245 results on '"Ikuya Yano"'
Search Results
2. Cationized liposomal keto-mycolic acids isolated from Mycobacterium bovis bacillus Calmette-Guérin induce antitumor immunity in a syngeneic murine bladder cancer model.
- Author
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Takayuki Yoshino, Jun Miyazaki, Takahiro Kojima, Shuya Kandori, Masanobu Shiga, Takashi Kawahara, Tomokazu Kimura, Takashi Naka, Hideyasu Kiyohara, Miyuki Watanabe, Sho Yamasaki, Hideyuki Akaza, Ikuya Yano, and Hiroyuki Nishiyama
- Subjects
Medicine ,Science - Abstract
Intravesical therapy using Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the most established cancer immunotherapy for bladder cancer. However, its underlying mechanisms are unknown. Mycolic acid (MA), the most abundant lipid of the BCG cell wall, is suspected to be one of the essential active components of this immunogenicity. Here, we developed cationic liposomes incorporating three subclasses (α, keto, and methoxy) of MA purified separately from BCG, using the dendron-bearing lipid D22. The cationic liposomes using D22 were efficiently taken up by the murine bladder cancer cell line MB49 in vitro, but the non-cationic liposomes were not. Lip-kMA, a cationic liposome containing keto-MA, presented strong antitumor activity in two murine syngeneic graft models using the murine bladder cancer cell lines MB49 and MBT-2 in comparison to both Lip-aMA and Lip-mMA, which contained α-MA and methoxy-MA, respectively. Interestingly, Lip-kMA(D12), which was made of D12 instead of D22, did not exhibit antitumor activity in the murine syngeneic graft model using MB49 cells, although it was successfully taken up by MB49 cells in vitro. Histologically, compared to the number of infiltrating CD4 lymphocytes, the number of CD8 lymphocytes was higher in the tumors treated with Lip-kMA. Antitumor effects of Lip-kMA were not observed in nude mice, whereas weak but significant effects were observed in beige mice with natural killer activity deficiency. Thus, a cationized liposome containing keto-MA derived from BCG induced in vivo antitumor immunity. These findings will provide new insights into lipid immunogenicity and the underlying mechanisms of BCG immunotherapy.
- Published
- 2019
- Full Text
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3. Lipids and Fatty Acids of Antarctic Giant Fish
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Yoshimi OHNO, Ikuya YANO, and Osamu WAGURI
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Geography (General) ,G1-922 - Abstract
Lipid and fatty acid composition of skeletal muscle of antarctic giant fish (Dissostichus mawsoni NORMAN) were examined. Thin-layer and column chromatography showed that the neutral lipids made up 98% of the total lipids, while phospholipids only 2% or less. The direct gas chromatographic analysis of triglycerides revealed that the major molecular species were C_, C_, C_, C_, C_ and C_, that their fatty acid composition resembled the other edible oil of marine fishes, and that the major components were C_, C_, C_, C_, C_, C_ and C_ with smaller amounts of C_, C_ and C_. The positional distributions of fatty acid on glycerides was also determined by lipase and phospholipase A_2 treatment and it showed that saturated and monoenoic fatty acids occurred in 1 position, while polyunsaturated fatty acids in 2 position, exclusively.
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- 1976
- Full Text
- View/download PDF
4. The liposome of trehalose dimycolate extracted from M. bovis BCG induces antitumor immunity via the activation of dendritic cells and CD8+ T cells
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Hiromitsu Negoro, Hideyasu Kiyohara, Jun Miyazaki, Shuya Kandori, Yasuhiro Fujisawa, Taka-Aki Sato, Makoto Watanabe, Yoshiyuki Nagumo, Naoko Okiyama, Hiroyuki Nishiyama, Sho Yamasaki, Ikuya Yano, Masanobu Shiga, Miyuki Watanabe, Hideaki Tahara, Ryota Tanaka, Kozaburo Tanuma, Takahiro Kojima, and Takayuki Yoshino
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Cancer Research ,Tumor microenvironment ,medicine.medical_treatment ,Immunology ,Dendritic cell ,Immunotherapy ,Trehalose dimycolate ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Oncology ,chemistry ,medicine ,Cancer research ,Immunology and Allergy ,Cytotoxic T cell ,Cationic liposome ,Adjuvant ,CD8 ,030215 immunology - Abstract
Intravesical Bovis bacillus Calmette-Guerin (BCG) therapy is the most effective immunotherapy for bladder cancer, but it sometime causes serious side effects because of its inclusion of live bacteria. It is necessary to develop a more active but less toxic immunotherapeutic agent. Trehalose 6,6'-dimycolate (TDM), the most abundant hydrophobic glycolipid of the BCG cell wall, has been reported to show various immunostimulatory activities such as granulomagenesis and adjuvant activity. Here, we developed cationic liposomes incorporating TDM purified from Mycobacterium bovis BCG Connaught, and we investigated the antitumor effect of the cationic liposome TDM (Lip-TDM). Lip-TDM exerted an antitumor effect in bladder cancer, colon cancer, and melanoma-bearing mouse models that was comparable or even superior to that of BCG, with no body weight loss or granuloma formation. The antitumor effect of Lip-TDM disappeared in two types of mice: those with depletion of CD8+ T cells, and those with knockout of macrophage-inducible C-type lectin (Mincle) which recognize TDM. Lip-TDM treatment enhanced the maturation and migration of dendritic cells in the tumor microenvironment in a Mincle-dependent manner. Our results elucidate mechanisms that underlie Lip-TDM treatment and suggest that Lip-TDM has potential as a safe and effective treatment for various cancers.
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- 2021
5. The rough colony morphotype of Mycobacterium avium exhibits high virulence in human macrophages and mice
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Masayuki Shimoda, Shoko Kashimura, Eiko Tamizu, Tomoyasu Nishimura, Yoshifumi Uwamino, Naoki Hasegawa, Shunsuke Uno, and Ikuya Yano
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0301 basic medicine ,Microbiology (medical) ,Chemokine ,Lung ,biology ,Virulence ,General Medicine ,biology.organism_classification ,Microbiology ,Peripheral blood mononuclear cell ,Proinflammatory cytokine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030228 respiratory system ,biology.protein ,medicine ,Secretion ,Bacteria ,Mycobacterium - Abstract
Introduction.The incidence ofMycobacterium aviumcomplex (MAC) pulmonary disease (MAC PD), a refractory chronic respiratory tract infection, is increasing worldwide. MAC has three predominant colony morphotypes: smooth opaque (SmO), smooth transparent (SmT) and rough (Rg).Aim.To determine whether colony morphotypes can predict the prognosis of MAC PD, we evaluated the virulence of SmO, SmT and Rg in mice and in human macrophages.Methodology.We compared the characteristics of mice and human macrophages infected with the SmO, SmT, or Rg morphotypes ofM. aviumsubsp.hominissuis104. C57BL/6 mice and human macrophages derived from peripheral mononuclear cells were used in these experiments.Results.In comparison to SmO- or SmT-infected mice, Rg-infected mice revealed severe pathologically confirmed pneumonia, increased lung weight and increased lung bacterial burden. Rg-infected macrophages revealed significant cytotoxicity, increased bacterial burden, secretion of proinflammatory cytokines (TNF-α and IL-6) and chemokines (CCL5 and CCL3), and formation of cell clusters. Rg formed larger bacterial aggregates than SmO and SmT. Cytotoxicity, bacterial burden and secretion of IL-6, CCL5 and CCL3 were induced strongly by Rg infection, and were decreased by disaggregation of the bacteria.Conclusion.M. aviumRg, which is associated with bacterial aggregation, has the highest virulence among the predominant colony morphotypes.
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- 2020
6. The liposome of trehalose dimycolate extracted from M. bovis BCG induces antitumor immunity via the activation of dendritic cells and CD8
- Author
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Masanobu, Shiga, Jun, Miyazaki, Kozaburo, Tanuma, Yoshiyuki, Nagumo, Takayuki, Yoshino, Shuya, Kandori, Hiromitsu, Negoro, Takahiro, Kojima, Ryota, Tanaka, Naoko, Okiyama, Yasuhiro, Fujisawa, Miyuki, Watanabe, Sho, Yamasaki, Hideyasu, Kiyohara, Makoto, Watanabe, Taka-Aki, Sato, Hideaki, Tahara, Hiroyuki, Nishiyama, and Ikuya, Yano
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Molecular Structure ,Dendritic Cells ,CD8-Positive T-Lymphocytes ,Chemical Fractionation ,Lymphocyte Activation ,Mycobacterium bovis ,Xenograft Model Antitumor Assays ,Immunophenotyping ,Disease Models, Animal ,Mice ,Antineoplastic Agents, Immunological ,Treatment Outcome ,Adjuvants, Immunologic ,Liposomes ,Solvents ,Animals ,Cord Factors ,Cytokines ,Humans ,Immunologic Factors ,Female ,Infusions, Parenteral - Abstract
Intravesical Bovis bacillus Calmette-Guérin (BCG) therapy is the most effective immunotherapy for bladder cancer, but it sometime causes serious side effects because of its inclusion of live bacteria. It is necessary to develop a more active but less toxic immunotherapeutic agent. Trehalose 6,6'-dimycolate (TDM), the most abundant hydrophobic glycolipid of the BCG cell wall, has been reported to show various immunostimulatory activities such as granulomagenesis and adjuvant activity. Here, we developed cationic liposomes incorporating TDM purified from Mycobacterium bovis BCG Connaught, and we investigated the antitumor effect of the cationic liposome TDM (Lip-TDM). Lip-TDM exerted an antitumor effect in bladder cancer, colon cancer, and melanoma-bearing mouse models that was comparable or even superior to that of BCG, with no body weight loss or granuloma formation. The antitumor effect of Lip-TDM disappeared in two types of mice: those with depletion of CD8
- Published
- 2020
7. Contrasting roles of the innate receptors TREM2 versus Mincle in the recognition and response of macrophages to mycolic acid-containing lipids in mycobacterial cell walls
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Hiroki Yoshida, Ikuya Yano, Hiromitsu Hara, Kenji Toyonaga, Sho Yamasaki, Hiroaki Kawaguchi, Marco Colonna, Ei’ichi Iizasa, Masayuki Umemura, Masahiko Sugita, Yasushi Chuma, Takayuki Uematsu, Mio Kubota, Goro Matsuzaki, and Hideyasu Kiyohara
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chemistry.chemical_classification ,Biochemistry ,chemistry ,TREM2 ,Receptor ,Mycobacterial cell ,Mycolic acid - Abstract
Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγ-associated C-type lectin receptors, including Mincle, and caspase-recruitment domain family member 9 (CARD9). Additionally, mycobacteria harbor immuno-evasive cell-wall lipids associated with virulence and latency; however, their mechanism of action remains unclear. Here, we show that the DAP12-associated triggering receptor expressed on myeloid cells 2 (TREM2) recognizes mycobacterial cell-wall mycolic acid (MA)-containing lipids and suggest a mechanism by which mycobacteria control host immunity via TREM2. Macrophages responded to glycosylated MA-containing lipids in a Mincle/FcRγ/CARD9-dependent manner to produce inflammatory cytokines and recruit inducible nitric oxide synthase (iNOS)-positive mycobactericidal macrophages. Conversely, macrophages responded to non-glycosylated MAs in a TREM2/DAP12-dependent but CARD9-independent manner to recruit iNOS-negative mycobacterium-permissive macrophages. Furthermore, TREM2 deletion enhanced Mincle-induced macrophage activation in vitro and inflammation in vivo and accelerated the elimination of mycobacterial infection, suggesting that TREM2-DAP12 signaling counteracts Mincle-FcRγ-CARD9-mediated anti-mycobacterial immunity. Mycobacteria, therefore, harness TREM2 for immune evasion.
- Published
- 2020
8. The rough colony morphotype of
- Author
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Tomoyasu, Nishimura, Masayuki, Shimoda, Eiko, Tamizu, Shunsuke, Uno, Yoshifumi, Uwamino, Shoko, Kashimura, Ikuya, Yano, and Naoki, Hasegawa
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Mice, Inbred C57BL ,Mice ,Phenotype ,Virulence ,Incidence ,Macrophages ,Animals ,Cytokines ,Humans ,Female ,Mycobacterium avium Complex ,Mycobacterium avium ,Mycobacterium avium-intracellulare Infection - Published
- 2020
9. TREM2 is a receptor for non-glycosylated mycolic acids of mycobacteria that limits anti-mycobacterial macrophage activation
- Author
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Hideyasu Kiyohara, Marco Colonna, Sho Yamasaki, Ei’ichi Iizasa, Hiroaki Kawaguchi, Masahiko Sugita, Ikuya Yano, Hiromitsu Hara, Mio Kubota, Goro Matsuzaki, Masayuki Umemura, Hiroki Yoshida, Takayuki Uematsu, Yasushi Chuma, and Kenji Toyonaga
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0301 basic medicine ,Male ,General Physics and Astronomy ,Mycolic acid ,Mice ,0302 clinical medicine ,Cell Wall ,Macrophage ,Receptors, Immunologic ,Receptor ,Cells, Cultured ,chemistry.chemical_classification ,Mice, Knockout ,Multidisciplinary ,Membrane Glycoproteins ,Chemistry ,Mycolic Acids ,lipids (amino acids, peptides, and proteins) ,Female ,medicine.symptom ,Pattern recognition receptors ,Virulence Factors ,Science ,Primary Cell Culture ,Inflammation ,General Biochemistry, Genetics and Molecular Biology ,Article ,Microbiology ,Proinflammatory cytokine ,03 medical and health sciences ,Immune system ,Glycolipid ,Immunity ,Latent Tuberculosis ,medicine ,Animals ,Humans ,Lectins, C-Type ,Monocytes and macrophages ,Adaptor Proteins, Signal Transducing ,Immune Evasion ,Macrophages ,Receptors, IgG ,Membrane Proteins ,General Chemistry ,Mycobacterium tuberculosis ,Antimicrobial responses ,Macrophage Activation ,CARD Signaling Adaptor Proteins ,Disease Models, Animal ,030104 developmental biology ,Glycolipids ,030217 neurology & neurosurgery - Abstract
Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγ-associated C-type lectin receptors, including Mincle, and caspase-recruitment domain family member 9 (CARD9). Additionally, mycobacteria harbor immuno-evasive cell-wall lipids associated with virulence and latency; however, a mechanism of action is unclear. Here, we show that the DAP12-associated triggering receptor expressed on myeloid cells 2 (TREM2) recognizes mycobacterial cell-wall mycolic acid (MA)-containing lipids and suggest a mechanism by which mycobacteria control host immunity via TREM2. Macrophages respond to glycosylated MA-containing lipids in a Mincle/FcRγ/CARD9-dependent manner to produce inflammatory cytokines and recruit inducible nitric oxide synthase (iNOS)-positive mycobactericidal macrophages. Conversely, macrophages respond to non-glycosylated MAs in a TREM2/DAP12-dependent but CARD9-independent manner to recruit iNOS-negative mycobacterium-permissive macrophages. Furthermore, TREM2 deletion enhances Mincle-induced macrophage activation in vitro and inflammation in vivo and accelerates the elimination of mycobacterial infection, suggesting that TREM2-DAP12 signaling counteracts Mincle-FcRγ-CARD9-mediated anti-mycobacterial immunity. Mycobacteria, therefore, harness TREM2 for immune evasion. Download PDF, 論文
- Published
- 2020
10. Anti-tumor immunity via the superoxide-eosinophil axis induced by a lipophilic component of Mycobacterium lipomannan
- Author
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Atsushi Onodera, Toshinori Nakayama, Toshihiro Ito, Ryo Koyama-Nasu, Kiyoshi Hirahara, and Ikuya Yano
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Cytotoxicity, Immunologic ,Lipopolysaccharides ,0301 basic medicine ,Carcinogenesis ,Immunology ,Immunotherapy, Adoptive ,complex mixtures ,CCL5 ,Cell therapy ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Th2 Cells ,0302 clinical medicine ,Immune system ,Cell Movement ,Cell Wall ,Superoxides ,Cell Line, Tumor ,Tumor Microenvironment ,Animals ,Immunology and Allergy ,Chemokine CCL5 ,Mice, Inbred BALB C ,Tumor microenvironment ,Lipomannan ,Lipoarabinomannan ,Chemistry ,Superoxide ,Dendritic Cells ,Neoplasms, Experimental ,General Medicine ,Mycobacterium bovis ,Tumor Burden ,Cell biology ,Eosinophils ,030104 developmental biology ,Tumor progression ,Female ,Transcriptome ,Immunologic Memory ,030215 immunology - Abstract
Mycobacterium bovis Bacille Calmette–Guérin (BCG) has been shown to possess potent anti-tumor activity particularly in various animal models, while the cellular and molecular mechanisms underlying its activity are not well understood. We found that lipomannan (BCG-LM), a lipophilic component of the mycobacterial cell envelope, specifically inhibits tumor growth and induces the infiltration of eosinophils at local tumor invasion sites. In contrast, neither lipoarabinomannan (BCG-LAM) nor the cell wall of Mycobacterium bovis BCG (BCG-CW) exerted anti-tumor immunity. BCG-LM enhances cytotoxic activity of eosinophils via the increased production of superoxide. Global transcriptomic analyses of BCG-LM-pulsed dendritic cells identified C-C motif ligand (CCL) 5 as a crucial chemokine for the anti-tumor immunity induced by BCG-LM, indicating that CCL5 plays an important role for the accumulation of eosinophils in the tumor microenvironment. Furthermore, BCG-LM and memory Th2 cells exerted a synergetic effect on tumor progression by cooperatively enhancing the eosinophil function. Thus, this study revealed an un-identified BCG-LM-mediated anti-tumor mechanism via superoxide produced by infiltrated eosinophils in the tumor microenvironment. Since BCG-LM activates this unique pathway, it may have potent therapeutic potential as immune cell therapy for cancer patients.
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- 2017
11. Cationized liposomal keto-mycolic acids isolated from Mycobacterium bovis bacillus Calmette-Guérin induce antitumor immunity in a syngeneic murine bladder cancer model
- Author
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Takahiro Kojima, Ikuya Yano, Miyuki Watanabe, Jun Miyazaki, Takayuki Yoshino, Masanobu Shiga, Hideyasu Kiyohara, Tomokazu Kimura, Shuya Kandori, Hideyuki Akaza, Takashi Kawahara, Takashi Naka, Sho Yamasaki, and Hiroyuki Nishiyama
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,medicine.medical_treatment ,Cancer Treatment ,CD8-Positive T-Lymphocytes ,Biochemistry ,Mice ,White Blood Cells ,0302 clinical medicine ,Cancer immunotherapy ,Animal Cells ,Medicine and Health Sciences ,Cationic liposome ,Mice, Inbred C3H ,Liposome ,Multidisciplinary ,Molecular Structure ,T Cells ,Chemistry ,Immunogenicity ,Animal Models ,Keto Acids ,Bladder Cancer ,Lipids ,Mycolic Acids ,Oncology ,Experimental Organism Systems ,Syngeneic Graft ,030220 oncology & carcinogenesis ,BCG Vaccine ,Medicine ,Female ,Immunotherapy ,Cellular Structures and Organelles ,Cellular Types ,Research Article ,Urology ,Immune Cells ,Science ,Immunology ,Mice, Nude ,Mouse Models ,Cytotoxic T cells ,Research and Analysis Methods ,Cancer Vaccines ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,Model Organisms ,Cell Walls ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Vesicles ,Particle Size ,Blood Cells ,Bladder cancer ,Biology and Life Sciences ,Cancers and Neoplasms ,Cell Biology ,medicine.disease ,Mice, Inbred C57BL ,Genitourinary Tract Tumors ,030104 developmental biology ,Urinary Bladder Neoplasms ,Liposomes ,Animal Studies ,Cancer research - Abstract
Intravesical therapy using Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the most established cancer immunotherapy for bladder cancer. However, its underlying mechanisms are unknown. Mycolic acid (MA), the most abundant lipid of the BCG cell wall, is suspected to be one of the essential active components of this immunogenicity. Here, we developed cationic liposomes incorporating three subclasses (α, keto, and methoxy) of MA purified separately from BCG, using the dendron-bearing lipid D22. The cationic liposomes using D22 were efficiently taken up by the murine bladder cancer cell line MB49 in vitro, but the non-cationic liposomes were not. Lip-kMA, a cationic liposome containing keto-MA, presented strong antitumor activity in two murine syngeneic graft models using the murine bladder cancer cell lines MB49 and MBT-2 in comparison to both Lip-aMA and Lip-mMA, which contained α-MA and methoxy-MA, respectively. Interestingly, Lip-kMA(D12), which was made of D12 instead of D22, did not exhibit antitumor activity in the murine syngeneic graft model using MB49 cells, although it was successfully taken up by MB49 cells in vitro. Histologically, compared to the number of infiltrating CD4 lymphocytes, the number of CD8 lymphocytes was higher in the tumors treated with Lip-kMA. Antitumor effects of Lip-kMA were not observed in nude mice, whereas weak but significant effects were observed in beige mice with natural killer activity deficiency. Thus, a cationized liposome containing keto-MA derived from BCG induced in vivo antitumor immunity. These findings will provide new insights into lipid immunogenicity and the underlying mechanisms of BCG immunotherapy.
- Published
- 2019
12. Immune Evasion of Mycobacteria Via TREM2 Through Induction of Permissive Macrophages And Suppression Of Mincle/CARD9-Induced Anti-Mycobacterial Immunity
- Author
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Goro Matsuzaki, Kenji Toyonaga, Ei’ichi Iizasa, Hideyasu Kiyohara, Ikuya Yano, Hiromitsu Hara, Hiroaki Kawaguchi, Mio Kubota, Masahiko Sugita, Masayuki Umemura, Yasushi Chuma, Sho Yamasaki, Marco Colonna, Hiroki Yoshida, and Takayuki Uematsu
- Subjects
chemistry.chemical_classification ,Immune system ,Glycolipid ,Innate immune system ,chemistry ,Immunity ,Macrophage ,Biology ,Receptor ,Mycolic acid ,Microbiology ,Proinflammatory cytokine - Abstract
Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγ-associated C-type lectin receptors, including Mincle, and caspase-recruitment domain family member 9 (CARD9). Additionally, mycobacteria harbor immuno-evasive cell-wall lipids associated with virulence and latency; however, their mechanism of action remains unclear. Here, we show that the DAP12-associated triggering receptor expressed on myeloid cells 2 (TREM2) recognizes mycobacterial cell-wall mycolic acid (MA)-containing lipids and suggest a mechanism by which mycobacteria control host immunity via TREM2. Macrophages responded to glycosylated MA-containing lipids in a Mincle/FcRγ/CARD9-dependent manner to produce inflammatory cytokines and recruit inducible nitric oxide synthase (iNOS)-positive mycobactericidal macrophages. Conversely, macrophages responded to non-glycosylated MAs in a TREM2/DAP12-dependent but CARD9-independent manner to recruit iNOS-negative mycobacterium-permissive macrophages. Furthermore, TREM2 deletion enhanced Mincle-induced macrophage activation in vitro and inflammation in vivo and accelerated the elimination of mycobacterial infection, suggesting that TREM2/DAP12 signaling counteracts Mincle/FcRg/CARD9-mediated anti-mycobacterial immunity. Mycobacteria, therefore, harness TREM2 to evade the host immunity.
- Published
- 2019
13. Middle-aged to elderly women have a higher asymptomatic infection rate withMycobacterium aviumcomplex, regardless of body habitus
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Yoshifumi Uwamino, Naoki Hasegawa, Hiroshi Fujiwara, Hiroshi Kawabe, Tomoyasu Nishimura, Ikuya Yano, Yukiko Fujita-Suzuki, Stephen M. Carpenter, Eiko Tamizu, and Masaaki Mori
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,biology ,business.industry ,Mycobacterium avium-intracellulare infection ,Thin body habitus ,medicine.disease ,biology.organism_classification ,Asymptomatic ,Infection rate ,03 medical and health sciences ,0302 clinical medicine ,030228 respiratory system ,Internal medicine ,Immunology ,medicine ,Habitus ,Mycobacterium avium complex ,030212 general & internal medicine ,medicine.symptom ,Young adult ,business ,Body mass index - Abstract
Mycobacterium avium complex (MAC) pulmonary disease is prevalent in middle-aged to elderly women with a thin body habitus. By comparing the rate of serologically diagnosed asymptomatic MAC infection and body mass index among 1033 healthy subjects, we find that middle-aged to elderly women became infected with MAC, regardless of their body habitus.
- Published
- 2015
14. Bacillus Calmette-Guérin strain differences as the basis for immunotherapies against bladder cancer
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Eiichiro Takaoka, Jun Miyazaki, Mizuki Onozawa, and Ikuya Yano
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Urology ,medicine.medical_treatment ,030232 urology & nephrology ,Microbiology ,Bacillus Calmette Guerin vaccine ,03 medical and health sciences ,0302 clinical medicine ,Genotype ,medicine ,Humans ,Bacillus (shape) ,Mycobacterium bovis ,Carcinoma, Transitional Cell ,Bladder cancer ,biology ,business.industry ,Strain (biology) ,fungi ,Immunotherapy ,History, 20th Century ,biology.organism_classification ,medicine.disease ,Administration, Intravesical ,Treatment Outcome ,Urinary Bladder Neoplasms ,Tumor progression ,030220 oncology & carcinogenesis ,BCG Vaccine ,bacteria ,Cytokines ,Neoplasm Recurrence, Local ,business - Abstract
In the past 40 years, intravesical immunotherapy with Mycobacterium bovis bacillus Calmette-Guerin has been carried out as the most effective treatment for preventing local recurrences and tumor progression of non-muscle-invasive bladder cancer. Bacillus Calmette-Guerin is a family of vaccines derived in 1921 by the in vitro attenuation of Mycobacterium bovis. Subsequently, bacillus Calmette-Guerin seed lots were spread around the world, and both phenotypic and genotypic differences among the strains have been compiled. In recent genomic comparisons, the evolution of the different bacillus Calmette-Guerin substrains has begun to emerge. However, some of these genetic alterations in bacillus Calmette-Guerin strains have yet to be shown to affect the therapeutic effects and/or adverse effects. There are thus ongoing research efforts to assess the effects of these genetic alterations on the properties of bacillus Calmette-Guerin strains, with the ultimate goal of identifying an ideal bacillus Calmette-Guerin strain for treatment of non-muscle-invasive bladder cancer and providing clues for the improvement of bacillus Calmette-Guerin strains. The present review provides a history of bacillus Calmette-Guerin immunotherapy, and discusses the genetic differences among bacillus Calmette-Guerin strains, the different clinical outcomes afforded by bacillus Calmette-Guerin strains and possible future developments.
- Published
- 2017
15. Nanoparticulation of BCG-CWS for application to bladder cancer therapy
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Hiroyuki Nishiyama, Akihiro Nakaya, Megumi Higuchi, Hideyuki Akaza, Toshinori Nakayama, Takashi Nakamura, Ikuya Yano, Jun Miyazaki, Toshihiro Ito, Hiroyuki Hosokawa, Hideyoshi Harashima, and Masafumi Fukiage
- Subjects
Adult ,Male ,Drug ,Pathology ,medicine.medical_specialty ,T-Lymphocytes ,media_common.quotation_subject ,medicine.medical_treatment ,Pharmaceutical Science ,Cancer immunotherapy ,Antineoplastic Agents ,Cell Wall Skeleton ,BCG-CWS ,Mice ,Young Adult ,Nanoparticle ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Tumor growth ,Delivery system ,Cells, Cultured ,media_common ,Mice, Inbred C3H ,Mycobacterium bovis ,Bladder cancer ,biology ,Chemistry ,Cell Differentiation ,medicine.disease ,biology.organism_classification ,Rats, Inbred F344 ,In vitro ,Rats ,Urinary Bladder Neoplasms ,Packaging ,Cancer research ,Nanoparticles ,Female ,Butylhydroxybutylnitrosamine - Abstract
The Mycobacterium bovis Bacille Calmette-Guerin cell wall skeleton (BCG-CWS) could be used to replace live BCG as a bladder cancer drug. However, because BCG-CWS is poorly soluble, has a strong-negative charge, very high molecular weight and heterogeneity in size of tens of mu m, it cannot be used in such an application. We report herein on the development of a novel packaging method that permits BCG-CWS to be encapsulated into 166 nm-sized lipid particles. The BCG-CWS encapsulated nano particle (CWS-NP) has a high uniformity and can be easily dispersed. Thus, it has the potential for use as a packaging method that would advance the scope of applications of BCG-CWS as a bladder cancer drug. In a functional evaluation, CWS-NP was efficiently taken up by mouse bladder tumor (MBT-2) cells in vitro and inhibited tumor growth in mice bearing MBT-2 tumors. Moreover, intravesically administered CWS-NP showed significant antitumor effects in a rat model with naturally developed bladder cancer. An enhancement in Th1 differentiation by CWS-NP was also confirmed in human T cells. In conclusion, CWS-NP represents a promising delivery system for BCG-CWS for clinical development as a potent bladder cancer drug. (C) 2013 Elsevier B. V. All rights reserved.
- Published
- 2014
16. C-Type Lectin Receptor DCAR Recognizes Mycobacterial Phosphatidyl-Inositol Mannosides to Promote a Th1 Response during Infection
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Yasu S. Morita, Masayuki Umemura, Kenji Toyonaga, Yoshitomo Motomura, Hiroshi Tanaka, Jennifer M. Hayashi, Masaki Ohmuraya, Kazuhiro Matsuo, Yasushi Chuma, Goro Matsuzaki, Tomofumi Miyamoto, Sho Yamasaki, Shota Torigoe, Takashi Yamamoto, Takane Kamichi, Yasunobu Yoshikai, Tetsushi Sakuma, Hideyasu Kiyohara, Naoto Noguchi, Ikuya Yano, and Yoshiko Nakagawa
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0301 basic medicine ,Immunology ,Spleen ,Biology ,Lymphocyte Activation ,Phosphatidylinositols ,Microbiology ,Mycobacterium ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Glycolipid ,Bacterial Proteins ,C-type lectin ,hemic and lymphatic diseases ,medicine ,Immunology and Allergy ,Animals ,Lectins, C-Type ,Receptors, Immunologic ,Receptor ,Mice, Knockout ,Mycobacterium Infections ,Monocyte ,Chemotaxis ,Dendritic cell ,Th1 Cells ,Mice, Inbred C57BL ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,030215 immunology - Abstract
Phosphatidyl-inositol mannosides (PIM) are glycolipids unique to mycobacteria and other related bacteria that stimulate host immune responses and are implicated in mycobacteria pathogenicity. Here, we found that the FcRγ-coupled C-type lectin receptor DCAR (dendritic cell immunoactivating receptor; gene symbol Clec4b1) is a direct receptor for PIM. Mycobacteria activated reporter cells expressing DCAR, and delipidation of mycobacteria abolished this activity. Acylated PIMs purified from mycobacteria were identified as ligands for DCAR. DCAR was predominantly expressed in small peritoneal macrophages and monocyte-derived inflammatory cells in lungs and spleen. These cells produced monocyte chemoattractant protein-1 (MCP-1) upon PIM treatment, and absence of DCAR or FcRγ abrogated MCP-1 production. Upon mycobacterial infection, Clec4b1-deficient mice showed reduced numbers of monocyte-derived inflammatory cells at the infection site, impaired IFNγ production by T cells, and an increased bacterial load. Thus, DCAR is a critical receptor for PIM that functions to promote T cell responses against mycobacteria.
- Published
- 2016
17. The effect of passages during Japanese BCG vaccine production on genetic stability and protective efficacy
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Saburo Yamamoto, Ikuya Yano, Kenji Iwama, Tadashi Udagawa, Ikuro Honda, Akira Hashimoto, Isamu Sugawara, Masaaki Seki, and Isao Fujita
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DNA, Bacterial ,Genetic stability ,Guinea Pigs ,Vaccine Production ,Polymerase Chain Reaction ,Genomic Instability ,Japan ,Serial passage ,Genotype ,Animals ,Humans ,Tuberculosis ,Medicine ,Serial Passage ,Lung ,General Veterinary ,General Immunology and Microbiology ,business.industry ,Public Health, Environmental and Occupational Health ,Mycobacterium bovis ,Virology ,Bacterial Load ,Disease Models, Animal ,Infectious Diseases ,Immunology ,BCG Vaccine ,Molecular Medicine ,Female ,business ,BCG vaccine - Abstract
Many genetic differences have been found among currently available BCG vaccines. To avoid continued accumulation of phenotypic or genotypic changes in the strains, WHO and most national regulatory authorities request that the vaccine should not be prepared by more than 12 passages from the master seed lot. However, it has recently been reported that genetic changes occur even during the passage for vaccine production. In this study, the genetic stability of Japanese BCG vaccine production using currently available PCR methods and protective efficacy using a guinea-pig model during the passages were examined. The results showed that there were no significant differences between the seed lot, the product manufactured by normal procedures, and the 20th passage product. These results indicate that the maximum number of passages as currently required by WHO for BCG vaccine production is adequate for the Japanese vaccine, and that new genetic tools may help to examine the quality control of the BCG vaccine.
- Published
- 2012
18. The liposome-incorporating cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guéin can directly enhance the susceptibility of cancer cells to lymphokine-activated killer cells through up-regulation of natural-killer group 2, member D ligands
- Author
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Takehiro Oikawa, Jun Miyazaki, Hideyoshi Harashima, Ikuya Yano, Akira Joraku, Akihiro Nakaya, Takashi Nakamura, Toru Shimazui, Takahiro Kojima, Koji Kawai, and Hideyuki Akaza
- Subjects
Urology ,Ligands ,Real-Time Polymerase Chain Reaction ,Cell Wall Skeleton ,Tumor Cells, Cultured ,Humans ,Medicine ,Cytotoxic T cell ,Killer Cells, Lymphokine-Activated ,CD40 ,Lymphokine-activated killer cell ,biology ,business.industry ,Histocompatibility Antigens Class I ,Natural killer T cell ,NKG2D ,Mycobacterium bovis ,Molecular biology ,Up-Regulation ,Killer Cells, Natural ,Urinary Bladder Neoplasms ,Cancer cell ,Immunology ,BCG Vaccine ,Interleukin 12 ,biology.protein ,business - Abstract
OBJECTIVE • To conduct a preclinical evaluation of the ability of natural killer cells to cytolyze bladder cancer cells that were modified to show enhanced expression of natural-killer group 2, member D (NKG2D) ligands by R8-liposome-bacillus Calmette-Guein (BCG)-cell wall skeleton (CWS) treatment. MATERIALS AND METHODS • The T24 cells and RT-112 cells were co-cultured with R8-liposome-BCG-CWS and BCG for 2, 4, or 6 h, and then the surface expression of NKG2D ligands was analyzed using TaqMan real-time quantitative RT-PCR. • Peripheral blood mononuclear cells were obtained with a conventional preparation kit, and then lymphokine-activated killer (LAK) cells were generated from these purified peripheral blood mononuclear cells via interleukin-2 stimulation. • The anti-tumour effect of LAK cells against untreated and R8-liposome-BCG-CWS co-cultured with cells of the human bladder cancer cell lines T24 and RT-112 was analyzed using the cytotoxic WST-8 assay method at 4 h of culture at various effector/target (E : T) ratios. RESULTS • Major histocompatibility complex class I-related chain B (MICB) expression was increased ≈1.5-fold on T24 cells and RT-112 cells with BCG. • UL-16-binding protein (ULBP) 1 expression was also increased ≈1.5-fold on T24 cells and RT-112 cells with BCG. R8-liposome-BCG-CWS increased the surface expression of MICB 2.2-fold on T24 cells but did not increase it significantly on RT-112 cells. • ULBP1 expression was increased ≈2.2-fold on RT-112 cells, although no differences were observed between the expression of ULBP2 and 3 with R8-liposome-BCG-CWS. • T24 cells that were co-cultured with R8-liposome-BCG-CWS showed an ≈1.3-fold increase in sensitivity to cytolysis by LAK cells at an E : T ratio of 4 and RT-112 cells showed an ≈1.4-fold increase at an E : T ratio of 2. CONCLUSIONS • In the present study, the induction of surface NKG2D ligands by R8-liposome-BCG-CWS rendered cancer cells more susceptible to cytolysis by LAK cells. • T24 cells and RT-112 cells, even when cultured singly in the absence of immune cells, can directly respond to R8-liposome-BCG-CWS. • The results obtained in the present study may therefore indicate a novel adoptive immunotherapy against bladder cancers.
- Published
- 2011
19. Novel Rhamnosyltransferase Involved in Biosynthesis of Serovar 4-Specific Glycopeptidolipid from Mycobacterium avium Complex
- Author
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Seiko Mizuno, Ikuya Yano, Yumi Maeda, Takashi Naka, Masahiko Makino, Tetsu Mukai, Masanori Kai, Nagatoshi Fujiwara, and Yuji Miyamoto
- Subjects
Molecular Biology of Pathogens ,Serotype ,Regulation of gene expression ,biology ,Molecular Sequence Data ,Glycopeptides ,Glycosyltransferases ,Gene Expression Regulation, Bacterial ,Mycobacterium avium Complex ,Microbiology ,Fucose ,chemistry.chemical_compound ,Glycolipid ,Bacterial Proteins ,chemistry ,Glycosyltransferase ,Gene cluster ,Carbohydrate Conformation ,biology.protein ,Carbohydrate conformation ,Glycolipids ,Serotyping ,Molecular Biology ,Gene - Abstract
Glycopeptidolipids (GPLs) are one of the major glycolipid components present on the surface of Mycobacterium avium complex (MAC) that belong to opportunistic pathogens distributed in the natural environment. The serovars of MAC, up to around 30 types, are defined by the variable oligosaccharide portions of the GPLs. Epidemiological studies show that serovar 4 is the most prevalent type, and the prognosis of pulmonary disease caused by serovar 4 is significantly worse than that caused by other serovars. However, little is known about the biosynthesis of serovar 4-specific GPL, particularly the formation of the oligosaccharide portion that determines the properties of serovar 4. To investigate the biosynthesis of serovar 4-specific GPL, we focused on one segment that included functionally unknown genes in the GPL biosynthetic gene cluster of a serovar 4 strain. In this segment, a putative hemolytic protein gene, hlpA , and its downstream gene were found to be responsible for the formation of the 4- O -methyl-rhamnose residue, which is unique to serovar 4-specific GPL. Moreover, functional characterization of the hlpA gene revealed that it encodes a rhamnosyltransferase that transfers a rhamnose residue via 1→4 linkage to a fucose residue of serovar 2-specific GPL, which is a key pathway leading to the synthesis of oligosaccharide of serovar 4-specific GPL. These findings may provide clues to understanding the biological role of serovar 4-specific GPL in MAC pathogenicity and may also provide new insights into glycosyltransferase, which generates structural and functional diversity of GPLs.
- Published
- 2010
20. Antitumor effect of cationic liposome incorporating keto-mycolic acid from Mycobacterium bovis bacillus Calmette-Guérin in mouse model
- Author
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Shuya Kandori, Ikuya Yano, Takahiro Kojima, Jun Miyazaki, Takayuki Yoshino, Hideyuki Akaza, and Hiroyuki Nishiyama
- Subjects
Bacillus (shape) ,chemistry.chemical_classification ,Cancer Research ,Mycobacterium bovis ,Bladder cancer ,biology ,business.industry ,medicine.medical_treatment ,Immunotherapy ,biology.organism_classification ,medicine.disease ,Microbiology ,Mycolic acid ,Oncology ,chemistry ,Intravesical instillation ,medicine ,Cationic liposome ,business - Abstract
461 Background: Intravesical instillation of live bacillus Calmette-Guérin (BCG) is an established immunotherapy for non-muscle invasive bladder cancer. However, development of non-infectious agents has been expected, because there are several problems due to instillation of live bacteria. BCG cell wall skeleton is known to stimulate host immune system, but the mechanism is still unknown. Mycolic acid (MA), which consist of three subclasses (α, keto, methoxy), is the most abundant lipid component of BCG cell wall and is expected to be one of essential active components. Objective: In order to identify active component from BCG cell wall and develop non-infectious BCG-derived immunotherapy, anti-tumor activities of cationic liposomes incorporating each subclass of MA were assessed using mouse syngeneic graft model. Methods: Heat killed packed cells of M. bovis BCG Tokyo 172 were fully hydrolyzed and MA was obtained. MA was separated to three subclasses by thin layer chromatography. Cationic and hydrophilic liposomes incorporating each subclass of MA were prepared. C57BL/6 mice were subcutaneously inoculated with a mixture of MB49 cells and PBS or liposome with/without MA followed by additional injection of PBS or liposome. Tumor growth was monitored. Infiltration of CD4/8 lymphocytes was examined by immunostaining. Results: Cationic liposomes were internalized into cytoplasm of MB49 cells, a mouse bladder cancer cell line. Cell proliferation was not affected by liposome incorporating MA. Tumor growth was significantly suppressed in mice treated with keto MA-liposome (vs PBS, p = 0.007), but not in mice treated withα-or methoxy-MA liposomes. Number of infiltrating CD8 lymphocytes was higher in tumor treated with keto MA-liposome than control. Antitumor effect of keto MA-liposome disappeared in nude mouse, while the effect existed in beige mouse with NK activity deficiency (vs PBS, p = 0.045). Conclusions: Keto MA-liposome showed the strongest antitumor effects in mouse model among three subclasses. T cell immunity may contribute to those effects.
- Published
- 2018
21. Comparable studies of immunostimulating activitiesin vitroamongMycobacterium bovisbacillus Calmette-Guérin (BCG) substrains
- Author
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Nagatoshi Fujiwara, Keita Kanai, Takemasa Takii, Emi Yasuda, Kikuo Onozaki, Saburo Yamamoto, Akiko Fujiwara, Yukiko Fujita, Emi Inagaki, Maki Kondo, Taku Chiba, Aya Kawarazaki, Daisuke Hayashi, and Ikuya Yano
- Subjects
Microbiology (medical) ,Immunology ,Nitric Oxide ,complex mixtures ,Microbiology ,Monocytes ,Cell Line ,Interferon-gamma ,Mice ,Serial passage ,Animals ,Humans ,Immunology and Allergy ,Interleukin 8 ,Cells, Cultured ,Mycobacterium bovis ,biology ,Tumor Necrosis Factor-alpha ,Interleukins ,Epithelial Cells ,General Medicine ,biology.organism_classification ,Virology ,In vitro ,Vaccination ,Infectious Diseases ,Cell culture ,Interleukin 12 ,Cord Factors ,Female ,Mycobacterium - Abstract
During the serial passage of Mycobacterium bovis bacillus Calmette-Guérin (BCG) in different countries after initial seed distribution from the Pasteur Institute, specific insertions and deletions in the genome among BCG substrains were observed and speculated to result in differences in immunological activities. 'Early-shared strains' of BCG (Russia, Moreau, Japan, Sweden, Birkhaug), distributed by the Pasteur Institute, which conserve three types of mycolate (alpha, methoxy, keto) in cell wall, exhibited stronger activities of induction of nitric oxide, interleukin-1beta (IL-1beta), IL-6, IL-8, IL-12 and tumor necrosis factor (TNF)-alpha, from human epithelial cell line A549, human myelomonocytic cell line THP-1 and mouse bone marrow cells in the presence of interferon-gamma (IFN-gamma) than did 'late-shared strains' of BCG (Danish, Glaxo, Mexico, Tice, Connaught, Montreal, Phipps, Australia, Pasteur). The stronger induction of IL-12 and TNF-alpha in the presence of IFN-gamma was also observed by trehalose 6,6'-dimycolate (TDM) extracted from BCG-Japan than by TDM from BCG-Connaught, which lacks the methoxymycolate residue. These results suggest that 'early-shared strains' are more potent immunostimulating agents than 'late-shared strains', which could be attributed partially to methoxymycolate. Our study provides the basic information for immunological characterization of various BCG strains and may contribute to a re-evaluation of them as a reference strain for vaccination against tuberculosis.
- Published
- 2009
22. Whole genome sequence analysis of Mycobacterium bovis bacillus Calmette–Guérin (BCG) Tokyo 172: A comparative study of BCG vaccine substrains
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Akira Koyama, Saburo Yamamoto, Ikuya Yano, Isao Fujita, Masaaki Seki, and Ikuro Honda
- Subjects
DNA, Bacterial ,medicine.medical_specialty ,Tuberculosis ,Molecular Sequence Data ,Single-nucleotide polymorphism ,Minisatellite Repeats ,Polymorphism, Single Nucleotide ,complex mixtures ,Genome ,Species Specificity ,Molecular genetics ,Genotype ,medicine ,Gene ,Mycobacterium bovis ,Base Sequence ,General Veterinary ,General Immunology and Microbiology ,biology ,Public Health, Environmental and Occupational Health ,biology.organism_classification ,medicine.disease ,Virology ,Infectious Diseases ,Genes, Bacterial ,BCG Vaccine ,Molecular Medicine ,BCG vaccine ,Genome, Bacterial - Abstract
To investigate the molecular characteristics of bacillus Calmette-Guérin (BCG) vaccines, the complete genomic sequence of Mycobacterium bovis BCG Tokyo 172 was determined, and the results were compared with those for BCG Pasteur and other M. tuberculosis complex. The genome of BCG Tokyo had a length of 4,371,711bp and contained 4033 genes, including 3950 genes coding for proteins (CDS). There were 18 regions of difference (showing differences of more than 20bp), 20 insertion or deletion (ins/del) mutations of less than 20bp, and 68 SNPs between the two BCG substrains. These findings are useful for better understanding of the genetic differences in BCG substrains due to in vitro evolution of BCG.
- Published
- 2009
23. The Mycobacterium avium Complex gtfTB Gene Encodes a Glucosyltransferase Required for the Biosynthesis of Serovar 8-Specific Glycopeptidolipid
- Author
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Yumi Maeda, Tetsu Mukai, Yuji Miyamoto, Masanori Kai, Ikuya Yano, Takashi Naka, and Masahiko Makino
- Subjects
DNA, Bacterial ,Serotype ,Glycosylation ,Molecular Sequence Data ,Mycobacterium smegmatis ,Virulence ,Microbiology ,Gas Chromatography-Mass Spectrometry ,Bacterial genetics ,Open Reading Frames ,Glycolipid ,Bacterial Proteins ,Humans ,Molecular Biology ,Gene ,Molecular Biology of Pathogens ,biology ,Glycopeptides ,Mycobacterium avium Complex ,biology.organism_classification ,Open reading frame ,Genes, Bacterial ,Glucosyltransferases ,Multigene Family ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,biology.protein ,Glucosyltransferase ,Glycolipids - Abstract
Mycobacterium avium complex (MAC) is one of the most common opportunistic pathogens widely distributed in the natural environment. The 28 serovars of MAC are defined by variable oligosaccharide portions of glycopeptidolipids (GPLs) that are abundant on the surface of the cell envelope. These GPLs are also known to contribute to the virulence of MAC. Serovar 8 is one of the dominant serovars isolated from AIDS patients, but the biosynthesis of serovar 8-specific GPL remains unknown. To clarify this, we compared gene clusters involved in the biosynthesis of several serovar-specific GPLs and identified the genomic region predicted to be responsible for GPL biosynthesis in a serovar 8 strain. Sequencing of this region revealed the presence of four open reading frames, three unnamed genes and gtfTB , the function of which has not been elucidated. The simultaneous expression of gtfTB and two downstream genes in a recombinant Mycobacterium smegmatis strain genetically modified to produce serovar 1-specific GPL resulted in the appearance of 4,6- O -(1-carboxyethylidene)-3- O -methyl-glucose, which is unique to serovar 8-specific GPL, suggesting that these three genes participate in its biosynthesis. Furthermore, functional analyses of gtfTB indicated that it encodes a glucosyltransferase that transfers a glucose residue via 1→3 linkage to a rhamnose residue of serovar 1-specific GPL, which is critical to the formation of the oligosaccharide portion of serovar 8-specific GPL. Our findings might provide a clue to understanding the biosynthetic regulation that modulates the biological functions of GPLs in MAC.
- Published
- 2008
24. Structural Analysis and Biosynthesis Gene Cluster of an Antigenic Glycopeptidolipid from Mycobacterium intracellulare
- Author
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Hisashi Ogura, Michael R. McNeil, Delphi Chatterjee, Ikuya Yano, Takashi Naka, Masahiko Makino, Noboru Nakata, Patrick J. Brennan, Matsumi Doe, Nagatoshi Fujiwara, Kazuo Kobayashi, Shinji Maeda, and Sohkichi Matsumoto
- Subjects
Serotype ,chemistry.chemical_classification ,Glycosylation ,Glycopeptides ,Oligosaccharide ,Biology ,Mycobacterium avium Complex ,biology.organism_classification ,Microbiology ,Epitope ,chemistry.chemical_compound ,Open reading frame ,Carbohydrate Sequence ,chemistry ,Genes, Bacterial ,Structural Biology ,Multigene Family ,Deoxy Sugars ,Gene cluster ,Glycolipids ,ORFS ,Molecular Biology ,Metabolic Networks and Pathways ,Mycobacterium - Abstract
Mycobacterium avium-Mycobacterium intracellulare complex (MAC) is the most common isolate of nontuberculous mycobacteria and causes pulmonary and extrapulmonary diseases. MAC species can be grouped into 31 serotypes by the epitopic oligosaccharide structure of the species-specific glycopeptidolipid (GPL) antigen. The GPL consists of a serotype-common fatty acyl peptide core with 3,4-di- O -methyl-rhamnose at the terminal alaninol and a 6-deoxy-talose at the allo -threonine and serotype-specific oligosaccharides extending from the 6-deoxy-talose. Although the complete structures of 15 serotype-specific GPLs have been defined, the serotype 16-specific GPL structure has not yet been elucidated. In this study, the chemical structure of the serotype 16 GPL derived from M. intracellulare was determined by using chromatography, mass spectrometry, and nuclear magnetic resonance analyses. The result indicates that the terminal carbohydrate epitope of the oligosaccharide is a novel N -acyl-dideoxy-hexose. By the combined linkage analysis, the oligosaccharide structure of serotype 16 GPL was determined to be 3-2′-methyl-3′-hydroxy-4′-methoxy-pentanoyl-amido-3,6-dideoxy-β-hexose-(1→3)-4- O -methyl-α- l -rhamnose-(1→3)-α- l -rhamnose-(1→3)-α- l -rhamnose-(1→2)-6-deoxy-α- l -talose. Next, the 22.9-kb serotype 16-specific gene cluster involved in the glycosylation of oligosaccharide was isolated and sequenced. The cluster contained 17 open reading frames (ORFs). Based on the similarity of the deduced amino acid sequences, it was assumed that the ORF functions include encoding three glycosyltransferases, an acyltransferase, an aminotransferase, and a methyltransferase. An M. avium serotype 1 strain was transformed with cosmid clone no. 253 containing gtfB - drrC of M. intracellulare serotype 16, and the transformant produced serotype 16 GPL. Together, the ORFs of this serotype 16-specific gene cluster are responsible for the biosynthesis of serotype 16 GPL.
- Published
- 2008
25. Comprehensive analysis of mycolic acid subclass and molecular species composition of Mycobacterium bovis BCG Tokyo 172 cell wall skeleton (SMP-105)
- Author
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Yukiko Fujita, Naoto Kusunose, Ikuya Yano, Yuko Uenishi, and Makoto Sunagawa
- Subjects
Microbiology (medical) ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Silica Gel ,Cell Wall Skeleton ,Microbiology ,Mass Spectrometry ,Cyclopropane ,Mycolic acid ,Cell wall ,chemistry.chemical_compound ,Organic chemistry ,Molecular Biology ,chemistry.chemical_classification ,Molecular Structure ,Molecular mass ,Nuclear magnetic resonance spectroscopy ,Fast atom bombardment ,Silicon Dioxide ,Mycobacterium bovis ,Matrix-assisted laser desorption/ionization ,Mycolic Acids ,chemistry ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Chromatography, Thin Layer ,Hydrogen - Abstract
The mycobacterial cell envelope consists of a characteristic cell wall skeleton (CWS), a mycoloyl arabinogalactan peptidoglycan complex, and related hydrophobic components that contribute to the cell surface properties. Since mycolic acids have recently been reported to play crucial roles in host immune response, detailed molecular characterization of mycolic acid subclasses and sub-subclasses of CWS from Mycobacterium bovis BCG Tokyo 172 (SMP-105) was performed. Mycolic acids were liberated by alkali hydrolysis from SMP-105, and their methyl esters were separated by silica gel TLC into three subclasses: alpha-, methoxy-, and keto-mycolates. Each mycolate subclass was further separated by silver nitrate (AgNO(3))-coated silica gel TLC into sub-subclasses. Molecular weights of individual mycolic acid were determined by MALDI-TOF mass spectrometry. alpha-Mycolates were sub-grouped into cis, cis-dicyclopropanoic (alpha1), and cis-monocyclopropanoic-cis-monoenoic (alpha2) series; methoxy-mycolates were sub-grouped into cis-monocyclopropanoic (m1), trans-monocyclopropanoic (m2), trans-monoenoic (m3), cis-monocyclopropanoic-trans-monoenoic (m4), cis-monoenoic (m5), and cis-monocyclopropanoic-cis-monoenoic (m6) series; and keto-mycolates were sub-grouped into cis-monocyclopropanoic (k1), trans-monocyclopropanoic (k2), trans-monoenoic (k3), cis-monoenoic (k4), and cis-monocyclopropanoic-cis-monoenoic (k5) series. The position of each functional group, including cyclopropane rings and methoxy and keto groups, was determined by analysis of the meromycolates with fast atom bombardment (FAB) mass spectrometry and FAB mass-mass spectrometry, and the cis/trans ratio of cyclopropane rings and double bonds were determined by NMR analysis of methyl mycolates. Mycolic acid subclass and molecular species composition of SMP-105 showed characteristic features including newly-identified cis-monocyclopropanoic-trans-monoenoic mycolic acid (m4).
- Published
- 2008
26. Serological response against Mycobacterium avium complex glycolipid antigens in patients with acquired immunodeficiency syndrome
- Author
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Toshio Hattori, Ikuya Yano, Aikichi Iwamoto, Heinner Guio, Takeshi Matsumura, and Yugo Ashino
- Subjects
Adult ,Male ,Immunology ,Microbiology ,Immunoglobulin G ,Serology ,Glycolipid ,Acquired immunodeficiency syndrome (AIDS) ,Antigen ,Virology ,medicine ,Humans ,In patient ,Aged ,Acquired Immunodeficiency Syndrome ,Antigens, Bacterial ,Mycobacterium bovis ,biology ,Middle Aged ,Mycobacterium avium Complex ,biology.organism_classification ,medicine.disease ,Antibodies, Bacterial ,biology.protein ,Female ,Glycolipids ,Antibody - Abstract
In 43 MAC infected patients (23 non-HIV and 20 AIDS) the IgG response against 3 BCG and 2 MAC antigens was assessed. The response to four antigens in patients with AIDS was considerably lower than in non-HIV infected patients. Therefore, antibody production against MAC glycolipid antigens was impaired in AIDS patients.
- Published
- 2008
27. New packaging method of mycobacterial cell wall using octaarginine-modified liposomes: Enhanced uptake by and immunostimulatory activity of dendritic cells
- Author
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Shiroh Futaki, Kentaro Kogure, Hideyoshi Harashima, Atthachai Homhuan, Hideyuki Akaza, Takashi Naka, Yukiko Fujita, and Ikuya Yano
- Subjects
Male ,Arginine ,medicine.drug_class ,Chemistry, Pharmaceutical ,Drug Compounding ,Pharmaceutical Science ,Cancer Vaccines ,Immunostimulant ,Cell wall ,Mice ,Cell Wall ,medicine ,Animals ,Particle Size ,Cells, Cultured ,CD86 ,MHC class II ,Liposome ,biology ,Interleukin-12 Subunit p40 ,Histocompatibility Antigens Class II ,Dendritic Cells ,Dendritic cell ,Lipids ,Mycobacterium bovis ,Mice, Inbred C57BL ,Cholesterol ,Solubility ,Biochemistry ,Liposomes ,B7-1 Antigen ,Phosphatidylcholines ,biology.protein ,Biophysics ,B7-2 Antigen ,Oligopeptides ,CD80 - Abstract
Despite the potential of mycobacterial cell wall (CW) components to serve as immunotherapeutic agents, this application is hampered by the molecules' unfavorable physicochemical properties, such as its high molecular weight, poor solubility and negatively charged nature. Here we describe a new mycobacterial CW delivery system that uses an efficient and simple packaging method. This is achieved by incorporating mycobacterial CW into liposomes and attaching arginine octamers (R8) to the liposome surface. R8-modified liposomes improve the uptake of mycobacterial CW by dendritic cells (DC) and enhance its immunostimulatory activity. High R8 surface density promoted high levels of mycobacterial CW uptake by DC compared to low density R8-modified liposomes. Maturation markers (CD80, CD86, MHC Class II molecules) showed significantly enhanced expression on DC pulsed with high density R8-modified liposomes containing mycobacterial CW. Moreover, R8-modified liposomes with mycobacterial CW incorporated induced production of IL-12 p40 by DC, at levels similar to those produced by lipopolysaccharide-pulsed DC. We assert that R8-modified liposomes with mycobacterial CW incorporated should have tremendous potential as immune-potentiating agents.
- Published
- 2007
28. Serological test and chest computed tomography findings in patients with Mycobacterium avium complex lung disease
- Author
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Touru Hiraga, T. Fujikawa, Ryoji Maekura, Seigo Kitada, Ikuya Yano, Hisako Hashimoto, M. Motone, Yukiko Nishiuchi, Mari Miki, N. Naka, Keisuke Miki, Kenji Yoshimura, and Kazuo Kobayashi
- Subjects
Lung Diseases ,Male ,Pulmonary and Respiratory Medicine ,Thorax ,Pathology ,medicine.medical_specialty ,Radiography ,Mycobacterium Infections, Nontuberculous ,Enzyme-Linked Immunosorbent Assay ,Disease ,Serology ,medicine ,Humans ,Serologic Tests ,Aged ,Mycobacterium Infections ,Bronchiectasis ,biology ,business.industry ,Respiratory disease ,Middle Aged ,Mycobacterium avium Complex ,medicine.disease ,Immunoglobulin A ,biology.protein ,Sputum ,Female ,Radiography, Thoracic ,Glycolipids ,medicine.symptom ,Antibody ,Tomography, X-Ray Computed ,business - Abstract
The present authors have previously reported the usefulness of a serodiagnostic test to detect serum glycopeptidolipid (GPL) core antibody in diagnosing Mycobacterium avium complex (MAC) lung disease in immunocompetent patients. The aim of the present study was to investigate correlations between the levels of antibody against GPL core and chest computed tomography (CCT) findings in patients with MAC lung disease. A total of 47 patients with MAC-positive culture from their sputum and who had radiographic abnormalities were investigated. Thirty-three patients met the American Thoracic Society criteria for MAC disease; 14 did not. All patients underwent both CCT examination and the serodiagnostic test for MAC at the same time. Small nodular shadows were seen on CCT in all 47 patients and bronchiectasis shadows were seen in 39 (83%) of them. There was a significant positive correlation between the extent of the disease and the level of GPL core immunoglobulin (Ig)A antibody. The levels of GPL core IgA antibody were significantly elevated in patients who had nodular shadows (10-30 mm) compared with patients who had small nodular shadows (
- Published
- 2007
29. Structural Characterization of a Specific Glycopeptidolipid Containing a Novel N -Acyl-Deoxy Sugar from Mycobacterium intracellulare Serotype 7 and Genetic Analysis of Its Glycosylation Pathway
- Author
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Nagatoshi Fujiwara, Kazuo Kobayashi, Noboru Nakata, Shinji Maeda, Takashi Naka, Ikuya Yano, and Matsumi Doe
- Subjects
Serotype ,Spectrometry, Mass, Electrospray Ionization ,Chromatography, Gas ,Glycosylation ,Magnetic Resonance Spectroscopy ,Rhamnose ,Molecular Sequence Data ,Genetics and Molecular Biology ,Spectrometry, Mass, Fast Atom Bombardment ,Microbiology ,chemistry.chemical_compound ,Glycolipid ,Deoxy Sugars ,Gene cluster ,Serotyping ,ORFS ,Molecular Biology ,Molecular Structure ,biology ,Mycobacterium avium Complex ,biology.organism_classification ,Carbohydrate Sequence ,chemistry ,Genes, Bacterial ,Nontuberculous mycobacteria ,Glycolipids ,Metabolic Networks and Pathways ,Mycobacterium - Abstract
The nontuberculous Mycobacterium avium-Mycobacterium intracellulare complex (MAC) is distributed ubiquitously in the environment and is an important cause of respiratory and lymphatic disease in humans and animals. These species produce polar glycopeptidolipids (GPLs), and of particular interest is their serotype-specific antigenicity. Structurally, GPLs contain an N-acylated tetrapeptide-amino alcohol core that is glycosylated at the C terminal with 3,4-di-O-methyl rhamnose and at the D-allo-threonine with a 6-deoxy-talose. This serotype nonspecific GPL is found in all MAC species. The serotype-specific GPLs are further glycosylated with a variable haptenic oligosaccharide at 6-deoxy-talose. At present, 31 distinct serotype-specific GPLs have been identified on the basis of oligosaccharide composition, and the complete structures of 14 serotype-specific GPLs have been defined. It is considered that the modification of the GPL structure plays an important role in bacterial physiology, pathogenesis, and host immune responses. In this study, we defined the complete structure of a novel serotype 7 GPL that has a unique terminal amido sugar. The main molecular mass is 1,874, and attached to the tetrapeptide-amino alcohol core is the serotype 7-specific oligosaccharide unit of 4-2-hydroxypropanoyl-amido-4,6-dideoxy-2-O-methyl--hexose-(133)--L-rhamnose-(133)--L-rhamnose-(133)--L-rhamnose-(132)--L-6-deoxy-talose. Moreover, we isolated and characterized the serotype 7-specific gene cluster involved in glycosylation of the oligosaccharide. Nine open reading frames (ORFs) were observed in the cluster. Based on the sequence homology, the ORFs are thought to participate in the biosynthesis of the serotype 7 GPL. About 10% of mycobacterial diseases are caused by nontuberculous mycobacteria. Among them, the closely related Mycobacterium avium and Mycobacterium intracellulare are commonly grouped as M. avium-intracellulare complex (MAC). Organisms of this complex are ubiquitous in nature and have been isolated from water, soil, plants, house dust, and other environmental sources. MAC infections have become increasingly common, and MAC is the most common cause of disease due to nontuberculous mycobacteria in humans (13). These organisms have distinctive laboratory characteristics, are not communicable from person to person, and are often resistant to standard antituberculosis drugs. The mycobacterial cell wall contains numerous antigenic or immunoregulatory glycolipid molecules with great structural diversity that are considered to be involved in the bacterial
- Published
- 2007
30. Middle-aged to elderly women have a higher asymptomatic infection rate with Mycobacterium avium complex, regardless of body habitus
- Author
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Tomoyasu, Nishimura, Yukiko, Fujita-Suzuki, Masaaki, Mori, Stephen M, Carpenter, Hiroshi, Fujiwara, Yoshifumi, Uwamino, Eiko, Tamizu, Ikuya, Yano, Hiroshi, Kawabe, and Naoki, Hasegawa
- Subjects
Adult ,Male ,Middle Aged ,Mycobacterium avium Complex ,Body Mass Index ,Young Adult ,Sex Factors ,Japan ,Prevalence ,Humans ,Female ,Asymptomatic Infections ,Aged ,Mycobacterium avium-intracellulare Infection - Abstract
Mycobacterium avium complex (MAC) pulmonary disease is prevalent in middle-aged to elderly women with a thin body habitus. By comparing the rate of serologically diagnosed asymptomatic MAC infection and body mass index among 1033 healthy subjects, we find that middle-aged to elderly women became infected with MAC, regardless of their body habitus.
- Published
- 2015
31. Recurrence of disseminated Mycobacterium avium complex disease in a patient with anti-gamma interferon autoantibodies by reinfection
- Author
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Yoshihito Otsuka, Yukiko Fujita-Suzuki, Naoki Hasegawa, Makoto Yonemaru, Kiyofumi Ohkusu, Ho Namkoong, Takuro Sakagami, Stephen M. Carpenter, Tomoyasu Nishimura, and Ikuya Yano
- Subjects
Microbiology (medical) ,Mycobacterium avium-intracellulare infection ,Disease ,Case Reports ,Interferon-gamma ,Interferon ,Gamma interferon ,medicine ,Humans ,Interferon gamma ,Mycobacterium avium complex ,Aged ,Autoantibodies ,Mycobacterium avium-intracellulare Infection ,biology ,business.industry ,Autoantibody ,Antibody titer ,medicine.disease ,biology.organism_classification ,Mycobacterium avium Complex ,Virology ,Immunology ,Female ,business ,medicine.drug - Abstract
We report a case of recurrent disseminated Mycobacterium avium complex (DMAC) disease with anti-gamma interferon autoantibodies. To our knowledge, this is the first reported case caused by reinfection with a separate isolate of M. avium . DMAC disease activity was monitored using serum IgG antibody titers against lipid antigens extracted from a MAC strain.
- Published
- 2015
32. Identification of two subpopulations of Bacillus Calmette-Guérin (BCG) Tokyo172 substrain with different RD16 regions
- Author
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Akira Koyama, Ichiro Toida, Saburo Yamamoto, Ikuro Honda, Masaaki Seki, Ikuya Yano, and Noriko Ikeda
- Subjects
Genotype ,Microbiology ,Mice ,chemistry.chemical_compound ,Multiplex polymerase chain reaction ,Animals ,Tuberculosis ,Lung ,Bacillus (shape) ,Bacillaceae ,General Veterinary ,General Immunology and Microbiology ,biology ,Public Health, Environmental and Occupational Health ,Colony morphology ,biology.organism_classification ,Mycobacterium bovis ,Bacillales ,Mice, Inbred C57BL ,Infectious Diseases ,Liver ,chemistry ,Genes, Bacterial ,Middlebrook 7H10 Agar ,Molecular Medicine ,Female ,Spleen ,Bacteria - Abstract
Two types of colonies with different morphologies (smooth: S and rough: R) formed when Bacillus Calmette-Guérin (BCG) Tokyo172 substrain was cultured on Middlebrook 7H10 agar medium, and their genotypes were analyzed by multiplex PCR on five RD regions and SenX3-RegX3. In most cases these two colony types had different genotypes, i.e., S colonies showed a characteristic 22 bp deletion in Rv3405c of the RD16 region (type I), and R colonies did not have this deletion (type II) similar to many other BCG substrains. Thus, there was a strong relationship between colony morphology and genotype. Both genotypes were found in every Tokyo172 preparation tested, including the seed lot for production, the origin of seed lot from the 1960s and ATCC BCG Japan. Type I was always in the majority. It was suggested that types I and II constituted independent subpopulations within the Tokyo172 substrain. Type I was shown to have a growth advantage over type II both on culture media and in mice organs.
- Published
- 2006
33. Mycobacterial sulfolipid shows a virulence by inhibiting cord factor induced granuloma formation and TNF-α release
- Author
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Manabu Hirai, Yukiko Fujita, Ikuya Yano, Yuko Okamoto, Ikuko Tomiyasu, and Takashi Naka
- Subjects
Male ,Virulence Factors ,medicine.medical_treatment ,Context (language use) ,Biology ,Microbiology ,Mice ,chemistry.chemical_compound ,Glycolipid ,Species Specificity ,medicine ,Animals ,Mice, Inbred BALB C ,Mice, Inbred C3H ,Mice, Inbred ICR ,Granuloma ,Cord factor ,Tumor Necrosis Factor-alpha ,Macrophages ,Mycobacterium tuberculosis ,In vitro ,Trehalose dimycolate ,Infectious Diseases ,Cytokine ,chemistry ,Toxicity ,Cord Factors ,Tumor necrosis factor alpha ,Glycolipids - Abstract
Virulence mechanism of infection with Mycobacterium tuberculosis is currently focused to be clarified in the context of cell surface lipid molecule. Comparing two mycobacterial glycolipids, we observed toxicity and prominent granulomatogenic activity of trehalose 6,6'-dimycolate (TDM) injection in mice, evident by delayed body weight gain and histological observations, whereas 2,3,6,6'-tetraacyl trehalose 2'-sulfate (SL) was non-toxic and non-granulomatogenic. Likewise, TDM but not SL caused temporarily, but marked increase of lung indices, indicative of massive granuloma formation. Interestingly, co-administration of TDM and SL prevented these symptoms distinctively and SL inhibited TDM-induced release of tumor necrosis factor alpha (TNF-alpha) in a dose-dependent manner. Histological findings and organ index changes also showed marked inhibition of TDM induced granuloma formation by co-administration of SL. Simultaneous injection of SL together with TDM was highly effective for this protection, as neither injection 1h before nor after TDM injection showed highly inhibitory. In parallel studies on a cellular level, TDM elicited strong TNF-alpha release from alveolar but not from peritoneal macrophages in vitro. This effect was blocked when alveolar macrophages were incubated in wells simultaneously coated with TDM and SL, indicating that SL suppresses TDM-induced TNF-alpha release from macrophages. Our results suggest a novel mechanism by which SL could contribute to virulence at early stage of mycobacterial infection or stimulation with the glycolipids by counteracting the immunopotentiating effect of TDM.
- Published
- 2006
34. Macrophage scavenger receptor down-regulates mycobacterial cord factor-induced proinflammatory cytokine production by alveolar and hepatic macrophages
- Author
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Kazuo Kobayashi, Yuriko Ozeki, Kenji Kaneda, Norifumi Kawada, Tatsuhiko Kodama, Hiroshi Suzuki, Hiroko Tsutsui, Ikuya Yano, and Motoyuki Kataoka
- Subjects
Kupffer Cells ,medicine.medical_treatment ,Down-Regulation ,Biology ,Microbiology ,Proinflammatory cytokine ,Mice ,Macrophages, Alveolar ,medicine ,Animals ,Macrophage ,Scavenger receptor ,Chemokine CCL4 ,Cord factor ,Tumor Necrosis Factor-alpha ,Kupffer cell ,Scavenger Receptors, Class A ,Mycobacterium tuberculosis ,Macrophage Activation ,Macrophage Inflammatory Proteins ,Molecular biology ,Infectious Diseases ,medicine.anatomical_structure ,Cytokine ,Immunology ,Alveolar macrophage ,Cord Factors ,Cytokines ,Tumor necrosis factor alpha - Abstract
We aimed to reveal the regulatory function of macrophage scavenger receptor-A (MSR-A) in proinflammatory cytokine production by macrophages stimulated with mycobacterial cord factor (CF). By the culture with CF, MSR-A (+/+) alveolar macrophages and Kupffer cells produced TNF-alpha/MIP-1alpha in a time- and dose-dependent manner. However, the amounts of cytokines produced by them were much less compared to those produced by MSR-A (-/-) macrophages. Consistent with this, treatment of MSR-A (+/+) macrophages with anti-MSR-A antibody increased TNF-alpha production. Binding of CF to MSR-A was demonstrated by measuring the binding affinity. These results indicate that CF binds MSR-A, and MSR-A down-regulates TNF-alpha/MIP-1alpha production by activated macrophages, suggesting the role of this receptor in suppression of excessive inflammatory responses during mycobacterial infection.
- Published
- 2006
35. Involvement of Mannose Receptor in Glycopeptidolipid-Mediated Inhibition of Phagosome-Lysosome Fusion
- Author
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Kenichi Shimada, Yoshio Kumazawa, Ikuya Yano, and Hiroaki Takimoto
- Subjects
Staphylococcus aureus ,Calmodulin ,Phagocytosis ,Immunology ,Receptors, Cell Surface ,Complement receptor ,Microbiology ,Cell Line ,Glycolipid ,Phagosomes ,Virology ,Humans ,Lectins, C-Type ,Opsonin ,Phagosome ,Phagosome-lysosome fusion ,biology ,Macrophages ,Glycopeptides ,Mycobacterium avium Complex ,Molecular biology ,Mannose-Binding Lectins ,Biochemistry ,biology.protein ,Glycolipids ,Lysosomes ,Mannose Receptor ,Mannose receptor - Abstract
We previously reported that glycopeptidolipid (GPL) isolated from Mycobacterium avium serovar 4 inhibited phagosome-lysosome (P-L) fusion when macrophages phagocytosed heat-killed Staphylococcus aureus (SA). In the present study we analyzed the underlying inhibitory mechanism of GPL coated on SA. Elimination of oligosaccharide from GPL abrogated its inhibitory activity. GPL did not inhibit P-L fusion of opsonized SA phagocytosed via complement receptors. The inhibitory activity of GPL was competitively reduced by the presence of alpha-methyl-D-mannoside and anti-mannose receptor antibody, suggesting that inhibition of P-L fusion by GPL is mediated through mannose receptor. Recruitment of early endosome antigen 1 and Ca2+/calmodulin kinase II in human macrophage-like THP-1 cells were significantly suppressed by GPL, indicating that GPL inhibits steps for leading to the P-L fusion.
- Published
- 2006
36. Temperature-dependent biosynthesis of glucose monomycolate and its recognition by CD1-restricted T cells
- Author
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Kazuo Shimizu, Tetsuo Kawashima, Masahiko Sugita, Takashi Naka, Akimasa Sato, Hidemi Takahashi, Isamu Matsunaga, Ikuya Yano, Yoshihiko Norose, and Yutaka Enomoto
- Subjects
Interleukin 2 ,Glycosylation ,T-Lymphocytes ,T cell ,Biophysics ,CD1 ,Human skin ,Biology ,Biochemistry ,Microbiology ,Antigens, CD1 ,Cell wall ,chemistry.chemical_compound ,Glycolipid ,Immune system ,Biosynthesis ,medicine ,Humans ,Molecular Biology ,Cells, Cultured ,Temperature ,Cell Biology ,medicine.anatomical_structure ,chemistry ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Interleukin-2 ,Glycolipids ,medicine.drug - Abstract
Mycolic acids are long chain fatty acids that constitute the lipid-rich cell wall framework of mycobacteria. Upon infection, mycobacteria begin to synthesize glucose monomycolate (GMM), a glucosylated species of mycolic acids, by utilizing host-derived glucose as sugar source. Accordingly, GMM production serves as a good indicator for local invasion of mycobacteria, and its detection by the host immune system would favor efficient monitoring of mycobacterial infection. Here, we found that GMM was produced abundantly at 30 degrees C rather than at 37 degrees C and recognized by a GMM-specific, CD1-restricted T cell line that was isolated from mycobacteria-infected human skin. Since the common portal sites for mycobacterial infection include ventilating alveoli of the lung and the externally exposed skin that often render invading microbes survive at reduced temperature, sampling GMM by CD1 lipid antigen-presenting molecules may allow the host to detect mycobacterial infection at its early phases.
- Published
- 2005
37. Clinical and Prognostic Importance of Serotyping Mycobacterium avium-Mycobacterium intracellulare Complex Isolates in Human Immunodeficiency Virus-Negative Patients
- Author
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Kenji Yoshimura, Atsusi Hirotani, Kazuo Kobayashi, Touru Hiraga, Ikuya Yano, Ryoji Maekura, Seigo Kitada, Masami Ito, and Yoshinari Okuda
- Subjects
Male ,Microbiology (medical) ,Serotype ,medicine.medical_specialty ,Mycobacterium avium-intracellulare infection ,Microbial Sensitivity Tests ,Gastroenterology ,Virus ,HIV Seronegativity ,Internal medicine ,Immunopathology ,medicine ,Humans ,Serotyping ,Sida ,Aged ,Mycobacterium avium-intracellulare Infection ,Aged, 80 and over ,biology ,Mycobacteriology and Aerobic Actinomycetes ,Middle Aged ,Mycobacterium avium Complex ,Prognosis ,biology.organism_classification ,medicine.disease ,Survival Analysis ,Anti-Bacterial Agents ,Radiography ,Respiratory failure ,Immunology ,Female ,Viral disease ,Mycobacterium - Abstract
We studied whether the serotypes of Mycobacterium avium-Mycobacterium intracellulare complex (MAC) isolates determine the prognosis for pulmonary MAC disease. We prospectively monitored a cohort of 68 patients with pulmonary MAC disease for whom the serotype-specific glycopeptidolipids in isolates were identified using thin-layer chromatography and fast atom bombardment mass-spectrometry in 1990 and 1995. Serovar 4 Mycobacterium avium was detected in 40/68 patients (58.8%). Other serotypes were serotypes 1 (five cases), 6 (three cases), 8 (seven cases), 9 (three cases), 14 (four cases), and 16 (six cases). Patients with serovar 4 were significantly ( P < 0.01) younger (63.0 ± 9.8 years) than patients with other serotypes (71.8 ± 10.3). Patients who failed treatment had a significantly poorer prognosis than other patients. There were no cases of MAC-related death in the cured group. Chest radiographic findings progressively worsened in 36 (90%) of patients with serotype 4, and 14/36 died from respiratory failure caused by pulmonary Mycobacterium avium disease. The patients with serotype 4 had a significantly poorer prognosis than patients with other serotypes. These results show that both the outcome of chemotherapy and the serotypes of MAC isolates are important for assessing the prognosis of pulmonary MAC disease.
- Published
- 2005
38. Use of Glycopeptidolipid Core Antigen for Serodiagnosis of Mycobacterium avium Complex Pulmonary Disease in Immunocompetent Patients
- Author
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Naomi Toyoshima, Seigo Kitada, Nagatoshi Fujiwara, Kazuo Kobayashi, Masami Kobayashi, Masami Ito, Ryoji Maekura, Ikuya Yano, and Takashi Naka
- Subjects
Adult ,Male ,Microbiology (medical) ,Immunoglobulin A ,Tuberculosis ,Clinical Biochemistry ,Immunology ,Mycobacterium avium-intracellulare infection ,Sensitivity and Specificity ,Immunoenzyme Techniques ,Antigen ,medicine ,Animals ,Humans ,Immunology and Allergy ,Aged ,Mycobacterium avium-intracellulare Infection ,Aged, 80 and over ,Mycobacterium kansasii ,Antigens, Bacterial ,biology ,medicine.diagnostic_test ,Middle Aged ,Mycobacterium avium Complex ,medicine.disease ,biology.organism_classification ,Antibodies, Bacterial ,Virology ,Anti-Bacterial Agents ,Immunoassay ,biology.protein ,Female ,Microbial Immunology ,Antibody ,Immunocompetence ,Mycobacterium avium - Abstract
We report the development of a serodiagnostic method for Mycobacterium avium complex (MAC) disease with an enzyme immunoassay (EIA) with the MAC-specific glycopeptidolipid (GPL) core as the antigen. In this study, we confirmed by EIA that the GPL core antibody was in the sera of immunocompetent patients with MAC disease. The EIA for quantifying the GPL core antibody was evaluated as a clinical tool for serodiagnosis of pulmonary MAC disease. A significant increase in GPL core antibodies (immunoglobulins G, A, and M) was detected in sera of patients with MAC pulmonary diseases when they were compared to patients who were colonized with MAC, patients with Mycobacterium kansasii disease or tuberculosis, and healthy subjects. The sensitivities and specificities of the GPL core-based EIA for diagnosis of MAC pulmonary disease were 72.6% and 92.2%, respectively, for IgG, 92.5% and 95.1%, respectively, for IgA, and 78.3% and 91.0%, respectively, for IgM. The best sensitivity and specificity were obtained by measuring immunoglobulin A antibodies against GPL core antigen. The level of GPL core antibodies reflected disease activity, since it decreased in cured MAC patients who had responded to chemotherapy. Measurement of serum antibodies against GPL core is useful for both diagnosis and assessment of disease activity in MAC disease of the lung.
- Published
- 2005
39. Serotype-Specific Modulation of Human Monocyte Functions by Glycopeptidolipid (GPL) Isolated from Mycobacterium avium Complex
- Author
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Takeshi Doi, Yukiko Fujita, Yoshio Kumazawa, Hideyuki Kano, Ikuya Yano, and Hiroaki Takimoto
- Subjects
Pharmacology ,Serotype ,Dose-Response Relationship, Drug ,medicine.drug_class ,Phagocytosis ,Monocyte ,T cell ,Glycopeptides ,Pharmaceutical Science ,General Medicine ,Biology ,Monoclonal antibody ,medicine.disease_cause ,Peripheral blood mononuclear cell ,Monocytes ,Microbiology ,medicine.anatomical_structure ,Staphylococcus aureus ,medicine ,Humans ,Macrophage ,Glycolipids ,Serotyping ,Mycobacterium avium - Abstract
Immunomodulating activity of glycopeptidolipids (GPL), separated from different serovars of Mycobacterium avium complex (MAC), on macrophage functions was compared. When peripheral blood mononuclear cells (PBMC), from healthy donors showing strongly positive reactions to mycobacterial purified protein derivatives (PPD), were incubated with heat-killed Staphylococcus aureus coated with GPL serovar 4, phagocytosis of monocytes increased in dose-dependent manner. However, coating with GPL serovar 9 did not show any effects. After phagocytosis of heat-killed S. aureus, the phagosome-lysosome (P-L) fusion in monocytes was inhibited dose-dependently by coating of S. aureus with GPL serovar 4, but not serovar 9. These results indicate that GPL serovar 4 facilitates invasion of MAC into monocytes and renders resistance to bactericidal reactions due to the inhibition of P-L fusion. Regarding accessory function of macrophages in proliferative responses of T cells, the addition of GPL serovar 4 to cultures resulted in significant inhibition of anti-CD3 monoclonal antibody (mAb)-induced proliferation, whereas both serovar GPLs did not cause reduction of cell viability. Furthermore, the PPD-specific T cell proliferative response was downregulated markedly by GPL serovar 4, but weakly suppressed by GPL serovar 9. These results indicated that the immunomodulating activity of GPL on macrophage functions is serovar-dependent.
- Published
- 2005
40. Structural analysis of sphingophospholipids derived from Sphingobacterium spiritivorum, the type species of genus Sphingobacterium
- Author
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Norikazu Ikeda, Yoshio Kumazawa, Yoshiko Kato, Miki Minamino, Nagatoshi Fujiwara, Ikuko Tomiyasu, Takashi Naka, Ikuya Yano, Matsumi Doe, Kazuo Kobayashi, Shinji Maeda, and Kazuhito Watabe
- Subjects
Ceramide ,Magnetic Resonance Spectroscopy ,Sphingobacterium mizutaii ,Spectrophotometry, Infrared ,Sphingobacterium multivorum ,Spectrometry, Mass, Fast Atom Bombardment ,Biology ,Ceramides ,medicine.disease_cause ,Microbiology ,Genus Sphingobacterium ,chemistry.chemical_compound ,medicine ,Sphingobacterium spiritivorum ,Sphingobacterium ,Molecular Biology ,Phospholipids ,Sphingolipids ,Molecular Structure ,Fatty Acids ,Sphingobacterium thalpophilum ,Cell Biology ,Sphingobacterium faecium ,Type species ,Solubility ,chemistry ,Biochemistry ,Chromatography, Thin Layer - Abstract
The unique feature of the genus Sphingobacterium is the presence of sphingophospholipids and ceramides, besides diacylglycerophospholipids. As major cellular lipid components, five kinds of sphingophospholipids were purified from Sphingobacterium spiritivorum ATCC 33861(T), the type species of genus Sphingobacterium. They were identified as ceramide phosphorylethanolamines (CerPE-1 and CerPE-2), ceramide phosphoryl-myo-inositols (CerPI-1 and CerPI-2), and ceramide phosphorylmannose (CerPM-1). The ceramide of CerPE-1, CerPI-1, and CerPM-1 was composed of 15-methylhexadecasphinganine (isoheptadeca sphinganine, iso-C17:0) and 13-methyltetradecanoic acid (isopentadecanoic acid, iso-C15:0), whereas that of CerPE-2 and CerPI-2 was composed of isoheptadeca sphinganine and 2-hydroxy-13-methyltetradecanoic acid (2-hydroxy isopentadecanoic acid, 2-OH iso-C15:0). These sphingophospholipids were also found in cellular lipids of Sphingobacterium multivorum ATCC 33613(T), Sphingobacterium mizutaii ATCC 33299(T), Sphingobacterium faecium IFO 15299(T), Sphingobacterium thalpophilum ATCC 43320(T), and Sphingobacterium antarcticum ATCC 51969(T). To our knowledge, the existence of CerPM-1 is a novel sphingophospholipid through eukaryotic and prokaryotic cells.
- Published
- 2003
41. Prospective Clinical Evaluation of the Serologic Tuberculous Glycolipid Test in Combination with the Nucleic Acid Amplification Test
- Author
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Ryoji Maekura, Takeshi Ogura, Yoshinari Okuda, Atsushi Hirotani, Masami Ito, Hiroaki Kohno, and Ikuya Yano
- Subjects
DNA, Bacterial ,Microbiology (medical) ,medicine.medical_specialty ,Tuberculosis ,Gastroenterology ,Serology ,Mycobacterium tuberculosis ,Glycolipid ,Internal medicine ,medicine ,Humans ,Serologic Tests ,Prospective Studies ,Prospective cohort study ,Tuberculosis, Pulmonary ,biology ,Mycobacteriology and Aerobic Actinomycetes ,Nucleic acid amplification technique ,biology.organism_classification ,medicine.disease ,Test (assessment) ,Immunology ,Nucleic acid ,Glycolipids ,Nucleic Acid Amplification Techniques - Abstract
We have conducted a prospective controlled multicenter study to evaluate differences in the levels of clinical utility of the tuberculous glycolipid (TBGL) serodiagnostic test and the nucleic acid amplification test in patients with smear-negative active pulmonary tuberculosis (TB). The TBGL test and the PCR test were individually not so useful for the rapid diagnosis of smear-negative active pulmonary TB. However, clinical utility was considerably improved by using the TBGL test and the PCR test in combination, especially in patients with smear-negative and culture-negative active pulmonary TB and in patients with minimally advanced lesions.
- Published
- 2003
42. A murine model of granulomatous colitis with mesenteric lymphadenitis induced by mycobacterial cord factor
- Author
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Tamaki Yamada, Hirokazu Yamagami, Takayuki Matsumoto, Kenji Kaneda, Ikuya Yano, Tetsuo Arakawa, Mitsue Sogawa, Yuriko Ozeki, and Yuji Nakajima
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Colon ,Spleen ,Inflammation ,Mycobacterium ,Pathology and Forensic Medicine ,Immunoenzyme Techniques ,Adjuvants, Immunologic ,Crohn Disease ,Antigens, CD ,T-Lymphocyte Subsets ,Fibrosis ,medicine ,Animals ,Mesenteric lymph nodes ,Rats, Wistar ,Molecular Biology ,Mesenteric Lymphadenitis ,Lamina propria ,Cord factor ,business.industry ,Macrophages ,Organ Size ,Cell Biology ,General Medicine ,medicine.disease ,Rats ,Specific Pathogen-Free Organisms ,Disease Models, Animal ,medicine.anatomical_structure ,Lymphatic system ,Liposomes ,Immunology ,Subserosa ,Cord Factors ,medicine.symptom ,business - Abstract
Granulomatous colitis is a major entity of human intestinal diseases. We previously reported that intravenous injection of mycobacterial cord factor (CF), a potent macrophage activator, induced pulmonary granulomas in mice with enhanced production of Th1 cytokines and chemokines. In this study we made a murine model of granulomatous colitis by intramural injection of CF. A single dose of 300 microg CF was injected into the wall of the rat and mouse colon in the form of liposomes. After 1 week granulomas developed at the injection site, extending from the subserosa to the lamina propria, and persisted for longer than 6 weeks. They were composed mainly of ED1-positive macrophages, which often underwent apoptosis, and CD4(+) and CD8(+) lymphocytes, which preferentially infiltrated around the macrophage accumulation. Myofibroblast proliferation was not prominent, and no appreciable fibrosis resulted after the decline of granulomas. Although the intestinal epithelium was involved in inflammation, tissue injuries such as mucosal erosion or ulceration were not induced. When granulomas were formed near the Peyer's patches, they invaded deeply into the lymphoid tissue, producing many small islands. The mesenteric lymph nodes also had many granulomatous islands in the cortex and medulla, but the liver and spleen displayed no granulomatous changes, suggesting that liposomal CF spreads via the lymphatic vessels from the injection site. The CF-induced colonic granulomas associated with mesenteric lymphadenitis will be useful for investigating human granulomatous colitis.
- Published
- 2003
43. Mechanism responsible for the antitumor effect of BCG-CWS using the LEEL method in a mouse bladder cancer model
- Author
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Hideyoshi Harashima, Takashi Nakamura, Hideyuki Akaza, Ikuya Yano, Masafumi Fukiage, Hiroyuki Nishiyama, Jun Miyazaki, and Yoshiteru Suzuki
- Subjects
medicine.medical_treatment ,media_common.quotation_subject ,Cancer Model ,Pharmaceutical Science ,Cancer immunotherapy ,Antineoplastic Agents ,Cell Wall Skeleton ,complex mixtures ,BCG-CWS ,Leukocyte Count ,Mice ,Immune system ,Nanoparticle ,Cell Line, Tumor ,Medicine ,Animals ,Internalization ,Delivery system ,media_common ,Mice, Inbred C3H ,Bladder cancer ,business.industry ,Mechanism (biology) ,Cancer ,Dendritic Cells ,medicine.disease ,Lipids ,Xenograft Model Antitumor Assays ,Urinary Bladder Neoplasms ,Immunology ,BCG Vaccine ,Emulsions ,Female ,business - Abstract
We previously reported on the development of a water soluble formulation of the cell wall skeleton of BCG (BCG-CWS), a major immune active center of BCG, by encapsulating it into a nanoparticle (CWS-NP). The CWS-NP allowed us to clarify the machinery associated with the BCG mediated anti-bladder tumor effect, especially the roles of bladder cancer cells and dendritic cells (DCs) in the initial step, which remains poorly understood. We show herein that the internalization of BCG-CWS by bladder cancer cells, but not DCs, is indispensable for the induction of an antitumor effect against bladder cancer. Tumor growth was significantly inhibited in mice that had been inoculated with mouse bladder cancer (MBT-2) cells containing internalized BCG-CWS. On the other hand, the internalization of BCG-CWS by DCs had only a minor effect on inducing an antitumor effect against MBT-2 tumors. This was clarified for the first time by using the CWS-NP. This finding provides insights into our understanding of the role of bladder cancer cells and DCs in BCG therapy against bladder cancer. (C) 2014 Elsevier B.V. All rights reserved.
- Published
- 2014
44. Immunological Properties of Trehalose Dimycolate (Cord Factor) and Other Mycotic Acid-Containing Glycolipids--A Review
- Author
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Ikuya Yano, Roland Ryll, and Yoshio Kumazawa
- Subjects
Cellular immunity ,Immunology ,Antineoplastic Agents ,Microbiology ,Mycolic acid ,Mice ,chemistry.chemical_compound ,Glycolipid ,Adjuvants, Immunologic ,Virology ,Animals ,Humans ,chemistry.chemical_classification ,Granuloma ,Cord factor ,Neovascularization, Pathologic ,biology ,Mycobacterium tuberculosis ,biology.organism_classification ,Acquired immune system ,Trehalose dimycolate ,Biochemistry ,chemistry ,Humoral immunity ,Cord Factors ,Cytokines ,Mycobacterium - Abstract
Mycolic acids are characteristic fatty acids of Mycobacteria and are responsible for the wax-like consistence of these microorganisms. Decades of research revealed that mycolic acid-containing glycolipids, in particular trehalose-6,6'-dimycolate (TDM, cord factor) as their best-studied representative, exert a number of immunomodifying effects. They are able to stimulate innate, early adaptive and both humoral and cellular adaptive immunity. Most functions can be associated with their ability to induce a wide range of chemokines (MCP-1, MIP-1alpha, IL-8) and cytokines (e.g., IL-12, IFN-gamma, TNF-alpha, IL-4, IL-6, IL-10). This review tries to link well-known properties of mycolic acid-containing glycolipids, e.g., stimulation of cellular and humoral immunity, granuloma formation and anti-tumor activity, with recent findings in molecular immunology and to give an outlook on potential practical applications.
- Published
- 2001
45. Clinical Evaluation of Anti-Tuberculous Glycolipid Immunoglobulin G Antibody Assay for Rapid Serodiagnosis of Pulmonary Tuberculosis
- Author
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Chiyoji Abe, Toshio Kishimoto, Masako Wada, Masaru Nakagawa, Masami Ito, Takeo Toyoda, Touru Hiraga, Ryoji Maekura, Takeshi Ogura, Yoshinari Okuda, Souichirou Yokota, Hiroaki Kohno, and Ikuya Yano
- Subjects
Microbiology (medical) ,Tuberculosis ,Enzyme-Linked Immunosorbent Assay ,Immunoglobulin E ,Immunoglobulin G ,Mycobacterium tuberculosis ,Glycolipid ,Humans ,Medicine ,Tuberculosis, Pulmonary ,Antigens, Bacterial ,biology ,business.industry ,Respiratory disease ,Antibody titer ,Mycobacteriology and Aerobic Actinomycetes ,medicine.disease ,biology.organism_classification ,Antibodies, Bacterial ,Immunology ,biology.protein ,Reagent Kits, Diagnostic ,Glycolipids ,Antibody ,business - Abstract
Previously we reported the development of a highly sensitive enzyme-linked immunosorbent assay specific for anti-tuberculous glycolipid (anti-TBGL) for the rapid serodiagnosis of tuberculosis. In this study, the usefulness of an anti-TBGL antibody assay kit for rapid serodiagnosis was evaluated in a controlled multicenter study. Antibody titers in sera from 318 patients with active pulmonary tuberculosis (216 positive for Mycobacterium tuberculosis in smear and/or culture tests and 102 smear and culture negative and clinically diagnosed), 58 patients with old tuberculosis, 177 patients with other respiratory diseases, 156 patients with nonrespiratory diseases, and 454 healthy subjects were examined. Sera from 256 younger healthy subjects from among the 454 healthy subjects were examined as a control. When the cutoff point of anti-TBGL antibody titer was determined as 2.0 U/ml, the sensitivity for active tuberculosis patients was 81.1% and the specificity was 95.7%. Sensitivity in patients with smear-negative and culture-negative active pulmonary tuberculosis was 73.5%. Even in patients with noncavitary minimally advanced lesions, the positivity rate (60.0%) and the antibody titer (4.6 ± 9.4 U/ml) were significantly higher than those in the healthy group. These results indicate that this assay using anti-TBGL antibody is useful for the rapid serodiagnosis of active pulmonary tuberculosis.
- Published
- 2001
46. Mycobacterial cord factor, but not sulfolipid, causes depletion of NKT cells and upregulation of CD1d1 on murine macrophages
- Author
-
Ryoichi Hasunuma, Yoshio Kumazawa, Masaji Okada, Nagatoshi Fujiwara, Ikuya Yano, Hiroaki Takimoto, Kenji Watanabe, and Roland Ryll
- Subjects
Cellular immunity ,Receptors, Antigen, T-Cell, alpha-beta ,Immunology ,Antigen presentation ,CD1 ,Biology ,Microbiology ,Lymphocyte Depletion ,Natural killer cell ,Antigens, CD1 ,Interferon-gamma ,Mice ,chemistry.chemical_compound ,Immune system ,Adjuvants, Immunologic ,medicine ,Animals ,Humans ,Cord factor ,Macrophages ,Mycobacterium tuberculosis ,Th1 Cells ,Natural killer T cell ,Lipids ,Up-Regulation ,Cell biology ,Killer Cells, Natural ,Trehalose dimycolate ,Infectious Diseases ,medicine.anatomical_structure ,chemistry ,Cord Factors ,Female ,Antigens, CD1d - Abstract
Trehalose 6,6'-dimycolate (TDM, cord factor) has frequently been used as an adjuvant to stimulate antibody production. Although it also induces cellular immunity, detailed studies about the underlying events do not exist. To determine the kinetics of TDM-specific changes promoting a T helper 1 (Th1) response, we injected mice with TDM or 2,3,6,6'-tetraacyl trehalose 2'-sulfate (SL, sulfolipid), another mycobacterial trehalose-containing glycolipid without mycolic acid. TDM, but not SL, caused a strong increase in serum interferon-gamma (IFN-gamma) levels 2 days later, accompanied by expansion of natural killer (NK) cells. Subsequent TDM effects included depletion of normal-density CD4(+) NK1.1(+) TCRalpha/beta(intermediate) cells from day 7 on, upregulation of MHC class II and CD1d1 on macrophages (peaking on day 21), and an increased proportion of Th1 cells evident after 3 weeks. TDM, but not a similar glycolipid without mycolic acid, can therefore initiate a cascade of events starting with strong release of IFN-gamma and NK cell expansion, resulting in the appearance of macrophages activated for antigen presentation. Our data therefore provide the basis for optimized immunization schedules with TDM as the adjuvant component of a Th1 vaccine.
- Published
- 2001
47. Trehalose 6,6′-Dimycolate (Cord Factor) ofMycobacterium tuberculosisInduces Foreign-Body- and Hypersensitivity-Type Granulomas in Mice
- Author
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Nagatoshi Fujiwara, Kazuo Kobayashi, Takayuki Matsumoto, Kenji Kaneda, Ikuya Yano, Hirokazu Yamagami, and Tetsuo Arakawa
- Subjects
medicine.medical_treatment ,Immunology ,Biology ,Microbiology ,Proinflammatory cytokine ,Mycobacterium tuberculosis ,Mice ,Immune system ,Antigen ,medicine ,Animals ,Hypersensitivity, Delayed ,Lung ,Mice, Inbred BALB C ,Host Response and Inflammation ,Granuloma ,Cord factor ,Monocyte ,Immunogenicity ,Foreign Bodies ,biology.organism_classification ,Infectious Diseases ,medicine.anatomical_structure ,Cytokine ,Cord Factors ,Cytokines ,Female ,Parasitology ,Chemokines - Abstract
Granulomatous inflammation is characterized morphologically by a compact organized collection of macrophages and their derivatives. It is classified as either a hypersensitivity type or a foreign-body type. Lipid components of theMycobacterium tuberculosiscell wall participate in the pathogenesis of infection. Strains ofM. tuberculosishave cord factor (trehalose 6,6′-dimycolate [TDM]) on their surface. To clarify host responses to TDM, including immunogenicity and pathogenicity, we have analyzed the footpad reaction, histopathology, and cytokine profiles of experimental granulomatous lesions in immunized and unimmunized mice challenged with TDM. In the present study, we have demonstrated for the first time that TDM can induce both foreign-body-type (nonimmune) and hypersensitivity-type (immune) granulomas by acting as a nonspecific irritant and T-cell-dependent antigen. Immunized mice challenged with TDM developed more severe lesions than unimmunized mice. At the active lesion, we found monocyte chemotactic, proinflammatory, and immunoregulatory cytokines. The level was enhanced in immunized mice challenged with TDM. This result implies that both nonimmune and immune mechanisms participate in granulomatous inflammation induced by mycobacterial infection. Taken together with a previous report, this study shows that TDM is a pleiotropic molecule against the host and plays an important role in the pathogenesis of tuberculosis.
- Published
- 2001
48. Structure–activity relationship of mycoloyl glycolipids derived from Rhodococcus sp. 4306
- Author
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Yuriko Ozeki, Ikuya Yano, Sadao Ueda, Takashi Naka, Tsuyoshi Kasama, Ikuyo Sakaguchi, Nagatoshi Fujiwara, and Kazuo Kobayashi
- Subjects
Male ,Mannose ,Microbiology ,Mycolic acid ,Mycobacterium tuberculosis ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Glycolipid ,Animals ,Rhodococcus ,chemistry.chemical_classification ,Mice, Inbred ICR ,Granuloma ,biology ,Trehalose ,biology.organism_classification ,Infectious Diseases ,chemistry ,Biochemistry ,Cord Factors ,lipids (amino acids, peptides, and proteins) ,Chromatography, Thin Layer ,Actinomycetales ,Actinomycetales Infections ,Bacteria - Abstract
Novel mycoloyl glycolipids with short carbon chains were isolated and purified from Rhodococcus sp. 4306, a soil origin of Actinomycetales. Their chemical structures were identified as trehalose 6,6′-dimycolate (TDM), trehalose 6-monomycolate, glucose 6-monomycolate, mannose 6-monoImycolate and fructose 6-monomycolate. The length of carbon chains and number of double bonds of mycolic acids were C34, C36and C38saturated, monoenoic and dienoic molecular species, which were much shorter than those of Mycobacterium tuberculosis (C78–88monoenoic and dienoic). Among them, only TDM could induce prominent granulomatous inflammation of the lung and spleen in mice. By contrast, other mycoloyl glycolipids induced mild lesions. The small-sized TDM of Rhodococcus possessed granulomatogenic activity, however, the toxicity was much lower than that of M. tuberculosis. Rhodococcal TDM was composed of mycolic acid with the shortest carbon chains, when compared to granulomatogenic TDM of Mycobacterium,Nocardia and Rhodococcus reported previously. Our results imply that rhodococcal TDM is a pathogenetic factor similar to that of M. tuberculosis, although rhodococcal TDM exhibits low toxicity.
- Published
- 2001
49. New diagnostic approach for ocular tuberculosis by ELISA using the cord factor as antigen
- Author
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Masahiko Usui, Jun-ichi Sakai, Suguru Matsuzawa, and Ikuya Yano
- Subjects
Systemic disease ,Cord factor ,Tuberculosis ,biology ,business.industry ,Retinal vasculitis ,Original articles - Clinical science ,biology.organism_classification ,medicine.disease ,Sensory Systems ,Mycobacterium tuberculosis ,Cellular and Molecular Neuroscience ,Ophthalmology ,Antigen ,Immunology ,Medicine ,Sarcoidosis ,business ,Vasculitis - Abstract
BACKGROUND/AIMS Diagnosis of ocular tuberculosis is difficult, particularly the retinal vasculitis type, because most cases occur without concurrent active pulmonary tuberculosis. Recently, it has been reported that detection of antibodies against purified cord factor (trehalose-6,6′-dimycolate, TDM), the best studied, most antigenic, and most abundant cell wall component of tubercule bacilli, is very useful for rapid serodiagnosis of pulmonary tuberculosis. In this study, an attempt was made to evaluate whether the detection of anticord factor antibody is also useful for diagnosis of ocular tuberculosis and the necessity of antituberculous therapy for tuberculous retinochoroiditis was discussed. METHODS Cases consisted of 15 patients with uveitis and retinal vasculitis, nine patients with presumed ocular tuberculosis, three patients with sarcoidosis, and three patients with Behcet's disease. IgG antibodies against purified cord factor prepared from Mycobacterium tuberculosis H37Rv were detected by enzyme linked immunosorbent assay. RESULTS All cases of clinically presumed ocular tuberculosis were positive, whereas all of the cases of sarcoidosis or Behcet's disease were negative for anticord factor antibodies. When the anticord factor antibody titres were compared on the basis of the presence or absence of previous antituberculosis chemotherapy, the mean anticord factor antibody titre of the untreated group showed a tendency to be higher than in the treated group, but not significantly (p=0.07). CONCLUSIONS The detection of anticord factor antibody may be useful to support the diagnosis of ocular tuberculosis. Additionally, a positive result for anticord factor antibody may indicate that tubercule bacilli are present in some organ(s) of the patient even in the absence of active systemic disease.
- Published
- 2001
50. Mycobacterial glycolipids in host responses against tuberculosis
- Author
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Kazuo Kobayashi, Nagatoshi Fujiwara, Sadao Ueda, Ikuya Yano, and Hirokazu Yamagami
- Subjects
Chemokine ,Immunogen ,Tuberculosis ,biology ,medicine.disease ,Peripheral blood mononuclear cell ,Microbiology ,Proinflammatory cytokine ,Pathogenesis ,Glycolipid ,Immune system ,Immunology ,biology.protein ,medicine - Abstract
Host responses against mycobacterial infection result in protection and granulomatous inflammation. Mycobacterial and host factors participate in the process. Mycobacteria are rich in lipids that may be involved in the pathogenesis. Host responses against the infection include both cell-mediated immune responses (host defense) and delayed-type hypersensitivity (expression of lesions) . A surface glycolipid of tubercle bacilli acts as both nonspecific inflammatory stimulus and specific T cell-dependent immunogen. Hosts produce chemokines, proinflammatory and immunoregulatory cytokines in response to glycolipids. The event leads to the recruitment of mononuclear cells, angiogenesis, and apoptosis. Mycobacterial glycolipid is a pleiotropic molecule, which induces pathogenesis and protective responses in the host. The pathogenesis of mycobacterial disease is a multistep process, involving a complex interaction between a range of bacterial and host factors.
- Published
- 2001
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