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Article ; Online: Fatty Acids Play a Critical Role in Mitochondrial Oxidative Phosphorylation in Effector T Cells in Graft-versus-Host Disease.

Nakano, Hirofumi / Sato, Kazuya / Izawa, Junko / Takayama, Norihito / Hayakawa, Hiroko / Ikeda, Takashi / Kawaguchi, Shin-Ichiro / Mashima, Kiyomi / Umino, Kento / Morita, Kaoru / Ito, Ryoji / Ohno, Nobuhiko / Tominaga, Kaoru / Endo, Hitoshi / Kanda, Yoshinobu

ImmunoHorizons

2024 Volume 8, Issue 3, Page(s) 228–241

Abstract: Although the role of aerobic glycolysis in activated T cells has been well characterized, whether and how fatty acids (FAs) contribute to donor T cell function in allogeneic hematopoietic stem cell transplantation is unclear. Using xenogeneic graft- ... ...

Abstract	Although the role of aerobic glycolysis in activated T cells has been well characterized, whether and how fatty acids (FAs) contribute to donor T cell function in allogeneic hematopoietic stem cell transplantation is unclear. Using xenogeneic graft-versus-host disease (GVHD) models, this study demonstrated that exogenous FAs serve as a crucial source of mitochondrial respiration in donor T cells in humans. By comparing human T cells isolated from wild-type NOD/Shi-scid-IL2rγnull (NOG) mice with those from MHC class I/II-deficient NOG mice, we found that donor T cells increased extracellular FA uptake, the extent of which correlates with their proliferation, and continued to increase FA uptake during effector differentiation. Gene expression analysis showed the upregulation of a wide range of lipid metabolism-related genes, including lipid hydrolysis, mitochondrial FA transport, and FA oxidation. Extracellular flux analysis demonstrated that mitochondrial FA transport was required to fully achieve the mitochondrial maximal respiration rate and spare respiratory capacity, whereas the substantial disruption of glucose supply by either glucose deprivation or mitochondrial pyruvate transport blockade did not impair oxidative phosphorylation. Taken together, FA-driven mitochondrial respiration is a hallmark that differentiates TCR-dependent T cell activation from TCR-independent immune response after hematopoietic stem cell transplant.
MeSH term(s)	Humans ; Animals ; Mice ; Mice, Inbred NOD ; Oxidative Phosphorylation ; T-Lymphocytes ; Graft vs Host Disease ; Fatty Acids ; Glucose ; Mice, SCID ; Receptors, Antigen, T-Cell
Chemical Substances	Fatty Acids ; Glucose (IY9XDZ35W2) ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2024-03-05
Publishing country	United States
Document type	Journal Article
ISSN	2573-7732
ISSN (online)	2573-7732
DOI	10.4049/immunohorizons.2300115
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Article ; Online: Forodesine Enhances Immune Responses through Guanosine-Mediated TLR7 Activation while Preventing Graft-versus-Host Disease.

Ikeda, Takashi / Sato, Kazuya / Kawaguchi, Shin-Ichiro / Izawa, Junko / Takayama, Norihito / Hayakawa, Hiroko / Umino, Kento / Morita, Kaoru / Matsumoto, Kana / Ushijima, Kentaro / Kanda, Yoshinobu

Journal of immunology (Baltimore, Md. : 1950)

2023 Volume 212, Issue 1, Page(s) 143–153

Abstract: Recent evidence indicates that specific types of nuclear acids, including guanosine and its derivatives, act as natural ligands for TLR7. This led us to hypothesize that purine nucleoside phosphorylase inhibitors not only can induce apoptosis of T cells ... ...

Abstract	Recent evidence indicates that specific types of nuclear acids, including guanosine and its derivatives, act as natural ligands for TLR7. This led us to hypothesize that purine nucleoside phosphorylase inhibitors not only can induce apoptosis of T cells but also can lead to TLR7 activation by accumulation of guanine nucleosides, in particular under systemic inflammation, where damaged tissues release a large amount of nucleotides. We demonstrate in the present study that a purine nucleoside phosphorylase inhibitor, forodesine, can reduce the disease severity and prolong the survival in a xenogeneic mouse model of graft-versus-host disease (GVHD). Guanine nucleosides were undetectable in mice during GVHD but increased significantly following forodesine treatment. Our in vitro experiments showed that forodesine enhanced guanosine-mediated cytokine production from APCs, including alveolar macrophages and plasmacytoid dendritic cells, through TLR7 signaling. Forodesine also enhanced Ag-presenting capacity, as demonstrated by increased CD8+ T cell proliferation and higher secretion of IFN-γ and IL-12p40 in an MLR with plasmacytoid dendritic cells. Furthermore, forodesine stimulated IFN-γ production from activated T cells in the presence of a low concentration of guanosine while inhibiting their proliferation and inducing apoptotic cell death. Although forodesine ameliorated GVHD severity, mice treated with forodesine showed significantly higher levels of multiple proinflammatory cytokines and chemokines in plasma, suggesting in vivo upregulation of TLR7 signaling. Our study suggests that forodesine may activate a wide range of immune cells, including T cells, through TLR7 stimulation while inhibiting GVHD by inducing apoptosis of T cells, after allogeneic hematopoietic stem cell transplant.
MeSH term(s)	Animals ; Mice ; Purine-Nucleoside Phosphorylase ; Toll-Like Receptor 7 ; Guanosine/pharmacology ; Enzyme Inhibitors/pharmacology ; Graft vs Host Disease ; Immunity ; Guanine
Chemical Substances	forodesine (426X066ELK) ; Purine-Nucleoside Phosphorylase (EC 2.4.2.1) ; Toll-Like Receptor 7 ; Guanosine (12133JR80S) ; Enzyme Inhibitors ; Guanine (5Z93L87A1R)
Language	English
Publishing date	2023-11-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2300003
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Article ; Online: The Use of Chemical Compounds to Identify the Regulatory Mechanisms of Vertebrate Circadian Clocks.

Okamoto-Uchida, Yoshimi / Nishimura, Akari / Izawa, Junko / Hattori, Atsuhiko / Suzuki, Nobuo / Hirayama, Jun

Current drug targets

2019 Volume 21, Issue 5, Page(s) 425–432

Abstract: Circadian clocks are intrinsic, time-tracking processes that confer a survival advantage on an organism. Under natural conditions, they follow approximately a 24-h day, modulated by environmental time cues, such as light, to maximize an organism's ... ...

Abstract	Circadian clocks are intrinsic, time-tracking processes that confer a survival advantage on an organism. Under natural conditions, they follow approximately a 24-h day, modulated by environmental time cues, such as light, to maximize an organism's physiological efficiency. The exact timing of this rhythm is established by cell-autonomous oscillators called cellular clocks, which are controlled by transcription-translation negative feedback loops. Studies of cell-based systems and wholeanimal models have utilized a pharmacological approach in which chemical compounds are used to identify molecular mechanisms capable of establishing and maintaining cellular clocks, such as posttranslational modifications of cellular clock regulators, chromatin remodeling of cellular clock target genes' promoters, and stability control of cellular clock components. In addition, studies with chemical compounds have contributed to the characterization of light-signaling pathways and their impact on the cellular clock. Here, the use of chemical compounds to study the molecular, cellular, and behavioral aspects of the vertebrate circadian clock system is described.
MeSH term(s)	Animals ; Circadian Clocks/drug effects ; Humans ; Laboratory Chemicals/pharmacology ; Light Signal Transduction/drug effects ; MAP Kinase Signaling System/drug effects ; Protein Processing, Post-Translational/drug effects ; Vertebrates/physiology
Chemical Substances	Laboratory Chemicals
Language	English
Publishing date	2019-09-26
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2064859-5
ISSN	1873-5592 ; 1389-4501
ISSN (online)	1873-5592
ISSN	1389-4501
DOI	10.2174/1389450120666190926143120
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Article ; Online: Dimethyl fumarate ameliorates graft-versus-host disease by inhibiting T-cell metabolism and immune responses through a reactive oxygen species-dependent mechanism.

Mashima, Kiyomi / Sato, Kazuya / Ikeda, Takashi / Izawa, Junko / Takayama, Norihito / Hayakawa, Hiroko / Kawaguchi, Shin-Ichiro / Nakano, Hirofumi / Nagayama, Takashi / Umino, Kento / Morita, Kaoru / Tominaga, Kaoru / Endo, Hitoshi / Kanda, Yoshinobu

British journal of haematology

2022 Volume 197, Issue 6, Page(s) e78–e82

MeSH term(s)	Dimethyl Fumarate/pharmacology ; Dimethyl Fumarate/therapeutic use ; Graft vs Host Disease/drug therapy ; Humans ; Immunity ; Reactive Oxygen Species/metabolism ; T-Lymphocytes/metabolism
Chemical Substances	Reactive Oxygen Species ; Dimethyl Fumarate (FO2303MNI2)
Language	English
Publishing date	2022-02-15
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.18082
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Article: Post-translational Modifications are Required for Circadian Clock Regulation in Vertebrates.

Okamoto-Uchida, Yoshimi / Izawa, Junko / Nishimura, Akari / Hattori, Atsuhiko / Suzuki, Nobuo / Hirayama, Jun

Current genomics

2018 Volume 20, Issue 5, Page(s) 332–339

Abstract: Circadian clocks are intrinsic, time-tracking systems that bestow upon organisms a survival advantage. Under natural conditions, organisms are trained to follow a 24-h cycle under environmental time cues such as light to maximize their physiological ... ...

Abstract	Circadian clocks are intrinsic, time-tracking systems that bestow upon organisms a survival advantage. Under natural conditions, organisms are trained to follow a 24-h cycle under environmental time cues such as light to maximize their physiological efficiency. The exact timing of this rhythm is established
Language	English
Publishing date	2018-11-02
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	2033677-9
ISSN	1875-5488 ; 1389-2029
ISSN (online)	1875-5488
ISSN	1389-2029
DOI	10.2174/1389202919666191014094349
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Zs.A 5571: Show issues

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Article ; Online: Mesenchymal Stromal Cells Inhibit Aerobic Glycolysis in Activated T Cells by Negatively Regulating Hexokinase II Activity Through PD-1/PD-L1 Interaction.

Kawasaki, Yasufumi / Sato, Kazuya / Mashima, Kiyomi / Nakano, Hirofumi / Ikeda, Takashi / Umino, Kento / Morita, Kaoru / Izawa, Junko / Takayama, Norihito / Hayakawa, Hiroko / Tominaga, Kaoru / Endo, Hitoshi / Kanda, Yoshinobu

Transplantation and cellular therapy

2020 Volume 27, Issue 3, Page(s) 231.e1–231.e8

Abstract: Mesenchymal stromal cells (MSCs) have been shown to inhibit aerobic glycolysis in activated T cells, leading to increased autophagy. Although tryptophan depletion induced by indoleamine 2,3-dioxygenase (IDO) generated by MSCs has been suggested as a ... ...

Abstract	Mesenchymal stromal cells (MSCs) have been shown to inhibit aerobic glycolysis in activated T cells, leading to increased autophagy. Although tryptophan depletion induced by indoleamine 2,3-dioxygenase (IDO) generated by MSCs has been suggested as a potential mechanism, we found that this inhibition was completely abolished when T cells were physically separated from MSCs using the Transwell system. Instead, in the current study, we demonstrate that programmed cell death 1 receptor (PD-1) and its ligand PD-L1, the expression of which is induced on activated T cells and MSCs, respectively, in response to IFN-γ are involved in this inhibition. Blockade of PD-1/PD-L1 interaction by blocking antibodies significantly restored glucose uptake, glycolytic activity, and cluster formation of activated T cells, whereas a specific inhibitor of IDO, 1-methyl-DL-tryptophan, had no effect. Neither surface nor cytoplasmic glucose transporter-1 expression on T cells was changed by MSCs. In addition, glycolytic gene expression in activated T cells was not inhibited despite the presence of MSCs. However, we found that hexokinase II (HK2) protein expression was markedly decreased in activated T cells that had been cocultured with MSCs. PD-1 blocking antibody restored HK2 expression. Taken together, our findings indicate that the PD-1/PD-L1 axis is involved in the MSC-mediated suppression of T cell glycolysis by negatively regulating HK2 activity at the protein level, but not at the mRNA level.
MeSH term(s)	B7-H1 Antigen/genetics ; Glycolysis ; Hexokinase/genetics ; Lymphocyte Activation ; Mesenchymal Stem Cells ; Programmed Cell Death 1 Receptor/genetics ; T-Lymphocytes ; Tryptophan/metabolism
Chemical Substances	B7-H1 Antigen ; Programmed Cell Death 1 Receptor ; Tryptophan (8DUH1N11BX) ; Hexokinase (EC 2.7.1.1)
Language	English
Publishing date	2020-12-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3062231-1
ISSN	2666-6367
ISSN (online)	2666-6367
DOI	10.1016/j.jtct.2020.11.012
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Article ; Online: Comparison of alemtuzumab, anti-thymocyte globulin, and post-transplant cyclophosphamide for graft-versus-host disease and graft-versus-leukemia in murine models.

Mashima, Kiyomi / Oh, Iekuni / Fujiwara, Ken / Izawa, Junko / Takayama, Norihito / Nakano, Hirofumi / Kawasaki, Yasufumi / Minakata, Daisuke / Yamasaki, Ryoko / Morita, Kaoru / Ashizawa, Masahiro / Yamamoto, Chihiro / Hatano, Kaoru / Sato, Kazuya / Ohmine, Ken / Fujiwara, Shin-Ichiro / Ohno, Nobuhiko / Kanda, Yoshinobu

PloS one

2021 Volume 16, Issue 1, Page(s) e0245232

Abstract: Graft-versus-host disease is a major complication after allogeneic hematopoietic stem cell transplantation for hematological malignancies. Immunosuppressive drugs, such as anti-thymocyte globulin, alemtuzumab, and post-transplant cyclophosphamide, have ... ...

Abstract	Graft-versus-host disease is a major complication after allogeneic hematopoietic stem cell transplantation for hematological malignancies. Immunosuppressive drugs, such as anti-thymocyte globulin, alemtuzumab, and post-transplant cyclophosphamide, have been used to prevent graft-versus-host disease in HLA-mismatched haploidentical hematopoietic stem cell transplantation. Here, we investigated whether these drugs could ameliorate graft-versus-host disease without diminishing the graft-versus-leukemia effect by using a xenogeneic transplanted graft-versus-host disease/graft-versus-leukemia model. Anti-thymocyte globulin treatment diminished graft-versus-host disease symptoms, completely depleted the infiltration of inflammatory cells in the liver and intestine, and led to prolonged survival. By contrast, improvement after post-transplant cyclophosphamide treatment remained minimal. Alemtuzumab treatment modestly prolonged survival despite an apparent decrease of Tregs. In the graft-versus-leukemia model, 1.5 to 2.0 mg/kg of anti-thymocyte globulin and 0.6 to 0.9 mg/kg of alemtuzumab reduced graft-versus-host disease with minimal loss of graft-versus-leukemia effect. Mice treated with 400 mg/kg of post-transplant cyclophosphamide did not develop graft-versus-host disease or leukemia, but it was difficult to evaluate the graft-versus-leukemia effect due to the sensitivity of A20 cells to cyclophosphamide. Although the current settings provide narrow optimal therapeutic windows, further studies are warranted to maximize the benefits of each immunosuppressant.
MeSH term(s)	Adult ; Alemtuzumab/therapeutic use ; Animals ; Antilymphocyte Serum/therapeutic use ; Cyclophosphamide/therapeutic use ; Disease Models, Animal ; Female ; Graft vs Host Disease/drug therapy ; Graft vs Host Disease/etiology ; Graft vs Host Disease/prevention & control ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Mice, Inbred NOD ; Mice, SCID ; Severity of Illness Index ; Tumor Burden ; Mice
Chemical Substances	Antilymphocyte Serum ; Alemtuzumab (3A189DH42V) ; Cyclophosphamide (8N3DW7272P)
Language	English
Publishing date	2021-01-11
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0245232
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Article ; Online: Alloreactive T Cells Display a Distinct Chemokine Profile in Response to Conditioning in Xenogeneic GVHD Models.

Transplantation

2019 Volume 103, Issue 9, Page(s) 1834–1843

Abstract: Background: Chemokines and chemokine receptors are potential targets for the prevention and treatment of graft-versus-host disease (GVHD). The objective of the current study is to determine the clinical relevance of xenogeneic transplantation models in ... ...

Abstract	Background: Chemokines and chemokine receptors are potential targets for the prevention and treatment of graft-versus-host disease (GVHD). The objective of the current study is to determine the clinical relevance of xenogeneic transplantation models in terms of host and donor chemokine profiles and, if this is the case, to assess the clinical efficacy of C-C chemokine receptor (CCR) 5 antagonist maraviroc for the prevention of GVHD using this model. Methods: Xenogeneic GVHD was induced by intravenous injection of 5 × 10 human pan T cells into NOD/Shi-scid-IL2rγ (NOG) mice or MHC class I/II-deficient NOG mice in the presence or absence of total body irradiation before transplantation. Results: Extensive tissue destruction with human T-cell infiltration was observed throughout the body, particularly in lungs and liver, but relatively mild in gut. Consistent with this finding, quantitative polymerase chain reaction confirmed the upregulation of mouse CXC chemokine ligand (CXCL) 9 and CXCL10 in lungs and CCL4 in lungs and liver but not in gut. The addition of total body irradiation (1) led to the early release of mouse CCL4 and CXCL10, (2) upregulated a number of chemokine-related genes in human T cells, (3) induced higher expression of CCR5 on human CD4 and CD8 T cells and CXCR3 on human CD4 T cells, and (4) promoted their migration and proliferation in organs, resulting in more severe tissue damage. In this context, pharmacological CCR5 blockade neither ameliorated GVHD nor prolonged survival in NOG mice. Conclusions: Our experimental data do not demonstrate clinical benefit of CCR5 antagonist for the prevention of GVHD in a myeloablative setting.
MeSH term(s)	Animals ; CCR5 Receptor Antagonists/pharmacology ; Chemokines/blood ; Chemokines/genetics ; Chemokines/immunology ; Disease Models, Animal ; Female ; Graft vs Host Disease/blood ; Graft vs Host Disease/genetics ; Graft vs Host Disease/immunology ; Graft vs Host Disease/prevention & control ; Humans ; Isoantigens/immunology ; Lymphocyte Activation/drug effects ; Maraviroc/pharmacology ; Mice, Inbred NOD ; Mice, SCID ; Myeloablative Agonists/pharmacology ; T-Lymphocyte Subsets/drug effects ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/transplantation ; Transcriptome ; Transplantation Conditioning ; Transplantation, Heterologous
Chemical Substances	CCR5 Receptor Antagonists ; Chemokines ; Isoantigens ; Myeloablative Agonists ; Maraviroc (MD6P741W8A)
Language	English
Publishing date	2019-08-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208424-7
ISSN	1534-6080 ; 0041-1337
ISSN (online)	1534-6080
ISSN	0041-1337
DOI	10.1097/TP.0000000000002756
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