207 results on '"Yasuhiro Yasutomi"'
Search Results
52. Establishment of SARS-CoV-2 respiratory tract infection model in CAG promoter-driven hACE2 transgenic mice
- Author
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Utsumi Daichi, Masamitsu Asaka, Haruhiko Kamada, Satoshi Nagata, Yutaka Nakachi, Tomokazu Yamaguchi, Yoshihiro Kawaoka, Keiji Kuba, and Yasuhiro Yasutomi
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Applied Mathematics ,General Mathematics - Published
- 2022
53. Gene expression dataset for whole cochlea of Macaca fascicularis
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Fuyuki Miya, Tatsuhiko Tsunoda, Hideki Mutai, Yasuhiro Yasutomi, Tatsuo Matsunaga, and Hiroaki Shibata
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0301 basic medicine ,Hearing loss ,lcsh:Medicine ,Computational biology ,Biology ,Macaque ,Article ,03 medical and health sciences ,0302 clinical medicine ,biology.animal ,medicine ,otorhinolaryngologic diseases ,Auditory system ,Animals ,Humans ,lcsh:Science ,Gene ,Cochlea ,Multidisciplinary ,Microarray analysis techniques ,Gene Expression Profiling ,lcsh:R ,Microarray Analysis ,Ear morphogenesis ,Gene expression profiling ,Macaca fascicularis ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Q ,sense organs ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
Macaca fascicularis is a highly advantageous model in which to study human cochlea with regard to both evolutionary proximity and physiological similarity of the auditory system. To better understand the properties of primate cochlear function, we analyzed the genes predominantly expressed in M. fascicularis cochlea. We compared the cochlear transcripts obtained from an adult male M. fascicularis by macaque and human GeneChip microarrays with those in multiple macaque and human tissues or cells and identified 344 genes with expression levels more than 2-fold greater than in the other tissues. These “cochlear signature genes” included 35 genes responsible for syndromic or nonsyndromic hereditary hearing loss. Gene set enrichment analysis revealed groups of genes categorized as “ear development” and “ear morphogenesis” in the top 20 gene ontology categories in the macaque and human arrays, respectively. This dataset will facilitate both the study of genes that contribute to primate cochlear function and provide insight to discover novel genes associated with hereditary hearing loss that have yet to be established using animal models.
- Published
- 2018
54. Superparamagnetic Iron Oxide-enhanced Magnetic Resonance Imaging of Spontaneous Hepatic Neoplasia in a Cynomolgus Macaque (Macaca fascicularis)
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Kiichi Kanayama, Shunya Nakayama, Hiroaki Shibata, Naohide Ageyama, Yasuhiro Yasutomi, Sachi Okabayashi, Yasuyo Ito Fujishiro, Hiroshi Koie, and Yuko Katakai
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Pathology ,medicine.medical_specialty ,General Veterinary ,medicine.diagnostic_test ,040301 veterinary sciences ,business.industry ,Radiography ,Magnetic resonance imaging ,04 agricultural and veterinary sciences ,Anorexia ,medicine.disease ,Cynomolgus macaque ,humanities ,General Biochemistry, Genetics and Molecular Biology ,030218 nuclear medicine & medical imaging ,Serology ,0403 veterinary science ,03 medical and health sciences ,0302 clinical medicine ,Hepatocellular carcinoma ,Hepatic neoplasms ,medicine ,medicine.symptom ,business ,Superparamagnetic iron oxide - Abstract
Although the number of reports describing tumors in aged NHP has increased, spontaneous neoplasias in NHP are extremely rare, with the notable exception of prosimians, in which spontaneous hepatic neoplasms arise. In addition to radiography and ultrasonography, superparamagnetic iron oxide (SPIO)-enhanced MRI tends to be applied in human practice to non-invasively locate, identify, and size liver tumors and to define the border between neoplastic and normal tissues. Here we report a 13-y-old female cynomolgus monkey with anorexia and serologically normal liver enzymes. After fluid therapy, the condition remained in remission for several months. Later, however, a palpable mass was assessed by using ultrasonography, radiology, and SPIO-MRI; T2-weighted images revealed a clear border between a hepatocellular carcinoma and normal liver tissue. Findings at necropsy supported the imaging data. Serologic assessment after euthanasia revealed a positive reaction to an abnormal form of prothrombin (PIVKA-II). We recommend SPIO-MRI as a practical and useful for diagnosing hepatocellular neoplasias in NHP. This study is the first to demonstrate the applicability of SPIO-MRI for the identification of hepatocellular carcinoma in NHP.
- Published
- 2018
55. An Antigen-Free, Plasmacytoid Dendritic Cell–Targeting Immunotherapy To Bolster Memory CD8+ T Cells in Nonhuman Primates
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Ken Ishii, Kenji Mizuguchi, Yasuhiro Yasutomi, Yayoi Natsume-Kitatani, Takuya Yamamoto, Eiko Moriishi, Yuji Masuta, Kouji Kobiyama, and Tomohiro Kanuma
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0301 basic medicine ,Chemistry ,medicine.medical_treatment ,Immunology ,TLR9 ,Plasmacytoid dendritic cell ,Immunotherapy ,Proinflammatory cytokine ,03 medical and health sciences ,CTL ,030104 developmental biology ,0302 clinical medicine ,Antigen ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,CD8 - Abstract
The priming, boosting, and restoration of memory cytotoxic CD8+ T lymphocytes by vaccination or immunotherapy in vivo is an area of active research. Particularly, nucleic acid–based compounds have attracted attention due to their ability to elicit strong Ag-specific CTL responses as a vaccine adjuvant. Nucleic acid–based compounds have been shown to act as anticancer monotherapeutic agents even without coadministration of cancer Ag(s); however, so far they have lacked efficacy in clinical trials. We recently developed a second-generation TLR9 agonist, a humanized CpG DNA (K3) complexed with schizophyllan (SPG), K3-SPG, a nonagonistic Dectin-1 ligand. K3-SPG was previously shown to act as a potent monoimmunotherapeutic agent against established tumors in mice in vivo. In this study we extend the monoimmunotherapeutic potential of K3-SPG to a nonhuman primate model. K3-SPG activated monkey plasmacytoid dendritic cells to produce both IFN-α and IL-12/23 p40 in vitro and in vivo. A single injection s.c. or i.v. with K3-SPG significantly increased the frequencies of activated memory CD8+ T cells in circulation, including Ag-specific memory CTLs, in cynomolgus macaques. This increase did not occur in macaques injected with free CpG K3 or polyinosinic-polycytidylic acid. Injection of 2 mg K3-SPG induced mild systemic inflammation, however, levels of proinflammatory serum cytokines and circulating neutrophil influx were lower than those induced by the same dose of polyinosinic-polycytidylic acid. Therefore, even in the absence of specific Ags, we show that K3-SPG has potent Ag-specific memory CTL response–boosting capabilities, highlighting its potential as a monoimmunotherapeutic agent for chronic infectious diseases and cancer.
- Published
- 2018
56. Relationship between menarche and fertility in long-tailed macaques (Macaca fascicularis)
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Maiko Kobayashi, Takamasa Koyama, Yasuhiro Yasutomi, and Tadashi Sankai
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0301 basic medicine ,Pregnancy ,biology ,media_common.quotation_subject ,Physiology ,Fertility ,030204 cardiovascular system & hematology ,medicine.disease ,Fecundity ,Menstruation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Animal model ,biology.animal ,medicine ,Menarche ,Animal Science and Zoology ,Primate ,Reproduction ,media_common - Abstract
We attempted to elucidate female reproduction in long-tailed macaques (Macaca fascicularis). These monkeys have a non-seasonal menstruation cycle, which makes them suitable subjects for studies in a variety fields including medical science and regenerative medicine. We analyzed individual breeding data including time of menarche, start of regular menstruation, and first pregnancy. These three events are related to the maturation of female long-tailed macaques. All research subjects were female long-tailed macaques bred at the Tsukuba Primate Research Center. The study comprised 45 females; we included time of menstruation, male-female cohabitation, and first pregnancy in their growth records. We extracted age and weight data relating to menarche, start of regular menstruation, and first pregnancy from these records. In the two years typically required from menarche to first pregnancy, the body weight increased by approximately 500 g (21% of the weight at menarche); it is clear that there is a significant physical change after menarche. Our findings suggest that female monkeys are not necessarily mature enough for pregnancy at menarche. Therefore, the use of the word "maturity" in terms of fecundity may be more accurate after the start of regular menstruation. This is what we term "adolescence" in the developmental process. Therefore, M. fascicularis monkeys are candidates for an animal model of human adolescence.
- Published
- 2018
57. Utility of arterial blood gas, CBC, biochemistry and cardiac hormones as evaluation parameters of cardiovascular disease in nonhuman primates
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Yasuyo Ito-Fujishiro, Shunya Nakayama, Naohide Ageyama, Kiichi Kanayama, Hiroshi Koie, Tadashi Sankai, Yasuhiro Yasutomi, and Yuko Katakai
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Male ,Primates ,complete blood count ,040301 veterinary sciences ,Cardiomyopathy ,nonhuman primate ,Inflammation ,Disease ,030204 cardiovascular system & hematology ,Cardiac hormones ,0403 veterinary science ,03 medical and health sciences ,0302 clinical medicine ,Laboratory Animal Science ,cardiovascular disease ,medicine ,Animals ,Acidosis ,Full Paper ,General Veterinary ,medicine.diagnostic_test ,business.industry ,Complete blood count ,Red blood cell distribution width ,arterial blood gas ,04 agricultural and veterinary sciences ,cardiac hormone ,medicine.disease ,Blood Cell Count ,Biochemistry ,Cardiovascular Diseases ,Quality of Life ,Arterial blood ,Female ,Blood Gas Analysis ,medicine.symptom ,business - Abstract
Cardiovascular disease (CVD) has a tremendous impact on the quality of life of humans. While experimental animals are valuable to medical research as models of human diseases, cardiac systems differ widely across various animal species. Thus, we examined a CVD model in cynomolgus monkeys. Laboratory primates are precious resources, making it imperative that symptoms of diseases and disorders are detected as early as possible. Thus, in this study we comprehensively examined important indicators of CVD in cynomolgus monkeys, including arterial blood gas, complete blood count (CBC), biochemistry and cardiac hormones. The control group included 20 healthy macaques showing non-abnormal findings in screening tests, whereas the CVD group included 20 macaques with valvular disease and cardiomyopathy. An increase of red blood cell distribution width was observed in the CBC, indicating chronic inflammation related to CVD. An increase of HCO3 was attributed to the correction of acidosis. Furthermore, development of the CVD model was supported by significant increases in natriuretic peptides. It is suggested that these results indicated a correlation between human CVD and the model in monkeys. Moreover, blood tests including arterial blood gas are non-invasive and can be performed more easily than other technical tests. CVD affected animals easily change their condition by anesthesia and surgical invasion. Pay attention to arterial blood gas and proper respond to their condition are important for research. This data may facilitate human research and aid in the management and veterinary care of nonhuman primates.
- Published
- 2018
58. Establishment of reference values for complete blood count and blood gases in cynomolgus monkeys (Macaca fascicularis)
- Author
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Yuko Katakai, Tadashi Sankai, Yasuyo Ito-Fujishiro, Yasuhiro Yasutomi, Kiichi Kanayama, Shunya Nakayama, Hiroshi Koie, and Naohide Ageyama
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0301 basic medicine ,General Veterinary ,medicine.diagnostic_test ,business.industry ,Physiology ,Complete blood count ,030204 cardiovascular system & hematology ,pCO2 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Animal management ,Reference values ,Circulatory system ,medicine ,Arterial blood ,Respiratory system ,business ,Hormone - Abstract
Cynomolgus monkeys are closely related to humans phylogenetically, and this has resulted in their widespread use as a preclinical model. Hematological data with regard to these monkeys are thus important. Although reference values for blood components and sex hormones have been established for cynomolgus monkeys, those for arterial blood gases have not. The arterial blood gases quickly reflect respiratory and circulatory dynamics, and are thus useful for animal management and safe general anesthesia and surgical operations. Furthermore, since O2 is transported by RBC, CBC and blood gases are closely related. The present study aimed to establish reference values for arterial blood gases and CBC in cynomolgus monkeys over a wide age range. Blood gases and CBC of arterial blood, collected from 41 female and 21 male anesthetized monkeys, were measured. Age correlated with RBC, HGB and HCT in the CBC. Values differed significantly between males and females in pCO2, CO2 concentration, MCV and MCH. The pH of blood was equivalent to that of humans and pCO2 was more stable, whereas MCV and MCH were lower than those in humans. Erythrocytes were smaller and less pigmented than in other Macaca species. Several relationships between gender and age, and blood gases and CBC were identified in cynomolgus monkeys. In conclusion, these reference values will be useful as markers for veterinary applications and in the care and maintenance of these animals.
- Published
- 2017
59. Simian immunodeficiency virus SIVmac239 infection and simian human immunodeficiency virus SHIV89.6P infection result in progression to AIDS in cynomolgus macaques of Asian origin
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Tomotaka Okamura, Ichiro Takahashi, Shogo Soma, Yusuke Tsujimura, Yasuhiro Yasutomi, and Kazuhiro Matsuo
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CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,Asia ,animal diseases ,viruses ,T cell ,Biology ,medicine.disease_cause ,Pathogenesis ,03 medical and health sciences ,Acquired immunodeficiency syndrome (AIDS) ,Virology ,medicine ,Animals ,Humans ,Infectivity ,Acquired Immunodeficiency Syndrome ,Simian human immunodeficiency virus ,HIV ,virus diseases ,Viral Load ,Simian immunodeficiency virus ,medicine.disease ,Vaccination ,Disease Models, Animal ,Macaca fascicularis ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,Disease Progression ,Simian Immunodeficiency Virus ,Viral load - Abstract
Simian immunodeficiency virus (SIV) infection models in cynomolgus macaques are important for analysis of the pathogenesis of immunodeficiency virus and for studies on the efficacy of new vaccine candidates. However, very little is known about the pathogenesis of SIV or simian human immunodeficiency virus (SHIV) in cynomolgus macaques from different Asian countries. In the present study, we analysed the infectivity and pathogenicity of CCR5-tropic SIVmac and those of dual-tropic SHIV89.6P inoculated into cynomolgus macaques in Indonesian, Malaysian or Philippine origin. The plasma viral loads in macaques infected with either SIVmac239 or SHIV89.6P were maintained at high levels. CD4+ T cell levels in macaques infected with SIVmac239 gradually decreased. All of the macaques infected with SHIV89.6P showed greatly reduced CD4+ T-cell numbers within 6 weeks of infection. Eight of the 11 macaques infected with SIVmac239 were killed due to AIDS symptoms after 2-4.5 years, while four of the five macaques infected with SHIV89.6P were killed due to AIDS symptoms after 1-3.5 years. We also analysed cynomolgus macaques infected intrarectally with repeated low, medium or high doses of SIVmac239, SIVmac251 or SHIV89.6P. Infection was confirmed by quantitative RT-PCR at more than 5000, 300 and 500 TCID50 for SIVmac239, SIVmac251 and SHIV89.6P, respectively. The present study indicates that cynomolgus macaques of Asian origin are highly susceptible to SIVmac and SHIV infection by both intravenous and mucosal routes. These models will be useful for studies on virus pathogenesis, vaccination and therapeutics against human immunodeficiency virus/AIDS.
- Published
- 2016
60. Leucine-rich alpha 2 glycoprotein is a new marker for active disease of tuberculosis
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Yusuke Tsujimura, Tetsuji Naka, Minoru Fujimoto, Tomoshige Matsumoto, Yasuhiro Yasutomi, Satoshi Serada, and Shoji Hashimoto
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0301 basic medicine ,Tuberculosis ,lcsh:Medicine ,Blood Sedimentation ,Article ,Mycobacterium tuberculosis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,lcsh:Science ,Lung ,Glycoproteins ,Multidisciplinary ,biology ,business.industry ,Interleukin-6 ,lcsh:R ,Diagnostic markers ,biology.organism_classification ,medicine.disease ,Vaccination ,Disease Models, Animal ,Macaca fascicularis ,030104 developmental biology ,medicine.anatomical_structure ,C-Reactive Protein ,Giant cell ,030220 oncology & carcinogenesis ,Case-Control Studies ,Immunology ,BCG Vaccine ,Biomarker (medicine) ,Immunohistochemistry ,lcsh:Q ,business ,Epithelioid cell ,Biomarkers - Abstract
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global health problem. At present, prior exposure to Mtb can be determined by blood-based interferon-gamma release assay (IGRA), but active TB is not always detectable by blood tests such as CRP and ESR. This study was undertaken to investigate whether leucine-rich alpha-2 glycoprotein (LRG), a new inflammatory biomarker, could be used to assess active disease of TB. Cynomolgus macaques pretreated with or without Bacille Calmette-Guerin (BCG) vaccination were inoculated with Mtb to induce active TB. Blood was collected over time from these animals and levels of LRG as well as CRP and ESR were quantified. In the macaques without BCG vaccination, Mtb inoculation caused extensive TB and significantly increased plasma CRP and LRG levels, but not ESR. In the macaques with BCG vaccination, whereas Mtb challenge caused pulmonary TB, only LRG levels were significantly elevated. By immunohistochemical analysis of the lung, LRG was visualized in epithelioid cells and giant cells of the granulation tissue. In humans, serum LRG levels in TB patients were significantly higher than those in healthy controls and declined one month after anti-tubercular therapy. These findings suggest that LRG is a promising biomarker when performed following IGRA for the detection of active TB.
- Published
- 2019
61. Intranasal vaccination with HBs and HBc protein combined with carboxyl vinyl polymer induces strong neutralizing antibody, anti-HBs IgA, and IFNG response
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Miyazaki Takashi, Goh Yasumasa, Osamu Yoshida, Hideki Hasegawa, Naoki Yamamoto, Yoichi Hiasa, Yumiko Shiogama, Michinori Kohara, Takahiro Sanada, Mohammad Enamul Hoque Kayesh, Kyoko Tsukiyama-Kohara, Yasuhiro Yasutomi, and Jun-ichiro Takano
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0301 basic medicine ,Hepatitis B virus ,Immunogen ,Genotype ,Polymers ,Biophysics ,medicine.disease_cause ,Antibodies, Viral ,Biochemistry ,03 medical and health sciences ,Interferon-gamma ,Mice ,0302 clinical medicine ,Antigen ,Interferon ,Neutralization Tests ,medicine ,Animals ,Humans ,Neutralizing antibody ,Molecular Biology ,Administration, Intranasal ,Hepatitis B Surface Antigens ,biology ,business.industry ,Tupaiidae ,virus diseases ,Cell Biology ,Hep G2 Cells ,Hepatitis B ,medicine.disease ,Virology ,Antibodies, Neutralizing ,Hepatitis B Core Antigens ,digestive system diseases ,Immunoglobulin A ,Vaccination ,030104 developmental biology ,Immunization ,Liver ,030220 oncology & carcinogenesis ,Immunoglobulin G ,biology.protein ,business ,medicine.drug - Abstract
Hepatitis B virus (HBV) infection causes acute and chronic hepatitis, which is a major public health concern worldwide. Immunization methods incorporating hepatitis B surface-small (HBs-S) antigen and hepatitis B core antigen (HBc) have been proposed as candidate therapeutic vaccines, but the elimination of existing HBV infection remains a challenge. To enhance the efficacy of HBs and HBc vaccination, we investigated HBs-large (HBs-L) as an immunogen, and carboxyl vinyl polymer (CVP) as an excipient. HBs-S or HBs-L, in combination with HBc antigen, was administered subcutaneously (without CVP) or intranasally (with or without CVP) for the evaluation of immune response in the tree shrew, which is considered to be a suitable small animal model of HBV infection. Immunization with HBs-L antigen by either route induced a rapid IgG response. Intranasal immunization with HBs-S or HBs-L and HBc formulated with CVP strongly induced neutralizing antibody activity, IgA response, and HBc-specific expression of the interferon gamma-encoding gene. These data indicated the potential of HBs-L and HBc intranasal immunization with CVP, not only as a therapeutic vaccine, but also as a prophylactic vaccine candidate.
- Published
- 2019
62. Establishment of a new formula for QT interval correction using a large colony of cynomolgus monkeys
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Yasuyo Ito-Fujishiro, Tadashi Sankai, Shunya Nakayama, Yasuhiro Yasutomi, Kiichi Kanayama, Chungyu Pai, Hiroshi Koie, Naohide Ageyama, and Miyoko Kato-Tateishi
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0301 basic medicine ,Male ,QT interval ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Correction method ,Original ,the corrected QT interval ,electrocardiogram ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Electrocardiography ,0302 clinical medicine ,Heart Rate ,cardiovascular disease ,Internal medicine ,Heart rate ,medicine ,Repolarization ,Animals ,cardiovascular diseases ,General Veterinary ,business.industry ,Mean value ,Prolongation ,Corrected qt ,General Medicine ,Long QT Syndrome ,Macaca fascicularis ,030104 developmental biology ,Underlying disease ,Cardiology ,cardiovascular system ,Animal Science and Zoology ,Female ,cynomolgus monkey ,business ,030217 neurology & neurosurgery ,circulatory and respiratory physiology - Abstract
The demand for monkeys for medical research is increasing, because their ionic mechanism of repolarization is similar to that of humans. The QT interval is the distance between the Q wave and T wave, but this interval is affected by heart rate. Therefore, QT correction methods are commonly used in clinical settings. However, an accurate correction formula for the QT interval in cynomolgus monkeys has not been reported. We assessed snapshot electrocardiograms (ECGs) of 353 ketamine-immobilized monkeys, including aged animals, and contrived a new formula for the corrected QT interval (QTc) as a marker of QT interval prolongation in cynomolgus monkeys. Values for QTc were calculated using the formula [QTc] = [QT] / [RR]n, along with several other formulas commonly used to calculate QTc. We found that the optimal exponent of the QT interval corrected for heart rate, n, was 0.576. The mean value of QTc in healthy monkeys determined using the new formula was 373 ± 31 mm, and there were no significant differences between the sexes. Other ECG parameters were not significantly different between the sexes and there were no age-related effects on QTc. Prolongation of QTc to over 405 ms, as calculated by the new formula, was observed in 50 monkeys with underlying diseases. Additionally, all monkeys with QTc above 440 ms by the new formula had some underlying disease. The results resemble those in humans, suggesting that the new QTc formula could be useful for diagnosis of QT interval prolongation in cynomolgus monkeys.
- Published
- 2019
63. STING agonists activate latently infected cells and enhance SIV-specific responses ex vivo in naturally SIV controlled cynomolgus macaques
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Takuya Yamamoto, Kazutaka Terahara, Ken Ishii, Yasuhiro Yasutomi, Eiko Moriishi, Tomotaka Okamura, Shokichi Takahama, and Tomohiro Kanuma
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0301 basic medicine ,Male ,medicine.medical_treatment ,Simian Acquired Immunodeficiency Syndrome ,lcsh:Medicine ,Biology ,CD8-Positive T-Lymphocytes ,Peripheral blood mononuclear cell ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Cytotoxic T cell ,Animals ,lcsh:Science ,Multidisciplinary ,lcsh:R ,Toll-Like Receptors ,Imidazoles ,virus diseases ,Membrane Proteins ,Viral Load ,Virology ,Virus Latency ,Sting ,CTL ,Macaca fascicularis ,030104 developmental biology ,Cytokine ,Leukocytes, Mononuclear ,lcsh:Q ,Simian Immunodeficiency Virus ,Virus Activation ,Nucleotides, Cyclic ,030217 neurology & neurosurgery ,CD8 ,Ex vivo ,Dinucleoside Phosphates ,T-Lymphocytes, Cytotoxic - Abstract
To achieve a functional cure for HIV, treatment regimens that eradicate latently HIV-infected cells must be established. For this, many groups have attempted to reactivate latently-infected cells to induce cytopathic effects and/or elicit cytotoxic T lymphocyte (CTL)/NK cell-mediated immune responses to kill these cells. We believe that not only the reactivation of latently-infected cells, but also the induction of strong CTL responses, would be required for this. Here, we used typical immune activators that target pattern recognition receptors (PRRs). For our experimental model, we identified eight SIV-infected cynomolgus monkeys that became natural controllers of viremia. Although plasma viral loads were undetectable, we could measure SIV-DNA by qPCR in peripheral blood mononuclear cells (PBMCs). Using these PBMCs, we screened 10 distinct PRR ligands to measure IFN-α and IFN-γ production. Among these, STING ligands, cGAMP and c-di-AMP, and the TLR7/8 agonist R848 markedly increased cytokine levels. Both R848 and STING ligands could reactivate latently-infected cells in both cynomolgus monkeys and human PBMCs in vitro. Furthermore, c-di-AMP increased the frequency of SIV Gag-specific CD8+ T cells including polyfunctional CD8+ T cells, as compared to that in untreated control or R848-treated cells. Together, STING ligands might be candidates for HIV treatment.
- Published
- 2019
64. Partial Deletion of Glycoprotein B5R Enhances Vaccinia Virus Neutralization Escape while Preserving Oncolytic Function
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Tomotaka Okamura, Hiromichi Kono, Mai Ito, Kosei Hasegawa, Nozomi Kuwano, Yasuhiro Yasutomi, Hajime Kurosaki, Motomu Nakatake, Takafumi Nakamura, and Kosuke Horita
- Subjects
0301 basic medicine ,Cancer Research ,viruses ,lcsh:RC254-282 ,Virus ,Neutralization ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,Viral envelope ,Pharmacology (medical) ,anti-virus antibody ,biology ,Chemistry ,EEV ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Virology ,neutralization escape ,Oncolytic virus ,030104 developmental biology ,B5R ,Oncology ,Viral replication ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,Antibody ,Vaccinia ,oncolytic vaccinia virus - Abstract
Vaccinia virus (VV) has been utilized in oncolytic virotherapy, but it risks a host antiviral immune response. VV has an extracellular enveloped virus (EEV) form consisting of a normal virion covered with a host-derived outer membrane that enables its spread via circulation while evading host immune mechanisms. However, the immune resistance of EEV is only partial, owing to expression of the surface protein B5R, which has four short consensus repeat (SCR) domains that are targeted by host immune factors. To engineer a more effective virus for oncolytic virotherapy, we developed an enhanced immune-evading oncolytic VV by removing the SCRs from the attenuated strain LC16mO. Although deletion of only the SCRs preserved viral replication, progeny production, and oncolytic activity, deletion of whole B5R led to attenuation of the virus. Importantly, SCR-deleted EEV had higher neutralization resistance than did B5R-wild-type EEV against VV-immunized animal serum; moreover, it retained oncolytic function, thereby prolonging the survival of tumor-bearing mice treated with anti-VV antibody. These results demonstrate that partial SCR deletion increases neutralization escape without affecting the oncolytic potency of VV, making it useful for the treatment of tumors under the anti-virus antibody existence. Keywords: oncolytic vaccinia virus, anti-virus antibody, neutralization escape, EEV, B5R
- Published
- 2018
65. Immunization with Components of the Viral Fusion Apparatus Elicits Antibodies That Neutralize Epstein-Barr Virus in B Cells and Epithelial Cells
- Author
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Sandeep Narpala, Yusuke Tsujimura, Masaru Kanekiyo, Adrian B. McDermott, Dalton V. Banh, Rebecca A. Gillespie, Sarah F. Andrews, M. Gordon Joyce, Moh Lan Yap, Fiona Aguilar, Wei Bu, Zeshan Tariq, Yasuhiro Yasutomi, Gary J. Nabel, Jeffrey I. Cohen, Michael G. Rossmann, Yaroslav Tsybovsky, and Hanh Nguyen
- Subjects
0301 basic medicine ,Male ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Immunology ,Virus Attachment ,CHO Cells ,medicine.disease_cause ,Antibodies, Viral ,Virus ,Epitope ,Article ,Cell Fusion ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cricetulus ,Viral Envelope Proteins ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Immunology and Allergy ,Animals ,Humans ,Vaccines, Virus-Like Particle ,B cell ,B-Lymphocytes ,Mice, Inbred BALB C ,Cell fusion ,Membrane Glycoproteins ,biology ,Viral Vaccine ,Immune Sera ,Epithelial Cells ,Viral Vaccines ,Epstein–Barr virus ,Virology ,Antibodies, Neutralizing ,Macaca fascicularis ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,HEK293 Cells ,Immunization ,030220 oncology & carcinogenesis ,biology.protein ,Female ,Antibody ,HeLa Cells - Abstract
Summary Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with epithelial-cell cancers and B cell lymphomas. An effective EBV vaccine is not available. We found that antibodies to the EBV glycoprotein gH/gL complex were the principal components in human plasma that neutralized infection of epithelial cells and that antibodies to gH/gL and gp42 contributed to B cell neutralization. Immunization of mice and nonhuman primates with nanoparticle vaccines that displayed components of the viral-fusion machinery EBV gH/gL or gH/gL/gp42 elicited antibodies that potently neutralized both epithelial-cell and B cell infection. Immune serum from nonhuman primates inhibited EBV-glycoprotein-mediated fusion of epithelial cells and B cells and targeted an epitope critical for virus-cell fusion. Therefore, unlike the leading EBV gp350 vaccine candidate, which only protects B cells from infection, these EBV nanoparticle vaccines elicit antibodies that inhibit the virus-fusion apparatus and provide cell-type-independent protection from virus infection.
- Published
- 2018
66. Primary Role of Suppressor of Cytokine Signaling 1 in Mycobacterium bovis BCG Infection
- Author
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Shogo Soma, Kenta Watanabe, Hiroyasu Inada, Seiichi Kato, Yasuhiro Yasutomi, Kazuhiro Matsuo, Satoru Mizuno, and Satoru Kawai
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0301 basic medicine ,Immunology ,Nitric Oxide Synthase Type II ,Nitric Oxide ,Microbiology ,law.invention ,Nitric oxide ,Mycobacterium tuberculosis ,03 medical and health sciences ,chemistry.chemical_compound ,Suppressor of Cytokine Signaling 1 Protein ,0302 clinical medicine ,law ,Animals ,Tuberculosis ,Stat signaling ,Homeodomain Proteins ,Mice, Knockout ,Mycobacterium bovis ,Cellular Microbiology: Pathogen-Host Cell Molecular Interactions ,biology ,Inoculation ,Suppressor of cytokine signaling 1 ,biology.organism_classification ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Infectious Diseases ,chemistry ,Host-Pathogen Interactions ,Recombinant DNA ,Parasitology ,Function (biology) ,Signal Transduction ,030215 immunology - Abstract
Suppressor of cytokine signaling 1 (SOCS1) is a negative regulator of JAK/STAT signaling and is induced by mycobacterial infection. To understand the major function of SOCS1 during infection, we established a novel system in which recombinant Mycobacterium bovis bacillus Calmette-Guérin expressed dominant-negative SOCS1 (rBCG-SOCS1DN) because it would not affect the function of SOCS1 in uninfected cells. When C57BL/6 mice and RAG1(−/−) mice were intratracheally inoculated with rBCG-SOCS1DN, the amount of rBCG-SOCS1DN in the lungs was significantly reduced compared to that in the lungs of mice inoculated with a vector control counterpart and wild-type BCG. However, these significant differences were not observed in NOS2(−/−) mice and RAG1(−/−) NOS2(−/−) double-knockout mice. These findings demonstrated that SOCS1 inhibits nitric oxide (NO) production to establish mycobacterial infection and that rBCG-SOCS1DN has the potential to be a powerful tool for studying the primary function of SOCS1 in mycobacterial infection.
- Published
- 2018
67. COVID-19 cynomolgus macaque model reflecting human COVID-19 pathological conditions.
- Author
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Emiko Urano, Tomotaka Okamura, Chikako Ono, Shiori Ueno, Satoshi Nagata, Haruhiko Kamada, Mahoko Higuchi, Mugi Furukawa, Wataru Kamitani, Yoshiharu Matsuura, Yoshihiro Kawaoka, and Yasuhiro Yasutomi
- Subjects
COVID-19 ,COVID-19 pandemic ,COMPUTED tomography ,KRA ,MACAQUES - Abstract
The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global threat to human health and life. A useful pathological animal model accurately reflecting human pathology is needed to overcome the COVID-19 crisis. In the present study, COVID-19 cynomolgus monkey models including monkeys with underlying diseases causing severe pathogenicity such as metabolic disease and elderly monkeys were examined. Cynomolgus macaques with various clinical conditions were intranasally and/or intratracheally inoculated with SARS-CoV-2. Infection with SARS-CoV-2 was found in mucosal swab samples, and a higher level and longer period of viral RNA was detected in elderly monkeys than in young monkeys. Pneumonia was confirmed in all of the monkeys by computed tomography images. When monkeys were readministrated SARS-CoV-2 at 56 d or later after initial infection all of the animals showed inflammatory responses without virus detection in swab samples. Surprisingly, in elderly monkeys reinfection showed transient severe pneumonia with increased levels of various serum cytokines and chemokines compared with those in primary infection. The results of this study indicated that the COVID-19 cynomolgus monkey model reflects the pathophysiology of humans and would be useful for elucidating the pathophysiology and developing therapeutic agents and vaccines. [ABSTRACT FROM AUTHOR]
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- 2021
- Full Text
- View/download PDF
68. A New Mouse Model of Chronic Myocarditis Induced by Recombinant Bacille Calmette–Guèrin Expressing a T-Cell Epitope of Cardiac Myosin Heavy Chain-α
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Kyoko Imanaka-Yoshida, Michiaki Hiroe, Yasuhiro Yasutomi, Masaki Ieda, Kazuhiro Matsuo, Yusuke Tsujimura, Kazutaka Aonuma, and Kazuko Tajiri
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Male ,0301 basic medicine ,Adoptive cell transfer ,recombinant BCG ,Epitopes, T-Lymphocyte ,Lymphocyte Activation ,medicine.disease_cause ,Epitope ,Autoimmunity ,lcsh:Chemistry ,0302 clinical medicine ,BCG ,lcsh:QH301-705.5 ,Spectroscopy ,Mice, Inbred BALB C ,Interleukin-17 ,autoimmunity ,Dilated cardiomyopathy ,General Medicine ,Recombinant Proteins ,Computer Science Applications ,medicine.anatomical_structure ,Echocardiography ,030220 oncology & carcinogenesis ,BCG Vaccine ,cardiovascular system ,Cytokines ,inflammatory dilated cardiomyopathy ,Cardiomyopathy, Dilated ,Cardiac function curve ,Myocarditis ,T cell ,Article ,Catalysis ,Proinflammatory cytokine ,Ventricular Myosins ,Inorganic Chemistry ,03 medical and health sciences ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,business.industry ,Organic Chemistry ,Th1 Cells ,medicine.disease ,autoimmune myocarditis ,Disease Models, Animal ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Chronic Disease ,Immunology ,Th17 Cells ,myocarditis ,business - Abstract
Dilated cardiomyopathy (DCM) is a potentially lethal disorder characterized by progressive impairment of cardiac function. Chronic myocarditis has long been hypothesized to be one of the causes of DCM. However, owing to the lack of suitable animal models of chronic myocarditis, its pathophysiology remains unclear. Here, we report a novel mouse model of chronic myocarditis induced by recombinant bacille Calmette-Gué, rin (rBCG) expressing a CD4+ T-cell epitope of cardiac myosin heavy chain-&alpha, (rBCG-MyHC&alpha, ). Mice immunized with rBCG-MyHC&alpha, developed chronic myocarditis, and echocardiography revealed dilation and impaired contraction of ventricles, similar to those observed in human DCM. In the heart, CD62L&minus, CD4+ T cells were increased and produced significant amounts of IFN-&gamma, and IL-17 in response to cardiac myosin. Adoptive transfer of CD62L&minus, CD4+ T cells induced myocarditis in the recipient mice, which indicated that CD62L&minus, CD4+ T cells were the effector cells in this model. rBCG-MyHC&alpha, infected dendritic cells produced proinflammatory cytokines and induced MyHC&alpha, specific T-cell proliferation and Th1 and Th17 polarization. This novel chronic myocarditis mouse model may allow the identification of the central pathophysiological and immunological processes involved in the progression to DCM.
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- 2021
69. Suppression of SARS-CoV-2-induced lung injury by ACE2-like carboxypeptidase B38-CAP in COVID-19 mouse model
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Midori Hoshizaki, Yumiko Imai, Satoru Nirasawa, Masaki Imai, Yoshihiro Kawaoka, Yasuhiro Yasutomi, Takafumi Minato, Saori Takahashi, Satoshi Nagata, Daichi Utsumi, Jianbo An, Haruhiko Kamada, Tomokazu Yamaguchi, Masamitsu N Asaka, Mayumi Niiyama, and Keiji Kuba
- Subjects
Lung ,medicine.anatomical_structure ,biology ,Chemistry ,Applied Mathematics ,General Mathematics ,medicine ,biology.protein ,Angiotensin-converting enzyme ,Virology ,Virus - Published
- 2021
70. Dynein Dysfunction Reproduces Age-Dependent Retromer Deficiency
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Eriko Samura, Yasuhiro Yasutomi, Sachi Okabayashi, Keiko Suzuki, Nobuyuki Kimura, and Nobuhiro Shimozawa
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0301 basic medicine ,Retromer ,Endosome ,Endocytic cycle ,Dynein ,macromolecular substances ,Biology ,Pathology and Forensic Medicine ,Cell biology ,Vesicular transport protein ,03 medical and health sciences ,030104 developmental biology ,Microtubule ,Axoplasmic transport ,Dynactin - Abstract
It is widely accepted that β-amyloid (Aβ) protein plays a pivotal role in Alzheimer disease pathogenesis, and accumulating evidence suggests that endocytic dysfunction is involved in Aβ pathology. Retromer, a conserved multisubunit complex, mediates the retrograde transport of numerous kinds of cargo from endosomes to the trans-Golgi network. Several studies have found that retromer deficiency enhances Aβ pathology both in vitro and in vivo . Cytoplasmic dynein, a microtubule-based motor protein, mediates minus-end-directed vesicle transport via interactions with dynactin, another microtubule-associated protein that also interacts with retromer. Aging attenuates the dynein-dynactin interaction, and dynein dysfunction reproduces age-dependent endocytic disturbance, resulting in the intracellular accumulation of beta-amyloid precursor protein (APP) and its β-cleavage products, including Aβ. Here, we report that aging itself affects retromer trafficking in cynomolgus monkey brains. In addition, dynein dysfunction reproduces this type of age-dependent retromer deficiency (ie, the endosomal accumulation of retromer-related proteins and APP. Moreover, we found that knockdown of Rab7, Rab9, or Rab11 did not alter endogenous APP metabolism, such as that observed in aged monkey brains and in dynein-depleted cells. These findings suggest that dynein dysfunction can cause retromer deficiency and that concomitant disruption of retrograde trafficking may be the key factor underlying age-dependent Aβ pathology.
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- 2016
71. Persistent replication of a hepatitis C virus genotype 1b-based chimeric clone carrying E1, E2 and p6 regions from GB virus B in a New World monkey
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Noboru Maki, Atsunori Higashino, Kenichi Mori, Hirofumi Akari, Yasuhiro Yasutomi, Yuki Iwasaki, and Saori Suzuki
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0301 basic medicine ,Hepatitis B virus DNA polymerase ,Hepatitis C virus ,Immunology ,virus diseases ,Viral transformation ,Biology ,medicine.disease_cause ,Microbiology ,Virology ,digestive system diseases ,Hepatitis B virus PRE beta ,Virus ,03 medical and health sciences ,Chimera (genetics) ,030104 developmental biology ,0302 clinical medicine ,Chimeric RNA ,medicine ,030211 gastroenterology & hepatology ,Oncovirus - Abstract
The development of effective hepatitis C virus (HCV) vaccines is essential for the prevention of further HCV dissemination, especially in developing countries. Therefore the aim of this study is to establish a feasible and immunocompetent surrogate animal model of HCV infection that will help in evaluation of the protective efficacy of newly developing HCV vaccine candidates. To circumvent the narrow host range of HCV, an HCV genotype 1b-based chimeric clone carrying E1, E2 and p6 regions from GB virus B (GBV-B), which is closely related to HCV, was generated. The chimera between HCV and GBV-B, named HCV/G, replicated more efficiently as compared with the HCV clone in primary marmoset hepatocytes. Furthermore, it was found that the chimera persistently replicated in a tamarin for more than 2 years after intrahepatic inoculation of the chimeric RNA. Although relatively low (
- Published
- 2016
72. Tracking cells implanted into cynomolgus monkeys (Macaca fascicularis) using MRI
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Sachi Okabayashi, Kiichi Kanayama, Hiroshi Koie, Yuko Katakai, Yasuhiro Yasutomi, Chieko Ohno, Hiroaki Shibata, Naohide Ageyama, and Yasuyo Ito-Fujishiro
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,General Veterinary ,medicine.diagnostic_test ,business.industry ,Magnetic resonance imaging ,General Medicine ,Blood flow ,030204 cardiovascular system & hematology ,medicine.disease ,Peripheral blood mononuclear cell ,Regenerative medicine ,General Biochemistry, Genetics and Molecular Biology ,Transplantation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Triceps surae muscle ,Heart failure ,medicine ,Animal Science and Zoology ,Stem cell ,business - Abstract
Regenerative therapy with stem cell transplantation is used to treat various diseases such as coronary syndrome and Buerger's disease. For instance, stem-cell transplantation into the infarcted myocardium is an innovative and promising strategy for treating heart failure due to ischemic heart disease. Basic studies using small animals have shown that transplanted cells improve blood flow in the infarcted region. Magnetic resonance imaging (MRI) can noninvasively identify and track transplanted cells labeled with superparamagnetic iron oxide (SPIO). Although clinical regenerative therapies have been clinically applied to patients, the fate of implanted cells remains unknown. In addition, follow-up studies have shown that some adverse events can occur after recovery. Therefore, the present study evaluated the ability of MRI using a 3T scanner to track implanted peripheral blood mononuclear cells labeled with SPIO on days 0 and 7 after intramuscular (i.m.) and intravenous (i.v.) injection into a cynomolgus monkey. Labeled cells were visualized at the liver and triceps surae muscle on MR images using T1- and T2-weighted sequences and histologically localized by Prussian blue staining. The transplanted cells were tracked without abnormal clinical manifestations throughout this study. Hence, MRI of cynomolgus monkey transplanted SPIO-labeled cells is a safe and efficient method of tracking labeled cells that could help to determine the mechanisms involved in regenerative therapy.
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- 2016
73. Development of an effective alternative model for in vivo hypnozoite-induced relapse infection: A Japanese macaque (Macaca fuscata) model experimentally infected with Plasmodium cynomolgi
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Takeshi Annoura, Shogo Soma, Yumiko Shiogama, Marcello Otake Sato, Yuichi Chigusa, Jun-ichiro Takano, Osamu Kaneko, Satoru Kawai, Tamasa Araki, and Yasuhiro Yasutomi
- Subjects
biology ,Inoculation ,biology.organism_classification ,Virology ,Macaca fuscata ,Malaria ,Disease Models, Animal ,Japanese macaque ,Rhesus macaque ,Chloroquine Sulfate ,Infectious Diseases ,Recurrence ,In vivo ,Primaquine Phosphate ,biology.animal ,Plasmodium cynomolgi ,Animals ,Parasite hosting ,Female ,Parasitology - Abstract
In the present study, we demonstrate that the Japanese macaque (Macaca fuscata) can be used as an effective alternative in vivo model for investigating hypnozoite-induced relapsing infection caused by Plasmodium cynomolgi B strain, and that this model is comparable to the rhesus macaque model. Two female Japanese macaques (JM-1 and JM-2; aged 5 years; weighing about 4.0 kg) were used for the experiment. To produce sporozoites in mosquitoes, blood infected with P. cynomolgi B strain was collected from the donor monkey JM-1 and fed to approximately 200 mosquitoes using the standard artificial membrane feeding method. The isolated sporozoites (2 × 105) were intravenously inoculated into the JM-2 monkey, and the blood stage of the parasite was detected on day 8 after the infection. Chloroquine sulfate (CQ) was intramuscularly administered at a dosage of 6.0 mg/kg into the JM-2 monkey for 6 consecutive days from day 12 onward, after which the parasites disappeared from the peripheral blood. The first relapse occurred on day 26, which was treated again with CQ. Then, the second relapse occurred on day 44, which was cured by CQ treatment followed by the administration of primaquine phosphate (PQ) at a dosage of 1.0 mg/kg/day for 15 days. The JM-2 monkey was observed until 69 days after PQ administration, and there was no relapse during the entire follow-up period. We propose that the Japanese macaque model could contribute not only to drug screening for anti-hypnozoite activity, but could also be used as a powerful tool for investigating hypnozoite biology.
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- 2020
74. Studies of incomplete control of Epstein-Barr virus infection in association with aging by using cynomolgus macaque colony
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Emiko Urano, Yoshiko Murakata, Yusuke Tsujimura, and Yasuhiro Yasutomi
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Immunology ,Immunology and Allergy - Abstract
The analysis of age-related immune senescent is extremely meaningful to understand the vital homeostasis in individuals among the aging society. Epstein-Barr virus (EBV) establishes latent infection in >90% of adults worldwide. In general, chronically infected EBV is controlled well for a lifelong in healthy adults. Since, EBV is reactivated by the failure of the host immune system, it can be an index to understand the hypofunction. A non-human-primate, controlled experimental animal, cynomolgus macaque (CM) has a long life span and can be used for longevity studies using aged animals that are more than 20 years old, which correspond to ≥60 years of age in humans. In this study, the state of EBV infection in the colony of CM was explored by detecting EBV in saliva as EBV reactivation, and the immunological functions were examined using PBMC from CMs concerned with the control of EBV. Age-related alteration of T cell and B cell subsets was observed in CM colony comparison with young (4–6 years) and elderly (24–26 years) group. T cell distribution was similar among young and elderly groups respectively; however, CD3 and CD28 stimulated cells from elderly EBV (+) group showed the lowest proliferation than the others. EBV-specific immune responses are under consideration. The CM colony will be a useful model of aging and the extensive study will help to elucidate the mechanisms of hypofunction through a long-life span.
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- 2020
75. Elevated Membrane Cholesterol Disrupts Lysosomal Degradation to Induce β-Amyloid Accumulation: The Potential Mechanism Underlying Augmentation of β-Amyloid Pathology by Type 2 Diabetes Mellitus
- Author
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Shingo, Takeuchi, Naoya, Ueda, Keiko, Suzuki, Nobuhiro, Shimozawa, Yasuhiro, Yasutomi, and Nobuyuki, Kimura
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Male ,Amyloid beta-Peptides ,Brain ,Cell Line ,Diabetes Mellitus, Experimental ,Diabetes Complications ,Macaca fascicularis ,Cholesterol ,Diabetes Mellitus, Type 2 ,Alzheimer Disease ,Animals ,Humans ,Female ,Lysosomes - Abstract
The endocytic membrane trafficking system is altered in the brains of early-stage Alzheimer disease (AD) patients, and endocytic disturbance affects the metabolism of β-amyloid (Aβ) protein, a key molecule in AD pathogenesis. It is widely accepted that type 2 diabetes mellitus (T2DM) is one of the strongest risk factors for development of AD. Supporting this link, experimentally induced T2DM enhances AD pathology in various animal models. Spontaneous T2DM also enhances Aβ pathology with severe endocytic pathology, even in nonhuman primate brains. However, it remains unclear how T2DM accelerates Aβ pathology. Herein, we demonstrate that cholesterol metabolism-related protein levels are increased and that membrane cholesterol level is elevated in spontaneous T2DM-affected cynomolgus monkey brains. Moreover, in vitro studies that manipulate cellular cholesterol reveal that elevated membrane cholesterol disrupts lysosomal degradation and enhances chemical-induced endocytic disturbance, resulting in great accumulation of Aβ in Neuro2a cells. These findings suggest that an alteration of cerebral cholesterol metabolism may be responsible for augmentation of Aβ pathology in T2DM-affected brains, which, in turn, may increase the risk for developing AD.
- Published
- 2018
76. Superparamagnetic Iron Oxide-enhanced Magnetic Resonance Imaging of Spontaneous Hepatic Neoplasia in a Cynomolgus Macaque (
- Author
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Yasuyo Ito, Fujishiro, Hiroshi, Koie, Shunya, Nakayama, Hiroaki, Shibata, Sachi, Okabayashi, Yuko, Katakai, Kiichi, Kanayama, Yasuhiro, Yasutomi, and Naohide, Ageyama
- Subjects
Macaca fascicularis ,Liver Neoplasms ,Nonhuman Primate Models ,Animals ,Contrast Media ,Female ,Ferric Compounds ,Magnetic Resonance Imaging ,humanities - Abstract
Although the number of reports describing tumors in aged NHP has increased, spontaneous neoplasias in NHP are extremely rare, with the notable exception of prosimians, in which spontaneous hepatic neoplasms arise. In addition to radiography and ultrasonography, superparamagnetic iron oxide (SPIO)-enhanced MRI tends to be applied in human practice to non-invasively locate, identify, and size liver tumors and to define the border between neoplastic and normal tissues. Here we report a 13-y-old female cynomolgus monkey with anorexia and serologically normal liver enzymes. After fluid therapy, the condition remained in remission for several months. Later, however, a palpable mass was assessed by using ultrasonography, radiology, and SPIO-MRI; T2-weighted images revealed a clear border between a hepatocellular carcinoma and normal liver tissue. Findings at necropsy supported the imaging data. Serologic assessment after euthanasia revealed a positive reaction to an abnormal form of prothrombin (PIVKA-II). We recommend SPIO-MRI as a practical and useful for diagnosing hepatocellular neoplasias in NHP. This study is the first to demonstrate the applicability of SPIO-MRI for the identification of hepatocellular carcinoma in NHP.
- Published
- 2018
77. Adaptation of the Plasmodium falciparum FCB strain for in vitro and in vivo analysis in squirrel monkeys (Saimiri sciureus)
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Sawako Itagaki, Takahiro Tougan, Yuko Katakai, Yasuhiro Yasutomi, Nobuko Arisue, and Toshihiro Horii
- Subjects
0301 basic medicine ,Plasmodium falciparum ,Biology ,Parasitemia ,03 medical and health sciences ,In vivo ,parasitic diseases ,medicine ,Parasite hosting ,Animals ,Saimiri ,Squirrel monkey ,Saimiri sciureus ,medicine.disease ,biology.organism_classification ,Virology ,Adaptation, Physiological ,Red blood cell ,Disease Models, Animal ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Parasitology ,Laboratories ,Genome, Protozoan ,Malaria ,Spleen - Abstract
The asexual blood stages of the Plasmodium falciparum parasite are responsible for inducing the clinical symptoms and the most severe presentations of malaria infection that causes frequent mortality and morbidity in tropical and subtropical areas of the world, making the blood stages of infection a key target of new malaria treatment and prevention strategies. Progress towards the development of more effective treatment and prevention strategies has been hindered by the limited availability of infection models that permit the sequential analysis of blood stage parasites in vitro followed by in vivo analysis to confirm therapeutic benefits. To advance a model for in vitro and in vivo analysis of blood stage parasites, we examined nine laboratory strains of P. falciparum to determine which strains could adapt to growth in vivo in splenectomized squirrel monkeys (Saimiri sciureus). Only one of the nine laboratory strains tested, the FCB strain, adapted to in vivo growth. Morphological analysis show that the adapted ring-stage parasites have a different morphology from original parasites cultured in vitro, and more often they were found to localize at the edge of the infected red blood cell. No remarkable differences were observed for both trophozoites and schizonts. The adapted strain can be cultured back in vitro similar to the original parasite, indicating that the adapted parasite can develop both in vitro and in vivo. This squirrel monkey-adapted P. falciparum parasite is expected to be suitable and is advantageous for the research and development of vaccines and antimalarial drugs.
- Published
- 2018
78. Immunological association of inducible bronchus-associated lymphoid tissue organogenesis in Ag85B-rHPIV2 vaccine-induced anti-tuberculosis mucosal immune responses in mice
- Author
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Ken Ishii, Sakiko Morimoto, Kentaro Ogami, Yusuke Tsujimura, Jun Kunisawa, Yasuko Wada, Yasuhiro Yasutomi, Takahiro Nagatake, Etsushi Kuroda, Ayaka Nasu, Soichiro Hirata, Norifumi Iijima, Tetsuya Nosaka, Michiko Shimojou, Koji Hosomi, Naomi Matsumoto, Mitsuo Kawano, and Hidehiko Suzuki
- Subjects
0301 basic medicine ,Immunoglobulin A ,Lymphoid Tissue ,Organogenesis ,Immunology ,Inflammation ,03 medical and health sciences ,Mice ,Immune system ,Antigen ,medicine ,Immunology and Allergy ,Animals ,Tuberculosis Vaccines ,Antigens, Bacterial ,biology ,General Medicine ,Mycobacterium tuberculosis ,Eosinophil ,Parainfluenza Virus 2, Human ,Mice, Inbred C57BL ,030104 developmental biology ,Lymphatic system ,medicine.anatomical_structure ,biology.protein ,Antibody ,medicine.symptom ,Tuberculosis vaccines ,Acyltransferases - Abstract
We previously reported that Ag85B-expressing human parainfluenza type 2 virus (Ag85B-rHPIV2) was effective as a nasal vaccine against tuberculosis in mice; however, the mechanism by which it induces an immune response remains to be investigated. In the present study, we found that organogenesis of inducible bronchus-associated lymphoid tissue (iBALT) played a role in the induction of antigen-specific T cells and IgA antibody responses in the lung of mice intra-nasally administered Ag85B-rHPIV2. We found that expression of Ag85B was dispensable for the development of iBALT, suggesting that HPIV2 acted as an iBALT-inducing vector. When iBALT organogenesis was disrupted in Ag85B-rHPIV2-immunized mice, either by neutralization of the lymphotoxin pathway or depletion of CD11b+ cells, Ag85B-specific immune responses (i.e. IFN γ-producing T cells and IgA antibody) were diminished in the lung. Furthermore, we found that immunization with Ag85B-rHPIV2 induced neutrophil and eosinophil infiltration temporally after the immunization in the lung. Thus, our results show that iBALT organogenesis contributes to the induction of antigen-specific immune responses by Ag85B-rHPIV2 and that Ag85B-rHPIV2 provokes its immune responses without inducing long-lasting inflammation.
- Published
- 2018
79. Nanogel-based pneumococcal surface protein A nasal vaccine induces microRNA-associated Th17 cell responses with neutralizing antibodies against Streptococcus pneumoniae in macaques
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David E. Briles, Kazunari Akiyoshi, Yoshikazu Yuki, Haruko Takahashi, Hideo Tsukada, Shiho Kurokawa, Norihiro Harada, Shigeo Takeda, Hiroshi Kiyono, Mio Mejima, Yasuhiro Yasutomi, H Shibata, Shin-ichi Sawada, Kohtaro Fujihashi, Yuko Katakai, Sunyi Joo, Yoshiko Fukuyama, and Eun Jeong Park
- Subjects
Male ,Nasal cavity ,Immunology ,medicine.disease_cause ,Article ,Microbiology ,Th2 Cells ,Immune system ,Bacterial Proteins ,Streptococcus pneumoniae ,otorhinolaryngologic diseases ,medicine ,Animals ,Humans ,Immunology and Allergy ,Glucans ,Administration, Intranasal ,Drug Carriers ,biology ,Pneumonia, Pneumococcal ,biology.organism_classification ,Antibodies, Bacterial ,Antibodies, Neutralizing ,Vaccination ,Macaca fascicularis ,MicroRNAs ,Rhesus macaque ,medicine.anatomical_structure ,biology.protein ,Nanoparticles ,Female ,Nasal administration ,Antibody ,Gels ,Respiratory tract - Abstract
We previously established a nanosized nasal vaccine delivery system by using a cationic cholesteryl group-bearing pullulan nanogel (cCHP nanogel), which is a universal protein-based antigen-delivery vehicle for adjuvant-free nasal vaccination. In the present study, we examined the central nervous system safety and efficacy of nasal vaccination with our developed cCHP nanogel containing pneumococcal surface protein A (PspA-nanogel) against pneumococcal infection in nonhuman primates. When [(18)F]-labeled PspA-nanogel was nasally administered to a rhesus macaque (Macaca mulatta), longer-term retention of PspA was noted in the nasal cavity when compared with administration of PspA alone. Of importance, no deposition of [(18)F]-PspA was seen in the olfactory bulbs or brain. Nasal PspA-nanogel vaccination effectively induced PspA-specific serum IgG with protective activity and mucosal secretory IgA (SIgA) Ab responses in cynomolgus macaques (Macaca fascicularis). Nasal PspA-nanogel-induced immune responses were mediated through T-helper (Th) 2 and Th17 cytokine responses concomitantly with marked increases in the levels of miR-181a and miR-326 in the serum and respiratory tract tissues, respectively, of the macaques. These results demonstrate that nasal PspA-nanogel vaccination is a safe and effective strategy for the development of a nasal vaccine for the prevention of pneumonia in humans.
- Published
- 2015
80. Contrasting infection susceptibility of the Japanese macaques and cynomolgus macaques to closely related malaria parasites, Plasmodium vivax and Plasmodium cynomolgi
- Author
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Yasuhiro Yasutomi, Toshihiro Horii, Yuko Katakai, Hideo Takahashi, Toru Nakade, Kazuyuki Tanabe, Shin-Ichiro Tachibana, and Satoru Kawai
- Subjects
Serotype ,Molecular Sequence Data ,Plasmodium vivax ,Protozoan Proteins ,Antigens, Protozoan ,Receptors, Cell Surface ,Old World monkey ,Macaque ,Species Specificity ,Antigen ,biology.animal ,parasitic diseases ,Malaria, Vivax ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Serotyping ,Infectivity ,biology ,Monkey Diseases ,biology.organism_classification ,medicine.disease ,Macaca mulatta ,Virology ,Malaria ,Macaca fascicularis ,Japanese macaque ,Infectious Diseases ,Macaca ,Parasitology ,Disease Susceptibility ,Plasmodium cynomolgi - Abstract
Although the human malaria parasite Plasmodium vivax is closely related to Asian Old World monkey malaria parasites, there are no reports of P. vivax infections in macaques. In this study, we compared the infectivity of P. vivax and Plasmodium cynomolgi in Japanese macaques (Macaca fuscata) and in cynomolgus macaques (Macaca fascicularis). The Japanese macaques were highly susceptible to P. cynomolgi but not to P. vivax, whereas cynomolgus macaques showed mild/limited P. cynomolgi infection and were, also, not susceptible to P. vivax. Serotyping and amino acid sequence comparison of erythrocyte surface Duffy antigen/receptor for chemokines (DARC) indicate that the Japanese macaque DARC sequence is nearly identical to that of rhesus (Macaca mulatta) and cynomolgus macaques. This suggests that the macaques share a common mechanism for preventing P. vivax infection. Comparison of amino acid sequences of the Duffy-binding-like (DBL) domain from several different Plasmodium species suggests that P. vivax DBLs will not bind to macaque DARCs, which can explain the lack of P. vivax infectivity. The DBL sequence analyses also suggest that P. cynomolgi DBLs may target Japanese macaque erythrocytes through a DARC-independent interaction.
- Published
- 2015
81. An Antigen-Free, Plasmacytoid Dendritic Cell-Targeting Immunotherapy To Bolster Memory CD8
- Author
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Yuji, Masuta, Takuya, Yamamoto, Yayoi, Natsume-Kitatani, Tomohiro, Kanuma, Eiko, Moriishi, Kouji, Kobiyama, Kenji, Mizuguchi, Yasuhiro, Yasutomi, and Ken J, Ishii
- Subjects
Inflammation ,Male ,Primates ,Neutrophils ,Sizofiran ,Dendritic Cells ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Macaca fascicularis ,Toll-Like Receptor 9 ,Animals ,Cytokines ,Lectins, C-Type ,Immunotherapy ,Antigens ,Immunologic Memory - Abstract
The priming, boosting, and restoration of memory cytotoxic CD8
- Published
- 2017
82. Establishment of reference values for complete blood count and blood gases in cynomolgus monkeys (Macaca fascicularis)
- Author
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Shunya, Nakayama, Hiroshi, Koie, Kiichi, Kanayama, Yuko, Katakai, Yasuyo, Ito-Fujishiro, Tadashi, Sankai, Yasuhiro, Yasutomi, and Naohide, Ageyama
- Subjects
Male ,Aging ,complete blood count ,Full Paper ,nonhuman primate ,arterial blood gas ,Blood Cell Count ,Macaca fascicularis ,Reference Values ,Laboratory Animal Science ,Animals ,Female ,cynomolgus monkey ,Blood Gas Analysis - Abstract
Cynomolgus monkeys are closely related to humans phylogenetically, and this has resulted in their widespread use as a preclinical model. Hematological data with regard to these monkeys are thus important. Although reference values for blood components and sex hormones have been established for cynomolgus monkeys, those for arterial blood gases have not. The arterial blood gases quickly reflect respiratory and circulatory dynamics, and are thus useful for animal management and safe general anesthesia and surgical operations. Furthermore, since O2 is transported by RBC, CBC and blood gases are closely related. The present study aimed to establish reference values for arterial blood gases and CBC in cynomolgus monkeys over a wide age range. Blood gases and CBC of arterial blood, collected from 41 female and 21 male anesthetized monkeys, were measured. Age correlated with RBC, HGB and HCT in the CBC. Values differed significantly between males and females in pCO2, CO2 concentration, MCV and MCH. The pH of blood was equivalent to that of humans and pCO2 was more stable, whereas MCV and MCH were lower than those in humans. Erythrocytes were smaller and less pigmented than in other Macaca species. Several relationships between gender and age, and blood gases and CBC were identified in cynomolgus monkeys. In conclusion, these reference values will be useful as markers for veterinary applications and in the care and maintenance of these animals.
- Published
- 2017
83. The 17,18-epoxyeicosatetraenoic acid-G protein-coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques
- Author
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Takayuki Kishi, Junken Aoki, Yasuhiro Yasutomi, Naomi Matsumoto, Makoto Arita, Masaru Ishii, Yumiko Shiogama, Sakiko Morimoto, Asuka Inoue, Pär Steneberg, Michiko Shimojou, Hidehiko Suzuki, So ichiro Hirata, Kenji Kabashima, Hiroshi Kiyono, Prabha Tiwari, Yosuke Isobe, Jun Kunisawa, Takahiro Nagatake, Tetsuya Honda, Junichi Kikuta, Helena Edlund, and Atsushi Yanagisawa
- Subjects
0301 basic medicine ,Neutrophils ,Immunology ,Anti-Inflammatory Agents ,Peroxisome proliferator-activated receptor ,Arachidonic Acids ,Pharmacology ,Dermatitis, Contact ,Fas ligand ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,Mice ,Cell Movement ,Anti-Allergic Agents ,Immunology and Allergy ,Animals ,Pseudopodia ,Cells, Cultured ,G protein-coupled receptor ,chemistry.chemical_classification ,Mice, Knockout ,biology ,Chemistry ,Cytochrome P450 ,Dendritic cell ,Intercellular adhesion molecule ,Eicosapentaenoic acid ,rac GTP-Binding Proteins ,Mice, Inbred C57BL ,Macaca fascicularis ,030104 developmental biology ,Docosahexaenoic acid ,biology.protein ,Female ,Signal Transduction - Abstract
Metabolites of eicosapentaenoic acid exert various physiologic actions. 17,18-Epoxyeicosatetraenoic acid (17,18-EpETE) is a recently identified new class of antiallergic and anti-inflammatory lipid metabolite of eicosapentaenoic acid, but its effects on skin inflammation and the underlying mechanisms remain to be investigated.We evaluated the effectiveness of 17,18-EpETE for control of contact hypersensitivity in mice and cynomolgus macaques. We further sought to reveal underlying mechanisms by identifying the responsible receptor and cellular target of 17,18-EpETE.Contact hypersensitivity was induced by topical application of 2,4-dinitrofluorobenzene. Skin inflammation and immune cell populations were analyzed by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. Neutrophil mobility was examined by means of imaging analysis in vivo and neutrophil culture in vitro. The receptor for 17,18-EpETE was identified by using the TGF-α shedding assay, and the receptor's involvement in the anti-inflammatory effects of 17,18-EpETE was examined by using KO mice and specific inhibitor treatment.We found that preventive or therapeutic treatment with 17,18-EpETE ameliorated contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. 17,18-EpETE was recognized by G protein-coupled receptor (GPR) 40 (also known as free fatty acid receptor 1) and inhibited chemoattractant-induced Rac activation and pseudopod formation in neutrophils. Indeed, the antiallergic inflammatory effect of 17,18-EpETE was abolished in the absence or inhibition of GPR40.17,18-EpETE inhibits neutrophil mobility through GPR40 activation, which is a potential therapeutic target to control allergic inflammatory diseases.
- Published
- 2017
84. Male Mate Choice Among Captive Long-tailed Macaques (Macaca Fascicularis)
- Author
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Tadashi Sankai, Maiko Kobayashi, Yasuhiro Yasutomi, and Takamasa Koyama
- Subjects
Sexual behavior ,Mate choice ,biology ,Offspring ,biology.animal ,Physiology ,Primate ,Mating ,Sperm ,General Psychology - Abstract
Author(s): Kobayashi, Maiko Yoshida | Abstract: The purpose of this study was to investigate male preference and to define the aspects of females that affect male preference. We set experimental conditions that enabled us to measure successful mating by gathering sperm from female vaginal washings and observing sexual behavior. The animal subjects in our study were cynomolgus monkeys, all of whom were bred in our primate institute. During the study, one male would be grouped with two females, each of whom lived in a cage adjacent to the male’s cage. This enabled each of the females to be housed with the male in turn; 12 males and 24 females were included in the study. After a male was housed with a female, we observed through a microscope the existence of sperm in the female’s vaginal washing, thus confirming copulation success. In some of the groups, behavioral observation was conducted on both the male and female subjects. According to our findings, in the multiparous females, successful mating was observed on 29% of cohabitation days. Among nulliparous females, the presence of sperm was observed on only 6% of cohabitation periods. Some 66.7% of nulliparous females never mated with a male. Our observations also revealed that sexual behaviors were more frequently observed when a male lived with a multiparous female. “Male-grooming-of-female” activities were seen more frequently between a male and multiparous female; that is, the male approached a multiparous female for copulation by grooming her. Our study suggests that male cynomolgus monkeys prefer multiparous females, as it is important that a male choose a female who more easily and regularly becomes pregnant and gives birth to offspring with a higher survival rate. Thus, male choice is biologically significant with respect to leaving more offspring.
- Published
- 2017
85. Nonagonistic Dectin-1 ligand transforms CpG into a multitask nanoparticulate TLR9 agonist
- Author
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Shizuo Akira, Masayuki Hayashi, Cevayir Coban, Etsushi Kuroda, Kouji Kobiyama, Yoichiro Iwakura, Shohei Koyama, Yuko Katakai, Ken Ishii, Shinobu Saijo, Shinichi Mochizuki, Taiki Aoshi, Hirotaka Narita, Kohhei Tetsutani, Yasuhiro Yasutomi, and Kazuo Sakurai
- Subjects
Interferon Inducers ,CpG Oligodeoxynucleotide ,Sizofiran ,Enzyme-Linked Immunosorbent Assay ,Biology ,Mice ,chemistry.chemical_compound ,Immune system ,Adjuvants, Immunologic ,Animals ,Humans ,Lectins, C-Type ,Cells, Cultured ,Multidisciplinary ,Interferon inducer ,TLR9 ,Biological Sciences ,Molecular biology ,Toll-Like Receptor 9 ,Mice, Inbred C57BL ,Microscopy, Electron ,CTL ,Oligodeoxyribonucleotides ,CpG site ,chemistry ,Leukocytes, Mononuclear ,Cancer research ,Nanoparticles ,CpG Islands ,Immunotherapy - Abstract
CpG DNA, a ligand for Toll-like receptor 9 (TLR9), has been one of the most promising immunotherapeutic agents. Although there are several types of potent humanized CpG oligodeoxynucleotide (ODN), developing "all-in-one" CpG ODNs activating both B cells and plasmacytoid dendritic cells forming a stable nanoparticle without aggregation has not been successful. In this study, we generated a novel nanoparticulate K CpG ODN (K3) wrapped by the nonagonistic Dectin-1 ligand schizophyllan (SPG), K3-SPG. In sharp contrast to K3 alone, K3-SPG stimulates human peripheral blood mononuclear cells to produce a large amount of both type I and type II IFN, targeting the same endosome where IFN-inducing D CpG ODN resides without losing its K-type activity. K3-SPG thus became a potent adjuvant for induction of both humoral and cellular immune responses, particularly CTL induction, to coadministered protein antigens without conjugation. Such potent adjuvant activity of K3-SPG is attributed to its nature of being a nanoparticle rather than targeting Dectin-1 by SPG, accumulating and activating antigen-bearing macrophages and dendritic cells in the draining lymph node. K3-SPG acting as an influenza vaccine adjuvant was demonstrated in vivo in both murine and nonhuman primate models. Taken together, K3-SPG may be useful for immunotherapeutic applications that require type I and type II IFN as well as CTL induction.
- Published
- 2014
86. Interferon-β response is impaired by hepatitis B virus infection in Tupaia belangeri
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Naoki Yamamoto, Mohammad Enamul Hoque Kayesh, Yasuhito Tanaka, Takahiro Sanada, Sayeh Ezzikouri, Chimène Nze Nkogue, Jun-ichiro Takano, Yasuhiro Yasutomi, Hitoshi Hatai, Haiying Chi, Michinori Kohara, Yumiko Shiogama, Takumi Haraguchi, Kyoko Tsukiyama-Kohara, Bouchra Kitab, Shuko Murakami, Noriaki Miyoshi, and Rika Matsuyama
- Subjects
0301 basic medicine ,Cancer Research ,HBsAg ,Hepatitis B virus ,Tupaia ,medicine.disease_cause ,Virus Replication ,03 medical and health sciences ,Tupaia belangeri ,Hepatitis B, Chronic ,Interferon ,Virology ,medicine ,Animals ,Immune Evasion ,Hepatitis B Surface Antigens ,biology ,Liver cell ,Gene Expression Profiling ,Toll-Like Receptors ,virus diseases ,TLR9 ,Interferon-beta ,biology.organism_classification ,digestive system diseases ,Immunity, Innate ,Chronic infection ,Disease Models, Animal ,030104 developmental biology ,Infectious Diseases ,Immunology ,Host-Pathogen Interactions ,Hepatocytes ,medicine.drug - Abstract
To date, the chimpanzee has been used as the natural infection model for hepatitis B virus (HBV). However, as this model is very costly and difficult to use because of ethical and animal welfare issues, we aimed to establish the tupaia (Tupaia belangeri) as a new model for HBV infection and characterized its intrahepatic innate immune response upon HBV infection. First, we compared the propagation of HBV genotypes A2 and C in vivo in tupaia hepatocytes. At 8-10days post infection (dpi), the level of HBV-A2 propagation in the tupaia liver was found to be higher than that of HBV-C. Abnormal architecture of liver cell cords and mitotic figures were also observed at 8 dpi with HBV-A2. Moreover, we found that HBV-A2 established chronic infection in some tupaias. We then aimed to characterize the intrahepatic innate immune response in this model. First, we infected six tupaias with HBV-A2 (strains JP1 and JP4). At 28 dpi, intrahepatic HBV-DNA and serum hepatitis B surface antigens (HBsAg) were detected in all tupaias. The levels of interferon (IFN)-β were found to be significantly suppressed in the three tupaias infected with HBV A2_JP4, while no significant change was observed in the three infected with HBV A2_JP1. Expression of toll-like receptor (TLR) 1 was suppressed, while that of TLR3 and TLR9 were induced, in HBV A2_JP1-infected tupaias. Expression of TLR8 was induced in all tupaias. Next, we infected nine tupaias with HBV-A2 (JP1, JP2, and JP4), and characterized the infected animals after 31 weeks. Serum HBsAg levels were detected at 31 weeks post-infection (wpi) and IFN-β was found to be significantly suppressed in all tupaias. TLR3 was not induced, except in tupaia #93 and #96. Suppression of TLR9 was observed in all tupaias, except tupaia #93. Also, we investigated the expression levels of cyclic GMP-AMP synthase, which was found to be induced in all tupaias at 28 dpi and in four tupaias at 31 wpi. Additionally, we evaluated the expression levels of sodium-taurocholate cotransporting polypeptide, which was found to be suppressed during chronic HBV infection. Thus, the tupaia infection model of HBV clearly indicated the suppression of IFN-β at 31 wpi, which might have contributed to the establishment of chronic HBV infection.
- Published
- 2016
87. Tau pathology in aged cynomolgus monkeys is progressive supranuclear palsy/corticobasal degeneration- but not Alzheimer disease-like -Ultrastructural mapping of tau by EDX
- Author
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Nobuhiro Shimozawa, Hiromi Kondo, Yasuhiro Yasutomi, Eijiro Adachi, Sachi Okabayashi, Kentaro Endo, Nobuyuki Kimura, and Toshiki Uchihara
- Subjects
0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,Aging ,Amyloid ,Hippocampus ,tau Proteins ,Biology ,Pathology and Forensic Medicine ,Progressive supranuclear palsy ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Alzheimer Disease ,Basal ganglia ,mental disorders ,medicine ,Corticobasal degeneration ,Immuno electron microscopy ,Animals ,Microscopy, Immunoelectron ,Neurons ,Neocortex ,Research ,Aged monkey ,Brain ,Spectrometry, X-Ray Emission ,Human brain ,medicine.disease ,Immunohistochemistry ,Four-repeat tau ,Macaca fascicularis ,Oligodendroglia ,030104 developmental biology ,medicine.anatomical_structure ,Astrocytes ,Female ,Neurology (clinical) ,Energy-dispersive X-ray analysis ,Supranuclear Palsy, Progressive ,Alzheimer's disease ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Concomitant deposition of amyloid -beta protein (Aβ) and neuronal tau as neurofibrillary tangles in the human brain is a hallmark of Alzheimer disease (AD). Because these deposits increase during normal aging, it has been proposed that aging brains may also undergo AD-like changes. To investigate the neuropathological changes that occur in the aging primate brain, we examined 21 brains of cynomolgus monkeys (7–36 years old) for Aβ- and tau-positive lesions. We found, 1) extensive deposition of Aβ in brains of cynomolgus monkeys over 25 years of age, 2) selective deposition of 4-repeat tau as pretangles in neurons, and as coiled body-like structures in oligodendroglia-like cells and astrocytes, 3) preferential distribution of tau in the basal ganglia and neocortex rather than the hippocampus, and 4) age-associated increases in 30–34 kDa AT8- and RD4-positive tau fragments in sarkosyl-insoluble fractions. We further labeled tau-positive structures using diaminobezidine enhanced with nickel, and visualized nickel-labeled structures by energy-dispersive X-ray (EDX) analysis of ultrathin sections. This allowed us to distinguish between nickel-labeled tau and background electron-dense structures, and we found that tau localized to 20–25 nm straight filaments in oligodendroglia-like cells and neurons. Our results indicate that the cytopathology and distribution of tau deposits in aged cynomolgus brains resemble those of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) rather than AD. Thus, even in the presence of Aβ, age-associated deposition of tau in non-human primates likely does not occur through AD-associated mechanisms. Electronic supplementary material The online version of this article (doi:10.1186/s40478-016-0385-5) contains supplementary material, which is available to authorized users.
- Published
- 2016
88. SOCS1 antagonist-expressing recombinant BCG enhances anti-tuberculosis protection in a mouse model
- Author
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Yasuhiro Yasutomi
- Subjects
Immunology ,Immunology and Allergy - Abstract
Suppressor of cytokine signaling 1 (SOCS1) plays a key role in the negative regulation of JAK/STAT signaling, which is involved in innate immunity and subsequent adaptive immunity. Bacillus Calmette-Guerin (BCG) induces up-regulation of SOCS1 expression in host cells, which may lead to the suppression of immune responses by BCG via inhibition of the JAK/STAT signaling pathway. This might cause reduction in the protective effect of a BCG vaccine. In the present study, we assessed the immune responses and protective efficacy of a recombinant BCG vaccine expressing an SOCS1 antagonist molecule (rBCG-SOCS1DN). C57BL/6 mice were immunized with rBCG-SOCS1DN or parental BCG Tokyo vaccine strain harboring an empty plasmid vector (rBCG-pSO). rBCG-SOCS1DN enhanced induction bone marrow-derived dendritic cell activation and T cells activation compared to rBCG-pSO. The amount of IFN-g, TNF-a and IL-6 produced by splenocytes of rBCG-SOCS1DN-immunized mice were larger than those produced by splenocytes of rBCG-pSO-immunized mice. Moreover, the rBCG-SOCS1DN-immunized mice showed a substantial reduction in the number of colony-forming units (CFU) of Mycobacterium tuberculosis (Mtb) in the lungs and spleens in comparison with that in control BCG-immunized mice when the immunized mice were infected with a highly pathogenic Mtb strain by inhalation. These findings provide evidence for the possibility of rBCG-SOCS1DN being an effective Mtb vaccine with a novel concept of rBCG as a tool for immunomodulation in host cells.
- Published
- 2019
89. The immune responses to influenza vaccine in aged and metabolic disease occurred cynomolgus macaques
- Author
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Emiko Urano, Yoshiko Murakata, Tomotaka Okamura, and Yasuhiro Yasutomi
- Subjects
Immunology ,Immunology and Allergy - Abstract
The analysis of age-related immune senescent is extremely meaningful to understand the vital homeostasis in individuals among the aging society. Influenza virus (FluV) infection is a major public health concern due to its high infectivity and ability to severe respiratory illness in elderly people. The reduced immune responses after Flu vaccination in humans are recognized in aging and also in lifestyle diseases such as diabetes mellitus (DM). Understanding the hypofunction in aging and lifestyle diseases is necessary to optimize vaccination resume and the comprehensive analysis of that will provide a great impact on public health burden. However, several factors affect the biofunctional analysis in human. Cynomolgus macaques (CMs) show human-like characteristics such as higher brain functions, long life span, single pregnancy. In the present study, several groups of CMs, including DM and hyperlipidemia (HL) occurred CMs, were subcutaneously immunized with seasonal trivalent Flu vaccine and assessed immune responses. The reduced humoral and cellular immune responses to Flu vaccine were observed in the elderly CMs group compare to the young group and induced anti-HA antibody titers were negatively correlated with age. In particular, Flu-specific immune responses were considerably decreased in DM group despite their youth. However, the reduced humoral and cellular immune responses were not observed in HL group, unlike DM CMs. These results suggested that elderly or DM and HL occurred CMs should be a powerful tool to reveal the comprehensive mechanisms for hypofunction in aging and lifestyle diseases through a long-life span. This study will help to enhance the immune response to vaccine in metabolic disease and aged person.
- Published
- 2019
90. Pitavastatin Regulates Helper T-Cell Differentiation and Ameliorates Autoimmune Myocarditis in Mice
- Author
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Michiaki Hiroe, Kyoko Imanaka-Yoshida, Kazutaka Aonuma, Yasuhiro Yasutomi, Tomoko Machino-Ohtsuka, Kazuko Tajiri, Nobutake Shimojo, Yusuke Tsujimura, Satoshi Sakai, Akira Sato, and Taizo Kimura
- Subjects
Male ,Autoimmune myocarditis ,Statin ,medicine.drug_class ,Cardiomyopathy ,Inflammation ,Mice, SCID ,medicine.disease_cause ,Autoimmune Diseases ,Autoimmunity ,Interferon-gamma ,Mice ,medicine ,Animals ,Pharmacology (medical) ,Pitavastatin ,Cell Proliferation ,Pharmacology ,Helper T cell differentiation ,Mice, Inbred BALB C ,business.industry ,Interleukin-17 ,Cell Differentiation ,General Medicine ,Th1 Cells ,medicine.disease ,Myocarditis ,Immunology ,Quinolines ,Th17 Cells ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Th17 cytokines ,medicine.drug - Abstract
Experimental autoimmune myocarditis (EAM) is a mouse model of inflammatory cardiomyopathy, and the involvement of T helper (Th) 1 and Th17 cytokines has been demonstrated. Accumulated evidence has shown that statins have anti-inflammatory and immunomodulatory effects; however, the mechanism has not been fully elucidated. This study was designed to test the hypothesis that pitavastatin affects T cell-mediated autoimmunity through inhibiting Th1 and Th17 responses and reduces the severity of EAM in mice.The EAM model was established in BALB/c mice by immunization with murine α-myosin heavy chain. Mice were fed pitavastatin (5 mg/kg) or vehicle once daily for 3 weeks from day 0 to day 21 after immunization.Pitavastatin reduced the pathophysiological severity of the myocarditis. Pitavastatin treatment inhibited the phosphorylation of signal transducer and activator of transcription (STAT)3 and STAT4, which have key roles in the Th1 and Th17 lineage commitment, respectively, in the heart, and suppressed production of Th1 cytokine interferon-γ and Th17 cytokine interleukin-17 from autoreactive CD4(+) T cells. In in vitro T-cell differentiation experiments, pitavastatin-treated T cells failed to differentiate into Th1 and Th17 cells through inhibiting the transcription of T-box expressed in T-cells (T-bet) and RAR-related orphan receptor γt (RORγT) which have critical roles in the development of Th1 and Th17 cells, respectively, and this failure was rescued by adding mevalonate.Pitavastatin inhibits Th1 and Th17 responses and ameliorates EAM. These results suggest that statins may be a promising novel therapeutic strategy for the clinical treatment of myocarditis and inflammatory cardiomyopathy.
- Published
- 2013
91. Cynomolgus monkey induced pluripotent stem cells established by using exogenous genes derived from the same monkey species
- Author
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Hiroyasu Inada, Nobuhiro Shimozawa, Tatsuyuki Takada, Tetsuya Nosaka, Yasuhiro Yasutomi, Ichiro Takahashi, Manami Shimada, Ryoichi Ono, and Hiroaki Shibata
- Subjects
Cancer Research ,Somatic cell ,Induced Pluripotent Stem Cells ,Cell Culture Techniques ,Genes, myc ,Cell Separation ,Biology ,Cell Line ,Kruppel-Like Factor 4 ,Immune system ,SOX2 ,Animals ,Transgenes ,Induced pluripotent stem cell ,Molecular Biology ,Embryonic Stem Cells ,SOXB1 Transcription Factors ,Teratoma ,Cell Differentiation ,Cell Biology ,Embryonic stem cell ,Virology ,Cell biology ,Macaca fascicularis ,Cell culture ,KLF4 ,Octamer Transcription Factor-3 ,Reprogramming ,Developmental Biology - Abstract
Induced pluripotent stem (iPS) cells established by introduction of the transgenes POU5F1 (also known as Oct3/4), SOX2, KLF4 and c-MYC have competence similar to embryonic stem (ES) cells. iPS cells generated from cynomolgus monkey somatic cells by using genes taken from the same species would be a particularly important resource, since various biomedical investigations, including studies on the safety and efficacy of drugs, medical technology development, and research resource development, have been performed using cynomolgus monkeys. In addition, the use of xenogeneic genes would cause complicating matters such as immune responses when they are expressed. In this study, therefore, we established iPS cells by infecting cells from the fetal liver and newborn skin with amphotropic retroviral vectors containing cDNAs for the cynomolgus monkey genes of POU5F1, SOX2, KLF4 and c-MYC. Flat colonies consisting of cells with large nuclei, similar to those in other primate ES cell lines, appeared and were stably maintained. These cell lines had normal chromosome numbers, expressed pluripotency markers and formed teratomas. We thus generated cynomolgus monkey iPS cell lines without the introduction of ecotropic retroviral receptors or other additional transgenes by using the four allogeneic transgenes. This may enable detailed analysis of the mechanisms underlying the reprogramming. In conclusion, we showed that iPS cells could be derived from cynomolgus monkey somatic cells. To the best of our knowledge, this is the first report on iPS cell lines established from cynomolgus monkey somatic cells by using genes from the same species.
- Published
- 2013
92. Dynamics of cellular immune responses in the acute phase of dengue virus infection
- Author
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Hirofumi Akari, Tomohiko Takasaki, Tomoyuki Yoshida, Atsunori Higashino, Yuko Katakai, Akatsuki Saito, Terue Kurosawa, Yasuhiro Yasutomi, Yuki Iwasaki, Shinichiro Nakamura, Tsutomu Omatsu, Ichiro Kurane, and Masataka Hamano
- Subjects
CD4-Positive T-Lymphocytes ,Male ,medicine.medical_specialty ,T-Lymphocytes ,viruses ,CD8-Positive T-Lymphocytes ,Dengue virus ,Virus Replication ,medicine.disease_cause ,Dengue fever ,Dengue ,Medical microbiology ,Immune system ,Virology ,medicine ,Animals ,Severe Dengue ,Neutralizing antibody ,Immunity, Cellular ,biology ,virus diseases ,Callithrix ,General Medicine ,Dengue Virus ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Natural killer T cell ,Antibodies, Neutralizing ,Immunity, Humoral ,Viral replication ,Immunology ,biology.protein ,Natural Killer T-Cells ,Immunologic Memory ,CD8 - Abstract
In this study, we examined the dynamics of cellular immune responses in the acute phase of dengue virus (DENV) infection in a marmoset model. Here, we found that DENV infection in marmosets greatly induced responses of CD4/CD8 central memory T and NKT cells. Interestingly, the strength of the immune response was greater in animals infected with a dengue fever strain than in those infected with a dengue hemorrhagic fever strain of DENV. In contrast, when animals were re-challenged with the same DENV strain used for primary infection, the neutralizing antibody induced appeared to play a critical role in sterilizing inhibition against viral replication, resulting in strong but delayed responses of CD4/CD8 central memory T and NKT cells. The results in this study may help to better understand the dynamics of cellular and humoral immune responses in the control of DENV infection.
- Published
- 2013
93. Gag-CA Q110D mutation elicits TRIM5-independent enhancement of HIV-1mt replication in macaque cells
- Author
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Akatsuki Saito, Ken Kono, Masako Nomaguchi, Hirofumi Akari, Emi E. Nakayama, Hironori Sato, Yasuhiro Yasutomi, Masaru Yokoyama, Tatsuo Shioda, Akio Adachi, and Tetsuro Matano
- Subjects
Immunology ,Mutagenesis (molecular biology technique) ,HIV Infections ,Biology ,Virus Replication ,medicine.disease_cause ,gag Gene Products, Human Immunodeficiency Virus ,Microbiology ,Macaque ,Cell Line ,Adaptive mutation ,biology.animal ,medicine ,Animals ,Humans ,Infectivity ,Mutation ,Virology ,Infectious Diseases ,Viral replication ,Capsid ,Cell culture ,Host-Pathogen Interactions ,Cats ,HIV-1 ,Mutagenesis, Site-Directed ,Macaca ,Capsid Proteins ,Carrier Proteins - Abstract
HIV-1 is strictly adapted to humans, and cause disease-inducing persistent infection only in humans. We have generated a series of macaque-tropic HIV-1 (HIV-1mt) to establish non-human primate models for basic and clinical studies. HIV-1mt clones available to date grow poorly in macaque cells relative to SIVmac239. In this study, viral adaptive mutation in macaque cells, G114E in capsid (CA) helix 6 of HIV-1mt, that enhances viral replication was identified. Computer-assisted structural analysis predicted that another Q110D mutation in CA helix 6 would also increase viral growth potential. A new proviral construct MN4Rh-3 carrying CA-Q110D exhibited exquisitely enhanced growth property specifically in macaque cells. Susceptibility of MN4Rh-3 to macaque TRIM5α/TRIMCyp proteins was examined by their expression systems. HIV-1mt clones so far constructed already completely evaded TRIMCyp restriction, and further enhancement of TRIMCyp resistance by Q110D was not observed. In addition, Q110D did not contribute to evasion from TRIM5α restriction. However, the single-cycle infectivity of MN4Rh-3 in macaque cells was enhanced relative to the other HIV-1mt clones. Our results here indicate that CA-Q110D accelerates viral growth in macaque cells irrelevant to TRIM5 proteins restriction.
- Published
- 2013
94. Single systemic administration of Ag85B of mycobacteria DNA inhibits allergic airway inflammation in a mouse model of asthma
- Author
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Yasuhiro Yasutomi, Hiroyasu Inada, Yumiko Shiogama, Mitsuo Kawano, Katsuo Karamatsu, Kazuhiro Matsuo, Akihiro Matsubara, and Yusuke Tsujimura
- Subjects
Pulmonary and Respiratory Medicine ,lcsh:Immunologic diseases. Allergy ,Allergy ,mycobacteria ,medicine.medical_treatment ,Ag85B ,Immunoglobulin E ,Immune system ,Antigen ,Journal of Asthma and Allergy ,medicine ,Immunology and Allergy ,Original Research ,biology ,business.industry ,Immunotherapy ,Eosinophil ,respiratory system ,asthma ,medicine.disease ,allergy ,Ovalbumin ,medicine.anatomical_structure ,Immunology ,Systemic administration ,biology.protein ,immunotherapy ,business ,lcsh:RC581-607 - Abstract
Katsuo Karamatsu,1,2 Kazuhiro Matsuo,3 Hiroyasu Inada,4 Yusuke Tsujimura,1 Yumiko Shiogama,1,2 Akihiro Matsubara,1,2 Mitsuo Kawano,5 Yasuhiro Yasutomi1,21Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, 2Division of Immunoregulation, Department of Molecular and Experimental Medicine, Mie University Graduate School of Medicine, Tsu, 3Department of Research and Development, Japan BCG Laboratory, Tokyo, 4Department of Pathology, Suzuka University of Medical Science, Suzuka, 5Department of Microbiology and Molecular Genetics, Mie University Graduate School of Medicine, Tsu, JapanAbstract: The immune responses of T-helper (Th) and T-regulatory cells are thought to play a crucial role in the pathogenesis of allergic airway inflammation observed in asthma. The correction of immune response by these cells should be considered in the prevention and treatment of asthma. Native antigen 85B (Ag85B) of mycobacteria, which cross-reacts among mycobacteria species, may play an important biological role in host–pathogen interaction since it elicits various immune responses by activation of Th cells. The current study investigated the antiallergic inflammatory effects of DNA administration of Ag85B from Mycobacterium kansasii in a mouse model of asthma. Immunization of BALB/c mice with alum-adsorbed ovalbumin followed by aspiration with aerosolized ovalbumin resulted in the development of allergic airway inflammation. Administration of Ag85B DNA before the aerosolized ovalbumin challenge protected the mice from subsequent induction of allergic airway inflammation. Serum and bronchoalveolar lavage immunoglobulin E levels, extent of eosinophil infiltration, and levels of Th2-type cytokines in Ag85B DNA-administered mice were significantly lower than those in control plasmid-immunized mice, and levels of Th1- and T-regulatory-type cytokines were enhanced by Ag85B administration. The results of this study provide evidence for the potential utility of Ag85B DNA inoculation as a novel approach for the treatment of asthma.Keywords: immunotherapy, asthma, Ag85B, mycobacteria, allergy
- Published
- 2012
95. Allergy Vaccines Using a Mycobacterium-Secreted Antigen, Ag85B, and an IL-4 Antagonist
- Author
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Yusuke, Tsujimura and Yasuhiro, Yasutomi
- Subjects
Antigens, Bacterial ,Mice ,Vaccines ,Bacterial Proteins ,Mutation ,Vaccines, DNA ,Animals ,Female ,Interleukin-4 ,Acyltransferases ,Asthma ,Recombinant Proteins ,Dermatitis, Atopic - Abstract
In recent decades, the prevalence of allergic diseases, including bronchial asthma, airway hypersensitivity, hay fever, and atopic dermatitis, has been increasing in the industrialized world, and effective treatments probably require manipulating the inflammatory response to pathogenic allergens. T helper (Th) 2 cells are thought to play a crucial role in the initiation, progression, and persistence of allergic responses in association with production of interleukin (IL)-4, IL-5, and IL-13. Therefore, a strategy of a shift from Th2- to Th1-type immune response may be valuable in the prophylaxis and management of allergic diseases. It is also necessary to develop prophylactic and therapeutic treatment that induces homeostatic functions in the multifaceted allergic environment, because various factors including innate and adaptive immunity, mucosal immune response, and functional and structural maintenance of local tissue might be involved in the pathogenesis of allergic disorders. We review herein recent findings related to the curative effect for mouse models of asthma and atopic dermatitis using DNA-, virus-, and protein-based vaccines of a Mycobacterium secretion antigen, Ag85B, and a plasmid encoding cDNA of antagonistic IL-4 mutant.
- Published
- 2016
96. Tracking cells implanted into cynomolgus monkeys (Macaca fascicularis) using MRI
- Author
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Yasuyo, Ito-Fujishiro, Hiroshi, Koie, Hiroaki, Shibata, Sachi, Okabayashi, Yuko, Katakai, Chieko, Ohno, Kiichi, Kanayama, Yasuhiro, Yasutomi, and Naohide, Ageyama
- Subjects
Male ,Peripheral Blood Stem Cell Transplantation ,Original ,nonhuman primate ,Regenerative Medicine ,Ferric Compounds ,Injections, Intramuscular ,Magnetic Resonance Imaging ,Macaca fascicularis ,Liver ,stem cells ,Injections, Intravenous ,Animals ,Muscle, Skeletal ,Magnetic Resonance Angiography ,MRI - Abstract
Regenerative therapy with stem cell transplantation is used to treat various diseases such as coronary syndrome and Buerger’s disease. For instance, stem-cell transplantation into the infarcted myocardium is an innovative and promising strategy for treating heart failure due to ischemic heart disease. Basic studies using small animals have shown that transplanted cells improve blood flow in the infarcted region. Magnetic resonance imaging (MRI) can noninvasively identify and track transplanted cells labeled with superparamagnetic iron oxide (SPIO). Although clinical regenerative therapies have been clinically applied to patients, the fate of implanted cells remains unknown. In addition, follow-up studies have shown that some adverse events can occur after recovery. Therefore, the present study evaluated the ability of MRI using a 3T scanner to track implanted peripheral blood mononuclear cells labeled with SPIO on days 0 and 7 after intramuscular (i.m.) and intravenous (i.v.) injection into a cynomolgus monkey. Labeled cells were visualized at the liver and triceps surae muscle on MR images using T1- and T2-weighted sequences and histologically localized by Prussian blue staining. The transplanted cells were tracked without abnormal clinical manifestations throughout this study. Hence, MRI of cynomolgus monkey transplanted SPIO-labeled cells is a safe and efficient method of tracking labeled cells that could help to determine the mechanisms involved in regenerative therapy.
- Published
- 2016
97. Allergy Vaccines Using a Mycobacterium-Secreted Antigen, Ag85B, and an IL-4 Antagonist
- Author
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Yusuke Tsujimura and Yasuhiro Yasutomi
- Subjects
0301 basic medicine ,Allergy ,Atopic dermatitis ,Biology ,medicine.disease ,Acquired immune system ,030207 dermatology & venereal diseases ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Antigen ,Immunology ,medicine ,Hay fever ,Interleukin 4 ,Asthma - Abstract
In recent decades, the prevalence of allergic diseases, including bronchial asthma, airway hypersensitivity, hay fever, and atopic dermatitis, has been increasing in the industrialized world, and effective treatments probably require manipulating the inflammatory response to pathogenic allergens. T helper (Th) 2 cells are thought to play a crucial role in the initiation, progression, and persistence of allergic responses in association with production of interleukin (IL)-4, IL-5, and IL-13. Therefore, a strategy of a shift from Th2- to Th1-type immune response may be valuable in the prophylaxis and management of allergic diseases. It is also necessary to develop prophylactic and therapeutic treatment that induces homeostatic functions in the multifaceted allergic environment, because various factors including innate and adaptive immunity, mucosal immune response, and functional and structural maintenance of local tissue might be involved in the pathogenesis of allergic disorders. We review herein recent findings related to the curative effect for mouse models of asthma and atopic dermatitis using DNA-, virus-, and protein-based vaccines of a Mycobacterium secretion antigen, Ag85B, and a plasmid encoding cDNA of antagonistic IL-4 mutant.
- Published
- 2016
98. Plasmodium cynomolgi genome sequences provide insight into Plasmodium vivax and the monkey malaria clade
- Author
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Jane M. Carlton, Kazuyuki Tanabe, Takahiro Tougan, Osamu Kaneko, Toshihiro Mita, Shin-Ichiro Tachibana, Steven A. Sullivan, Masanori Yagi, Nirianne Marie Q. Palacpac, John W. Barnwell, Hyunjae R. Kim, Nobuko Arisue, Shota Nakamura, Yasuhiro Yasutomi, Kiyoshi Kita, Ananias A. Escalante, Hajime Honma, Yuko Katakai, Rimma Shakhbatyan, Teruo Yasunaga, Satoru Kawai, Toshihiro Horii, Patrick L. Sutton, and Naohisa Goto
- Subjects
Plasmodium vivax ,Genes, Protozoan ,Simian ,Genome ,0302 clinical medicine ,single nucleotide polymorphism ,genetic variability ,Cluster Analysis ,Copy-number variation ,Clade ,Phylogeny ,Genetics ,0303 health sciences ,biology ,Monkey Diseases ,article ,copy number variation ,Cercopithecidae ,Haplorhini ,cell invasion ,3. Good health ,priority journal ,Plasmodium knowlesi ,Plasmodium cynomolgi ,030231 tropical medicine ,Molecular Sequence Data ,malaria ,gene sequence ,gene frequency ,Simiae ,03 medical and health sciences ,Genetic variation ,parasitic diseases ,Animals ,Genetic variability ,multigene family ,030304 developmental biology ,nonhuman ,Base Sequence ,Models, Genetic ,gene duplication ,nucleotide sequence ,Sequence Analysis, DNA ,biology.organism_classification ,unindexed sequence ,microsatellite DNA ,erythrocyte ,Genome, Protozoan - Abstract
P. cynomolgi, a malaria-causing parasite of Asian Old World monkeys, is the sister taxon of P. vivax, the most prevalent malaria-causing species in humans outside of Africa. Because P. cynomolgi shares many phenotypic, biological and genetic characteristics with P. vivax, we generated draft genome sequences for three P. cynomolgi strains and performed genomic analysis comparing them with the P. vivax genome, as well as with the genome of a third previously sequenced simian parasite, Plasmodium knowlesi. Here, we show that genomes of the monkey malaria clade can be characterized by copy-number variants (CNVs) in multigene families involved in evasion of the human immune system and invasion of host erythrocytes. We identify genome-wide SNPs, microsatellites and CNVs in the P. cynomolgi genome, providing a map of genetic variation that can be used to map parasite traits and study parasite populations. The sequencing of the P. cynomolgi genome is a critical step in developing a model system for P. vivax research and in counteracting the neglect of P. vivax., Nature Genetics, 44(9), pp.1051-1055; 2012
- Published
- 2012
99. Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis
- Author
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Satoshi Sakai, Yasuhiro Yasutomi, Nobutake Shimojo, Kazuko Tajiri, Tetsuji Naka, Yusuke Tsujimura, Michiaki Hiroe, Akihiro Matsubara, Kyoko Imanaka-Yoshida, and Kazutaka Aonuma
- Subjects
Male ,Myocarditis ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Cardiomyopathy ,Suppressor of Cytokine Signaling Proteins ,Mice, SCID ,Real-Time Polymerase Chain Reaction ,Transfection ,medicine.disease_cause ,Autoimmune Diseases ,Autoimmunity ,Mice ,Suppressor of Cytokine Signaling 1 Protein ,medicine ,Animals ,Immunology and Allergy ,Inflammation ,Mice, Inbred BALB C ,Innate immune system ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Suppressor of cytokine signaling 1 ,Gene Transfer Techniques ,Dilated cardiomyopathy ,DNA ,Flow Cytometry ,medicine.disease ,Acquired immune system ,Adoptive Transfer ,Cytokine ,Models, Animal ,business - Abstract
Myocarditis and subsequent dilated cardiomyopathy are major causes of heart failure in young adults. Myocarditis in humans is highly heterogeneous in etiology. Recent studies have indicated that a subgroup of myocarditis patients may benefit from immune-targeted therapies, because autoimmunity plays an important role in myocarditis as well as contributing to the progression to cardiomyopathy and heart failure. Suppressor of cytokine signaling (SOCS) 1 plays a key role in the negative regulation of both TLR- and cytokine receptor-mediated signaling, which is involved in innate immunity and subsequent adaptive immunity. In this study, we investigated the therapeutic effect of SOCS1 DNA administration on experimental autoimmune myocarditis (EAM) in mice. EAM was induced by s.c. immunization with cardiac-specific peptides derived from α myosin H chain in BALB/c mice. In contrast to control myocarditis mice, SOCS1 DNA-injected mice were protected from development of EAM and heart failure. SOCS1 DNA administration was effective for reducing the activation of autoreactive CD4+ T cells by inhibition of the function of Ag-presenting dendritic cells. Our findings suggest that SOCS1 DNA administration has considerable therapeutic potential in individuals with autoimmune myocarditis and dilated cardiomyopathy.
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- 2012
100. Geographical, genetic and functional diversity of antiretroviral host factor TRIMCyp in cynomolgus macaque (Macaca fascicularis)
- Author
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Yasuhiro Yasutomi, Tatsuo Shioda, Emi E. Nakayama, Ken Kono, Akio Adachi, Akatsuki Saito, Hirofumi Akari, and Masako Nomaguchi
- Subjects
RNA viruses ,animal diseases ,Philippines ,Molecular Sequence Data ,Population ,Single-nucleotide polymorphism ,Old World monkey ,Simian ,Virology ,Genetic variation ,Animals ,Protein Isoforms ,education ,Host factor ,Genetics ,education.field_of_study ,biology ,Animal ,Macaca nemestrina ,Haplotype ,Malaysia ,Genetic Variation ,Sequence Analysis, DNA ,biology.organism_classification ,Standard ,Macaca fascicularis ,Phylogeography ,Haplotypes ,Indonesia ,HIV-2 ,HIV-1 ,Cyclophilin A - Abstract
The antiretroviral factor tripartite motif protein 5 (TRIM5) gene-derived isoform (TRIMCyp) has been found in at least three species of Old World monkey: rhesus (Macaca mulatta), pig-tailed (Macaca nemestrina) and cynomolgus (Macaca fascicularis) macaques. Although the frequency of TRIMCyp has been well studied in rhesus and pig-tailed macaques, the frequency and prevalence of TRIMCyp in cynomolgus macaques remain to be definitively elucidated. Here, the geographical and genetic diversity of TRIM5α/TRIMCyp in cynomolgus macaques was studied in comparison with their anti-lentiviral activity. It was found that the frequency of TRIMCyp in a population in the Philippines was significantly higher than those in Indonesian and Malaysian populations. Major and minor haplotypes of cynomolgus macaque TRIMCyp with single nucleotide polymorphisms in the cyclophilin A domain were also found. The functional significance of the polymorphism in TRIMCyp was examined, and it was demonstrated that the major haplotype of TRIMCyp suppressed human immunodeficiency virus type 1 (HIV-1) but not HIV-2, whilst the minor haplotype of TRIMCyp suppressed HIV-2 but not HIV-1. The major haplotype of TRIMCyp did not restrict a monkey-tropic HIV-1 clone, NL-DT5R, which contains a capsid with the simian immunodeficiency virus-derived loop between α-helices 4 and 5 and the entire vif gene. These results indicate that polymorphisms of TRIMCyp affect its anti-lentiviral activity. Overall, the results of this study will help our understanding of the genetic background of cynomolgus macaque TRIMCyp, as well as the host factors composing species barriers of primate lentiviruses.
- Published
- 2012
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