-induced airway hyperreactivity (AHR). In this study we demonstrated that the IL-17RB⁺iNKT cell subsets develop distinct from classical iNKT cell developmental stages in the thymus and play important roles in the pathogenesis of airway diseases.
PLoS Biology 02/2012; 10(2):e1001255. · 11.45 Impact Factor
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Masashi Satoh,
Yasuhiro Andoh,
Christopher Stuart Clingan,
Hisako Ogura,
Satoshi Fujii,
Koji Eshima,
Toshinori Nakayama, Masaru Taniguchi,
Noriyuki Hirata,
Naoki Ishimori,
Hiroyuki Tsutsui,
Kazunori Onoé,
Kazuya Iwabuchi
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ABSTRACT: The progression of obesity is accompanied by a chronic inflammatory process that involves both innate and acquired immunity. Natural killer T (NKT) cells recognize lipid antigens and are also distributed in adipose tissue. To examine the involvement of NKT cells in the development of obesity, C57BL/6 mice (wild type; WT), and two NKT-cell-deficient strains, Jα18(-/-) mice that lack the type I subset and CD1d(-/-) mice that lack both the type I and II subsets, were fed a high fat diet (HFD). CD1d(-/-) mice gained the least body weight with the least weight in perigonadal and brown adipose tissue as well as in the liver, compared to WT or Jα18(-/-) mice fed an HFD. Histologically, CD1d(-/-) mice had significantly smaller adipocytes and developed significantly milder hepatosteatosis than WT or Jα18(-/-) mice. The number of NK1.1(+)TCRβ(+) cells in adipose tissue increased when WT mice were fed an HFD and were mostly invariant Vα14Jα18-negative. CD11b(+) macrophages (Mφ) were another major subset of cells in adipose tissue infiltrates, and they were divided into F4/80(high) and F4/80(low) cells. The F4/80(low)-Mφ subset in adipose tissue was increased in CD1d(-/-) mice, and this population likely played an anti-inflammatory role. Glucose intolerance and insulin resistance in CD1d(-/-) mice were not aggravated as in WT or Jα18(-/-) mice fed an HFD, likely due to a lower grade of inflammation and adiposity. Collectively, our findings provide evidence that type II NKT cells initiate inflammation in the liver and adipose tissue and exacerbate the course of obesity that leads to insulin resistance.
PLoS ONE 01/2012; 7(2):e30568. · 4.09 Impact Factor
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ABSTRACT: Immunotherapy is considered to be the only curative treatment for allergic diseases such as pollinosis, perennial rhinitis, asthma, and food allergy. The sublingual route is widely applied for immunotherapy for allergy, instead of the conventional administration by subcutaneous route. A recent meta-analysis of sublingual immunotherapy (SLIT) has shown that this approach is safe, has positive clinical effects, and provides prolonged therapeutic effects after discontinuation of treatment. However, the mechanism of SLIT and associated biomarkers are not fully understood. Biomarkers that change after or during SLIT have been reported and may be useful for response monitoring or as prognostic indicators for SLIT. In this review, we focus on the safety, therapeutic effects, including prolonged effects after treatment, and new methods of SLIT. We also discuss response monitoring and prognostic biomarkers for SLIT. Finally, we discuss immunological mechanisms of SLIT with a focus on oral dendritic cells and facilitated antigen presentation.
Journal of Allergy 01/2012; 2012:381737.
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Hideki Fujii,
Manabu Ato,
Yoshimasa Takahashi,
Kaori Otake,
Shu-Ichi Hashimoto,
Tomohiro Kaji,
Yasuko Tsunetsugu-Yokota,
Mikako Fujita,
Akio Adachi,
Toshinori Nakayama, Masaru Taniguchi,
Shigeo Koyasu,
Toshitada Takemori
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ABSTRACT: The viral protein Nef is a key element for the progression of HIV disease. Previous in vitro studies suggested that Nef expression in T-cell lines enhanced TCR signaling pathways upon stimulation with TCR cross-linking, leading to the proposal that Nef lowers the threshold of T-cell activation, thus increasing susceptibility to viral replication in immune response. Likewise, the in vivo effects of Nef transgenic mouse models supported T-cell hyperresponse by Nef. However, the interpretation is complicated by Nef expression early in the development of T cells in these animal models. Here, we analyzed the consequence of Nef expression in ovalbumin-specific/CD4(+) peripheral T cells by using a novel mouse model and demonstrate that Nef inhibits antigen-specific T-cell proliferation and multiple functions required for immune response in vivo, which includes T-cell helper activity for the primary and memory B-cell response. However, Nef does not completely abrogate T-cell activity, as defined by low levels of cytokine production, which may afford the virus a replicative advantage. These results support a model, in which Nef expression does not cause T-cell hyperresponse in immune reaction, but instead reduces the T-cell activity, that may contribute to a low level of virus spread without viral cytopathic effects.
International Immunology 07/2011; 23(7):433-41. · 3.41 Impact Factor
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Yasutaka Motomura,
Hiroshi Kitamura,
Atsushi Hijikata,
Yuko Matsunaga,
Koichiro Matsumoto,
Hiromasa Inoue,
Koji Atarashi,
Shohei Hori,
Hiroshi Watarai,
Jinfang Zhu, Masaru Taniguchi,
Masato Kubo
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ABSTRACT: The immunoregulatory cytokine interleukin 10 (IL-10) is expressed mainly by T helper type 2 (T(H)2) cells but also by T(H)1 cells during chronic infection. Here we observed plasticity in the expression of IL-10 and IL-13 after chronic T(H)1 stimulation; furthermore, the expression of Il10 and Il13 was regulated by the transcription factor E4BP4. Chronically stimulated E4BP4-deficient (Nfil3(-/-); called 'E4bp4(-/-)' here) T(H)1 cells, regulatory T cells (T(reg) cells) and natural killer T cells (NKT cells) had attenuated expression of IL-10 and IL-13. Enforced expression of E4bp4 initiated the production of IL-10 and IL-13 by conventional T(H)1 cells. E4bp4(-/-) T(H)2 cells showed impairment of IL-10 production with no effect on IL-13. Our results indicate that E4BP4 has multiple functions in controlling the plasticity of IL-13 in T(H)1 cells and IL-10 in T(H)1 cells, T(H)2 cells, T(reg) cells and NKT cells.
Nature Immunology 04/2011; 12(5):450-9. · 26.01 Impact Factor
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Kazuki Yamasaki,
Shigetoshi Horiguchi,
Motoyoshi Kurosaki,
Naoki Kunii,
Kaoru Nagato,
Hideki Hanaoka,
Naomi Shimizu,
Naoyuki Ueno,
Seiji Yamamoto, Masaru Taniguchi,
Shinichiro Motohashi,
Toshinori Nakayama,
Yoshitaka Okamoto
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ABSTRACT: Vα24 natural killer T (NKT) cells have potent anti-tumor activity. We performed a phase II clinical study in patients with head and neck squamous cell carcinoma (HNSCC) using ex vivo expanded Vα24 NKT cells and α-galactosylceramide (αGalCer; KRN7000)-pulsed antigen-presenting cells (APCs) to investigate the efficacy and induction of NKT cell-specific immune responses. The subjects were 10 patients with locally recurrent and operable HNSCC. One course of nasal submucosal administration of αGalCer-pulsed APCs and intra-arterial infusion of activated NKT cells via tumor-feeding arteries was given before salvage surgery. Anti-tumor effects, NKT cell-specific immune responses in extirpated cancer tissue and peripheral blood, safety, and pathological effects were evaluated. Five cases achieved objective tumor regression. The number of NKT cells increased in cancer tissues in 7 cases and was associated with tumor regression. The combination therapy induced NKT cell-specific immune responses in cancer tissues that were associated with beneficial clinical effects.
Clinical Immunology 03/2011; 138(3):255-65. · 4.05 Impact Factor
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Takashi Fujimura,
Syuji Yonekura,
Shigetoshi Horiguchi,
Yuriko Taniguchi,
Akemi Saito,
Hiroshi Yasueda,
Ayako Inamine,
Toshinori Nakayama,
Toshitada Takemori, Masaru Taniguchi,
Masahiro Sakaguchi,
Yoshitaka Okamoto
[show abstract]
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ABSTRACT: The aims of this study were to examine the therapeutic effects of sublingual immunotherapy (SLIT) and to identify potential biomarkers that would predict the therapeutic response in a randomized, double-blind, placebo-controlled clinical trial. The trial was carried out over two pollinosis seasons in 2007 and 2008. Carry-over therapeutic effects were analyzed in 2009. SLIT significantly ameliorated the symptoms of pollinosis during the 2008 and 2009 pollen seasons. Cry j 1-specific cytokine production in a subgroup of patients with mild disease in the SLIT group was significantly attenuated. The ratio of specific IgE to total IgE before treatment correlated with the symptom-medication score in the SLIT group in 2008. Patients with increased Cry j 1-iTreg in the SLIT group had significantly improved QOL and QOL-symptom scores. In summary, the specific IgE to total IgE ratio and upregulation of Cry j 1-iTreg are candidates for biomarker of the clinical response to SLIT.
Clinical Immunology 02/2011; 139(1):65-74. · 4.05 Impact Factor
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Kohsuke Okita,
Shinichiro Motohashi,
Ryo Shinnakasu,
Kaoru Nagato,
Kazuki Yamasaki,
Yasunori Sato,
Hiroshi Kitamura,
Atsushi Hijikata,
Masakatsu Yamashita,
Kanako Shimizu,
Shin-Ichiro Fujii,
Osamu Ohara, Masaru Taniguchi,
Isao Sakaida,
Toshinori Nakayama
[show abstract]
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ABSTRACT: Invariant natural killer T (iNKT) cells possess potent antitumor effects after activation with a specific glycolipid antigen, α-galactosylceramide (αGalCer). A phase I-II clinical study of αGalCer-pulsed dendritic cells (DC) to activate endogenous iNKT cells was previously performed in patients with non-small-cell lung cancer (NSCLC). In this clinical trial, the patients with increased interferon-γ (IFN-γ) production (>two-fold) in PBMC after the DC treatment (good responder group) experienced a prolonged overall survival time in comparison with the poor responder group. We extended the previous study and performed a microarray-based gene expression analysis using peripheral blood CD56(+) cells and CD56(-) CD3(+) T cells from patients enrolled in the above-mentioned clinical study. We sought to identify any biomarkers associated with the immune responses in this immunotherapy trial. Six patient samples corresponding to three subjects in the good responder group and three subjects in the poor responder group were included in the microarray analysis. Genes differentially expressed between pre-treatment and post-treatment samples were selected for analysis. Subsequently, genes that were only expressed in the good responder group or poor responder group were chosen. After these procedures, four selected genes were quantified by reverse transcriptase-polymerase chain reaction in another eight patient samples, and two genes, LTB4DH and DPYSL3, were confirmed to be candidate genes for the predictor of a good immune response. The expression profile of these two genes may be associated with the responsiveness of IFN-γ production after αGalCer-pulsed DC treatment.
Cancer Science 11/2010; 101(11):2333-40. · 3.33 Impact Factor
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ABSTRACT: Alpha-Galactosylceramide (alphaGalCer, KRN7000) has been identified as a modulator of immunological processes through its capacity to bind iNKT cells mediated by CD1d molecules. Some analogues in while the amide group in alphaGalCer is replaced with ester or ether groups were synthesized from d-arabinitol or l-ribose to evaluate their ability to activate iNKT cells. Ester analogues 30a, 31a, and 61 showed activity for IFNgamma and IL-4 production of iNKT cells, while ether (31b) and 4-methoxy ester (76) analogues of alpha-galactosylceramide were not active for iNKT cells.
Carbohydrate research 08/2010; 345(12):1663-84. · 2.03 Impact Factor
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Hiroshi Watarai,
Shin-ichiro Fujii,
Daisuke Yamada,
Andrei Rybouchkin,
Sakura Sakata,
Yuko Nagata,
Midori Iida-Kobayashi,
Etsuko Sekine-Kondo,
Kanako Shimizu,
Yohei Shozaki, [......],
Masashi Matsuda,
Shinobu Mochiduki,
Takanori Hasegawa,
Genta Kitahara,
Takaho A Endo,
Tetsuro Toyoda,
Osamu Ohara,
Ken-ichi Harigaya,
Haruhiko Koseki, Masaru Taniguchi
[show abstract]
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ABSTRACT: NKT cells demonstrate antitumor activity when activated to produce Th1 cytokines by DCs loaded with alpha-galactosylceramide, the prototypic NKT cell-activating glycolipid antigen. However, most patients do not have sufficient numbers of NKT cells to induce an effective immune response in this context, indicating a need for a source of NKT cells that could be used to supplement the endogenous cell population. Induced pluripotent stem cells (iPSCs) hold tremendous potential for cell-replacement therapy, but whether it is possible to generate functionally competent NKT cells from iPSCs has not been rigorously assessed. In this study, we successfully derived iPSCs both from embryonic fibroblasts from mice harboring functional NKT cell-specific rearranged T cell receptor loci in the germline and from splenic NKT cells from WT adult mice. These iPSCs could be differentiated into NKT cells in vitro and secreted large amounts of the Th1 cytokine IFN-gamma. Importantly, iPSC-derived NKT cells recapitulated the known adjuvant effects of natural NKT cells and suppressed tumor growth in vivo. These studies demonstrate the feasibility of expanding functionally competent NKT cells via an iPSC phase, an approach that may be adapted for NKT cell-targeted therapy in humans.
The Journal of clinical investigation 07/2010; 120(7):2610-8. · 15.39 Impact Factor
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Nobuhide Matsuoka,
Takeshi Itoh,
Hiroshi Watarai,
Etsuko Sekine-Kondo,
Naoki Nagata,
Kohji Okamoto,
Toshiyuki Mera,
Hiroshi Yamamoto,
Shingo Yamada,
Ikuro Maruyama, Masaru Taniguchi,
Yohichi Yasunami
[show abstract]
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ABSTRACT: Islet transplantation for the treatment of type 1 diabetes mellitus is limited in its clinical application mainly due to early loss of the transplanted islets, resulting in low transplantation efficiency. NKT cell-dependent IFN-gamma production by Gr-1(+)CD11b(+) cells is essential for this loss, but the upstream events in the process remain undetermined. Here, we have demonstrated that high-mobility group box 1 (HMGB1) plays a crucial role in the initial events of early loss of transplanted islets in a mouse model of diabetes. Pancreatic islets contained abundant HMGB1, which was released into the circulation soon after islet transplantation into the liver. Treatment with an HMGB1-specific antibody prevented the early islet graft loss and inhibited IFN-gamma production by NKT cells and Gr-1(+)CD11b(+) cells. Moreover, mice lacking either of the known HMGB1 receptors TLR2 or receptor for advanced glycation end products (RAGE), but not the known HMGB1 receptor TLR4, failed to exhibit early islet graft loss. Mechanistically, HMGB1 stimulated hepatic mononuclear cells (MNCs) in vivo and in vitro; in particular, it upregulated CD40 expression and enhanced IL-12 production by DCs, leading to NKT cell activation and subsequent NKT cell-dependent augmented IFN-gamma production by Gr-1(+)CD11b(+) cells. Thus, treatment with either IL-12- or CD40L-specific antibody prevented the early islet graft loss. These findings indicate that the HMGB1-mediated pathway eliciting early islet loss is a potential target for intervention to improve the efficiency of islet transplantation.
The Journal of clinical investigation 03/2010; 120(3):735-43. · 15.39 Impact Factor
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Takuya Tashiro,
Etsuko Sekine-Kondo,
Tomokuni Shigeura,
Ryusuke Nakagawa,
Sayo Inoue,
Miyuki Omori-Miyake,
Tomoki Chiba,
Naomi Hongo,
Shin-Ichiro Fujii,
Kanako Shimizu,
Yohei Yoshiga,
Takayuki Sumida,
Kenji Mori,
Hiroshi Watarai, Masaru Taniguchi
[show abstract]
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ABSTRACT: NKT cells are characterized by their production of both T(h)1 and T(h)2 cytokines immediately after stimulation with alpha-galactosylceramide (alpha-GalCer), which is composed of alpha-galactopyranose linked to ceramide (itself composed of sphingosine and fatty-acyl chains); the chain length of the ceramide varies and this affects the ability of alpha-GalCer to stimulate cytokine production. However, the contribution of its galactopyranose sugar moiety remains unclear. We synthesized alpha-carba-GalCer, which has an alpha-linked carba-galactosyl moiety; here, the 5a'-oxygen atom of the D-galactopyranose ring of alpha-GalCer is replaced by a methylene group. The alpha-carba-GalCer was more stable and showed higher affinity to the NKT receptor. It thus enhanced and prolonged production of IL-12 and IFN-gamma compared with alpha-GalCer, resulting in augmented NKT cell-mediated adjuvant effects in vivo. The alpha-carba-GalCer, which has an ether linkage, was more resistant to degradation by liver microsomes than was alpha-GalCer, which has an acetal bond. Modulation of the sugar moiety in glycolipids might therefore provide optimal therapeutic reagents for protective immune responses against tumor or pathogens.
International Immunology 02/2010; 22(4):319-28. · 3.41 Impact Factor
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Takashi Fujimura,
Syuji Yonekura,
Yuriko Taniguchi,
Shigetoshi Horiguchi,
Akemi Saito,
Hiroshi Yasueda,
Toshinori Nakayama,
Toshitada Takemori, Masaru Taniguchi,
Masahiro Sakaguchi,
Yoshitaka Okamoto
[show abstract]
[hide abstract]
ABSTRACT: Japanese cedar (Cryptomeria japonica) pollinosis is one of the most prevalent allergies in Japan. Recently, two reports described the positive effects of sublingual immunotherapy (SLIT) against Japanese cedar pollinosis. However, the therapeutic biomarkers for SLIT are still unclear. We performed this unblinded, nonrandomized, open-label study to identify therapeutic biomarkers for SLIT against Japanese cedar pollinosis.
We performed an open-label study during one pollinosis season in 2007, enrolling 19 patients from in-house volunteers suffering from Japanese cedar pollinosis. Peripheral blood was obtained from all participants before SLIT treatment as well as before and after the pollen season. The plasma levels of an immunoglobulin specific to a major allergen (Cry j 1) were determined. We analyzed the induction of regulatory T cells (iTregs), namely IL-10(+)Foxp3(+) cells in CD25(+)CD4(+) leukocytes, by flow cytometry. The Th2-type responses were analyzed by cytokine production from peripheral blood mononuclear cells after stimulation with Cry j 1. Clinical symptoms were estimated using a quality of life questionnaire in the middle of the pollen season.
The difference in numbers of iTregs between the medium-only control cell culture and cells stimulat- ed with Cry j 1 was significantly decreased in the non-SLIT group but was unchanged in the SLIT group after the pollen season. The subgroup of the SLIT group with increased iTregs showed more attenuated Th2-type cytokine profiles, and symptom scores in the subgroup with increased iTregs were significantly lower than those in the subgroup with decreased iTregs.
The antigen-specific iTreg level is a potential therapeutic biomarker that correlates with clinical pollinosis symptoms and may be involved in the therapeutic mechanisms of SLIT.
International Archives of Allergy and Immunology 01/2010; 153(4):378-87. · 2.40 Impact Factor
