Article
Immunology
Inigo Terren, Victor Sanda, Ainhoa Amarilla-Irusta, Ainara Lopez-Pardo, Arrate Sevilla, Gabirel Astarloa-Pando, Laura Amo, Olatz Zenarruzabeitia, Luca Scorrano, Francisco Borrego
Summary: Cytokine-induced memory-like (CIML) NK cells, stimulated with IL-12, IL-15 and IL-18, show promise in cancer immunotherapy. However, the mitochondrial dynamics of these cells remain unknown. This study found that IL-12/15/18 stimulation led to decreased viability and increased superoxide levels in NK cells, along with changes in mitochondrial morphology possibly mediated by decreased levels of OPA1 protein. While mitophagy was slightly impaired, an increase in autophagic flux was observed. These findings are important for improving the mitochondrial fitness and therapeutic efficacy of IL-12/15/18-stimulated NK cells.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Multidisciplinary Sciences
Shoubao Ma, Tingting Tang, Xiaojin Wu, Anthony G. Mansour, Ting Lu, Jianying Zhang, Li-Shu Wang, Michael A. Caligiuri, Jianhua Yu
Summary: PDGF-D mediates cell survival through the PDGFR beta signaling pathway without modulating effector functions of NK cells, providing new insights into the study of human NK cells.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Immunology
Jutamas Suwanpradid, Min Jin Lee, Peter Hoang, Jeffery Kwock, Lauren P. Floyd, Jeffrey S. Smith, Zhinan Yin, Amber R. Atwater, Sudarshan Rajagopal, Ross M. Kedl, David L. Corcoran, Jennifer Y. Zhang, Amanda S. MacLeod
Summary: The crosstalk between T cells, dendritic cells, and macrophages in leukocyte clusters within barrier tissues provides a new concept for T cell activation in the skin. It was found that macrophages produce IL-27 which induces IL-15 production from other cells within leukocyte clusters, enhancing the survival of skin T cells. Blocking the IL-27 pathway in CHS mice led to decreased expression of the T cell survival gene BCL2, resulting in a decline in dermal CD8(+) T cells and T cell cluster numbers.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Oncology
Miriam Aarsund, Filip M. Segers, Yunjie Wu, Marit Inngjerdingen
Summary: This study compared the tumor-targeting potential of extracellular vesicles (EVs) derived from different sources of NK cells and found that EVs from activated primary NK cells or NK-92 cells have the best potential to infiltrate and target solid tumors.
CANCER IMMUNOLOGY IMMUNOTHERAPY
(2022)
Article
Biotechnology & Applied Microbiology
Emily Chiu, Martin Felices, Frank Cichocki, Zachary Davis, Hongbo Wang, Katie Tuninga, Daniel A. Vallera, Tom Lee, Ryan Bjordahl, Karl Johan Malmberg, Bahram Valamehr, Jeffrey S. Miller
Summary: The researchers developed an immune therapy called NKG2C-KE, which directs specific types of NK cells to attack leukemia cells. This method showed promising results in experiments and could potentially become a new treatment strategy for leukemia.
Article
Biochemistry & Molecular Biology
Min Liu, Yuan Meng, Leisheng Zhang, Zhongchao Han, Xiaoming Feng
Summary: Study found that the combined use of IL-2, IL-15, IL-18 can best promote the ex vivo expansion and proportion of NK cells in peripheral blood mononuclear cells. Meanwhile, the obtained NK cell population expressed high levels of activating molecules (CD16 and NKG2D) and exhibited splendid cytotoxicity against K562 cell line.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Allergy
Linda Quatrini, Paola Vacca, Nicola Tumino, Francesca Besi, Anna Laura Di Pace, Francesca Scordamaglia, Stefania Martini, Enrico Munari, Maria Cristina Mingari, Sophie Ugolini, Lorenzo Moretta
Summary: The induction of PD-1 expression on human NK cells in the tumor setting is dependent on the cooperative action of glucocorticoids and cytokines, leading to enhanced mRNA translation and increased PD-1 levels.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2021)
Article
Multidisciplinary Sciences
Ting Lu, Rui Ma, Wenjuan Dong, Kun-Yu Teng, Daniel S. Kollath, Zhiyao Li, Jinhee Yi, Christian Bustillos, Shoubao Ma, Lei Tian, Anthony G. Mansour, Zhenlong Li, Erik W. Settles, Jianying Zhang, Paul S. Keim, Bridget M. Barker, Michael A. Caligiuri, Jianhua Yu
Summary: Engineered NK cells expressing soluble interleukin-15 and a chimeric antigen receptor targeting the spike protein of SARS-CoV-2 show promising potential as an off-the-shelf therapy for COVID-19 patients, with enhanced antiviral activity and cytotoxicity against spike protein-expressing cells.
NATURE COMMUNICATIONS
(2022)
Article
Immunology
Renata Nacasaki Silvestre, Jiri Eitler, Julia Teixeira Cottas de Azevedo, Mariane Cariati Tirapelle, Daianne Maciely Carvalho Fantacini, Lucas Eduardo Botelho de Souza, Kamilla Swiech, Dimas Tadeu Covas, Rodrigo T. Calado, Paola Ortiz Montero, Kelen Cristina Ribeiro Malmegrim, Marxa L. Figueiredo, Torsten Tonn, Virginia Picanco-Castro
Summary: This study compared the effects of CD19-targeted CAR (CAR.19) co-expressing IL-15 (CAR.19-IL15) and IL-15/IL-15R alpha (CAR.19-IL15/IL15R alpha) on NK cell proliferation, activation, and cytotoxicity against B-cell leukemia. The results showed that the fourth-generation CD19-targeted CAR (CAR.19) co-expressing IL-15 and its receptor IL-15/IL-15R alpha (CAR.19-IL-15/IL-15R alpha) significantly enhanced NK-92 cell proliferation, cytokine secretion, and cytotoxicity against B-cell cancer cells both in vitro and in a mouse model. This suggests that IL-15/IL-15R alpha might overcome the limitations of NK-92 cell-based targeted tumor therapies by providing the necessary signals for growth and activation.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Oncology
Hans Bergman, Christer Lindqvist
Summary: This study highlights the significant impact of gamma chain receptor-dependent cytokines on the cytotoxic activity of NK cells against different target cells, while the removal of CD4+ cells does not significantly alter the NK cell activity profile.
ANTICANCER RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Ken-Edwin Aryee, Lisa M. Burzenski, Li-Chin Yao, James G. Keck, Dale L. Greiner, Leonard D. Shultz, Michael A. Brehm
Summary: Human innate immunity, including natural killer (NK) cells, plays a critical role in tumor surveillance and immunoregulation in the tumor microenvironment. Humanized mouse models have been developed to study human immuno-oncology, but the development and survival of human NK cells in these models are limited. Researchers have created a mouse model with constitutive expression of human Interleukin 15 (IL15) to enhance the development of functional human NK cells and limit tumor growth.
Article
Immunology
Guijie Kang, Xueqin Zhao, Jiafeng Sun, Chen Cheng, Cen Wang, Longxiang Tao, Lu Zong, Wenwei Yin, Jingjing Cong, Jing Li, Xuefu Wang
Summary: The characteristics of CD39+ NK cells in humans were investigated and it was found that the proportion of CD39+ NK cells was relatively low in healthy individuals. However, CD39+ NK cells expressed higher levels of CD107a. Stimulation with K562 cells or IL-12/IL-18 activated CD39+ NK cells to express higher levels of CD107a, IFN-gamma, and TNF-alpha. IL-15 induced the generation of CD39+ NK cells, while A2AR ligation suppressed their generation by inhibiting IL-15 signaling.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2023)
Article
Engineering, Biomedical
Dongyan Shao, Ting Bai, Bobo Zhu, Xiaojia Guo, Kai Dong, Junling Shi, Qingsheng Huang, Jie Kong
Summary: This study develops a polymeric micelle-based IL-15/IL-2 codelivery system (IL-15/2-PEG-PTMC) for natural killer (NK) cell activation. It noticeably delays the growth of tumors in mice compared to conventional NK cell activation approach, that is free IL-15 and IL-2. It is surprisingly found that cholesterol metabolism is highly involved in the NK cell activation by IL-15/2-PEG-PTMC.
ADVANCED HEALTHCARE MATERIALS
(2023)
Article
Biotechnology & Applied Microbiology
Huan Xu, Mingyang Shi, Changsheng Shao, Hao Li, Jing Wu, Yin Yu, Fang Fang, Yugang Guo, Weihua Xiao
Summary: IL-15/SuIL-15R alpha-dFc and IL-15/SuIL-15R alpha-mFc produced in P. pastoris demonstrate potent activities and prolonged half-lives, acting as superagonists for immunotherapy in the treatment of cancer and viral diseases. The two IL-15 complexes significantly increase NK cells, NKT cells, and memory CD8(+) T cells in mice, as well as enhance NK and CD8(+) T cell activation and proliferation in human peripheral blood mononuclear cells (PBMCs) from healthy donors, comparable to the effect of rhIL-15.
MICROBIAL CELL FACTORIES
(2021)
Review
Immunology
Stefanie N. N. Meyer, Sanjay Koul, Laura Pasqualucci
Summary: The DNA sequencing revolution has altered our understanding of B-cell lymphomas, with genetically engineered mouse models playing a key role in research. Accurate modeling of genetic alterations found in human GC B cell malignancies can help guide the design of novel therapeutic approaches for this disease.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Immunology
Yuyo Ka, Ikumi Katano, Eiko Nishinaka, Jochen Welcker, Misa Mochizuki, Kenji Kawai, Motohito Goto, Kayo Tomiyama, Tomoyuki Ogura, Taichi Yamamoto, Mamoru Ito, Ryoji Ito, Riichi Takahashi
Summary: A novel mouse model named dKO-em was established using CRISPR/Cas9 technology, showing improved support for human PBMC engraftment and prolonged survival. This model may serve as a promising platform for the development and preclinical testing of novel therapeutics for human diseases.
IMMUNOLOGY LETTERS
(2021)
Article
Pharmacology & Pharmacy
Akiko Toda, Makiko Shimizu, Shotaro Uehara, Tatsuro Sasaki, Tomonori Miura, Masayuki Mogi, Masahiro Utoh, Hiroshi Suemizu, Hiroshi Yamazaki
Summary: Experimental studies in various animals showed differences in the metabolism of acetaminophen, with only rats favoring sulfate conjugates over glucuronide conjugates. Marmosets and minipigs exhibited similar plasma concentration curves to humans after oral administration. Physiologically based pharmacokinetic models accurately estimated acetaminophen concentrations in experimental animals and humans, with the potential for predicting hepatotoxicity based on plasma data.
Article
Pharmacology & Pharmacy
Shotaro Uehara, Nao Yoneda, Yuichiro Higuchi, Hiroshi Yamazaki, Hiroshi Suemizu
Summary: This study investigated tolbutamide metabolism in chimeric TK-NOG mice transplanted with human hepatocytes, showing that humanised-liver mice may be a suitable animal model for studying the successive oxidative metabolism of tolbutamide by multiple drug-metabolising enzymes.
Article
Pharmacology & Pharmacy
Tomonori Miura, Yusuke Kamiya, Shotaro Uehara, Norie Murayama, Makiko Shimizu, Hiroshi Suemizu, Hiroshi Yamazaki
Summary: The study revealed slower biotransformation of p-Toluic acid in humanized-liver mice compared to regular mice, leading to higher hepatic concentrations of p-Toluic acid. The PBPK modeling also showed slow elimination of p-Toluic acid in humans, highlighting a potential overestimation of NOELs in humanized-liver mice or humans when extrapolated from rapid conjugation observed in rats.
Article
Pharmacology & Pharmacy
Shotaro Uehara, Yuichiro Higuchi, Nao Yoneda, Hiroshi Yamazaki, Hiroshi Suemizu
Summary: Lamotrigine metabolism in humanised-liver mice showed similarities to humans, while differences were observed in mice. The study indicates that humanised-liver mice may be a valuable animal model for studying UGT1A4-mediated lamotrigine metabolism.
Article
Multidisciplinary Sciences
Mina Ogawa, Jia-Xin Jiang, Sunny Xia, Donghe Yang, Avrilynn Ding, Onofrio Laselva, Marcela Hernandez, Changyi Cui, Yuichiro Higuchi, Hiroshi Suemizu, Craig Dorrell, Markus Grompe, Christine E. Bear, Shinichiro Ogawa
Summary: The study identifies key pathways regulating cholangiocyte maturation and successfully generates functional cholangiocytes with mature characteristics, enhancing their potential for therapeutic applications in biliary diseases.
NATURE COMMUNICATIONS
(2021)
Article
Pharmacology & Pharmacy
Shotaro Uehara, Norie Murayama, Yuichiro Higuchi, Nao Yoneda, Hiroshi Yamazaki, Hiroshi Suemizu
Summary: This study compared the P450-dependent drug oxidation activity and distribution patterns of P450 protein/mRNA in tissue microsomes between humans and mice. It found similarities and differences between humans and mice in terms of drug oxidation activity and the expression of P450 proteins and mRNAs.
Article
Pharmacology & Pharmacy
Naoki Cho, Hiroshi Suemizu, Hidetaka Kamimura, Tomoyuki Ohe, Fumi Ito, Hidetaka Akita, Kaoru Kobayashi
Summary: This study used a humanized-liver mouse model to investigate the pharmacokinetic profiles of benzbromarone and the generation of reactive metabolites. The results showed that the metabolic profiles of benzbromarone in humanized-liver mice were similar to those in humans, and the detected reactive metabolites were associated with benzbromarone-induced hepatotoxicity.
DRUG METABOLISM AND PHARMACOKINETICS
(2022)
Article
Pharmacology & Pharmacy
Shotaro Uehara, Yuichiro Higuchi, Nao Yoneda, Hiroaki Kato, Hiroshi Yamazaki, Hiroshi Suemizu
Summary: Human-specific olanzapine N10-glucuronide isomers were produced in humanized-liver mice, and high UGT1A4-dependent N10-glucuronidation was observed in their liver microsomes. Therefore, humanized-liver mice may be a suitable model for studying UGT1A4-dependent biotransformation of drugs in humans.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Pharmacology & Pharmacy
Yasuhiro Uno, Shotaro Uehara, Genki Ushirozako, Norie Murayama, Hiroshi Suemizu, Hiroshi Yamazaki
Summary: The induction assay for cytochromes P450 is an essential tool in drug development. This study characterized the induction of dog P450 1A2 and 3A12 by omeprazole and rifampicin in dog hepatocytes and compared it with induction in human HepaRG and HepaSH cells. It was found that omeprazole can induce the activity of P450 enzymes in both dog and human liver cells.
Article
Pharmacology & Pharmacy
Hidetaka Kamimura, Shotaro Uehara, Nao Yoneda, Hiroshi Suemizu
Summary: In this study, we evaluated the empirical method Css-MRTpo using chimeric mice with humanised livers to predict the plasma concentration-time profiles of disproportionate metabolites in humans. The results showed that the method could accurately predict the pharmacokinetic profiles of unchanged drugs, but had poor predictability for disproportionate metabolites. The introduction of an empirical scaling factor improved the prediction of metabolites, suggesting the potential usefulness of the Css-MRTpo method combined with humanised chimeric mice for predicting the pharmacokinetic profiles of disproportionate metabolites at the early stage of new drug development.
Article
Pharmacology & Pharmacy
Yasuhiro Uno, Shotaro Uehara, Genki Ushirozako, Tatsunori Masatani, Hiroshi Yamazaki
Summary: Chronic Toxoplasma infection affects drug metabolism by altering the gene expressions of drug-metabolizing enzymes, including P450s.
Article
Pharmacology & Pharmacy
Shogo Matsumoto, Shotaro Uehara, Hidetaka Kamimura, Naoki Cho, Hiroshi Ikeda, Satoshi Maeda, Kensuke Kagiyama, Atsunori Miyata, Hiroshi Suemizu, Kazumasa Fukasawa
Summary: The present study demonstrated the utility of common marmosets in the selection of valsartan as a candidate drug from a pharmacokinetic and metabolic perspective. The results suggested that common marmosets were a suitable species for the development of valsartan.
Article
Veterinary Sciences
Hanako Morita, Masahiko Yasuda, Masafumi Yamamoto, Yurina Tomiyama, Ritsuki Uchida, Yuyo Ka, Tomoyuki Ogura, Kenji Kawai, Hiroshi Suemizu, Nobuhito Hayashimoto
Summary: Astroviruses, including Murine astrovirus, are often linked to gastrointestinal diseases in mammals and birds. This study infected immunodeficient mice with MuAstV and found that the virus proliferated in the villous epithelial cells of the lower small intestine with weak pathogenicity. No abnormalities were detected in histopathological examination.
EXPERIMENTAL ANIMALS
(2021)
Article
Veterinary Sciences
Yuyo Ka, Tomoyuki Ogura, Kayo Tomiyama, Masami Ueno, Ryoko Nozu, Nobuyuki Tsuruzono, Yuya Nozawa, Mariko Hamano, Akira Takakura, Riichi Takahashi
Summary: In order to avoid microbial contamination risks in animal microbiome experiments, researchers developed a new rearing system combining individual ventilation cages and bioBUBBLE systems. Through a three-step evaluation, it was found that this system could not only be used for experiments with germ-free mice but also for Biosafety Level 2 experiments with bacteria. This new experimental method improved working time and efficiency compared to the previous vinyl isolator method.
EXPERIMENTAL ANIMALS
(2021)
