173 results on '"Hisakata Yamada"'
Search Results
52. Type I interferon limits influenza virus-induced acute lung injury by regulation of excessive inflammation in mice
- Author
-
Yojiro Arimori, Hisakata Yamada, Yasunobu Yoshikai, Naoyoshi Maeda, Kensuke Shibata, Risa Nakamura, and Tetsuo Kase
- Subjects
Male ,viruses ,Acute Lung Injury ,Down-Regulation ,Receptor, Interferon alpha-beta ,Biology ,Lung injury ,medicine.disease_cause ,Antiviral Agents ,Virus ,Proinflammatory cytokine ,Mice ,Influenza A Virus, H1N1 Subtype ,Immune system ,Interferon ,Virology ,Influenza, Human ,Influenza A virus ,medicine ,Animals ,Humans ,Lung ,Mice, Knockout ,Pharmacology ,Interleukin-10 ,Mice, Inbred C57BL ,Interferon Type I ,Immunology ,Female ,Viral load ,Interferon type I ,medicine.drug - Abstract
Antiviral immune responses play as a double edged sword in resolution of infection and pathogenesis of acute lung injury caused by infection with highly pathogenic influenza A viruses. Here we show that type I interferons (IFNs) are important in protection against acute influenza A virus infection not only via their antiviral activity but also via their anti-inflammatory activity. IFN α receptor (IFNAR) knock-out (KO) mice exhibited increased mortality and morbidity with higher viral load after infection with influenza virus A/FM/1/47 (H1N1, a mouse-adapted strain) compared with wild-type (WT) mice, though the viruses were finally eliminated in both groups. The levels of proinflammatory cytokines in the lungs were significantly higher, while the level of IL-10 in the lungs was significantly lower in IFNAR KO mice than in WT mice during the course of infection. Restoration of IL-10 during an ongoing virus infection significantly reduced the levels of proinflammatory cytokines and improved mortality of IFNAR KO mice. These results suggest that type I IFNs are responsible not only for direct resolution of viral load but also for suppression of immunopathology caused by influenza A virus through IL-10 production.
- Published
- 2013
53. CD4 T cell-intrinsic IL-2 signaling differentially affects Th1 and Th17 development
- Author
-
Kenjiro Fujimura, Akiko Oyamada, Hisakata Yamada, Yukihide Iwamoto, and Yasunobu Yoshikai
- Subjects
CD4-Positive T-Lymphocytes ,Male ,Ovalbumin ,medicine.medical_treatment ,T cell ,Immunology ,Cell ,Receptors, Antigen, T-Cell ,Mice, Transgenic ,chemical and pharmacologic phenomena ,Biology ,T-Lymphocytes, Regulatory ,Epitopes ,Mice ,In vivo ,medicine ,Animals ,Immunology and Allergy ,Lymphocyte Count ,IL-2 receptor ,Clonal Selection, Antigen-Mediated ,Cells, Cultured ,Bone Marrow Transplantation ,Mice, Knockout ,Lymphopoiesis ,Interleukin-2 Receptor alpha Subunit ,Antibodies, Monoclonal ,FOXP3 ,hemic and immune systems ,Cell Biology ,Th1 Cells ,Adoptive Transfer ,Peptide Fragments ,In vitro ,Specific Pathogen-Free Organisms ,Cell biology ,Mice, Inbred C57BL ,Cytokine ,medicine.anatomical_structure ,Radiation Chimera ,Interleukin-2 ,Th17 Cells ,Female ,Interleukin 17 - Abstract
IL-2 signaling is involved in clonal expansion of antigen-specific CD4 T cells. IL-2 is also reported to promote Th1 but inhibit Th17 differentiation, although in vivo relevance remains unclear. In addition, IL-2-dependent Foxp3+ CD4 Tregs suppress T cell proliferation, complicating the in vivo role of IL-2 in the development of Th cell responses. To elucidate the roles of cell-intrinsic IL-2 signaling in CD4 T cells, we cotransferred TCR-Tg CD4 T cells from IL-2Rα (CD25)-deficient and WT mice and analyzed development of antigen-specific Th1 and Th17 responses. It was revealed that Th17 development of antigen-specific CD4 T cells was largely unaffected, whereas Th1 development was impaired by the lack of IL-2 signaling. Similar data were obtained from mixed BM chimera experiments using BM cells from CD25-deficient and WT mice. In addition, although in vitro blockade of IL-2 during Th17 development greatly increased the percentages of Th17 cells, it did not affect their numbers, indicating that in vitro Th17 development is also IL-2-independent. Th1 development was dependent on IL-2 in vitro as well. Thus, our data suggest that cell-intrinsic IL-2 signaling is critical for Th1 development but plays a limited role in Th17 development in vitro as well as in vivo.
- Published
- 2013
54. Positive selection of self-antigen-specific CD8+T cells by hematopoietic cells
- Author
-
Yasunobu Yoshikai, Koji Sakuraba, Hisakata Yamada, Kensuke Shibata, and Kenjiro Fujimura
- Subjects
Interleukin 21 ,Immunology ,CD1 ,Immunology and Allergy ,Cytotoxic T cell ,IL-2 receptor ,Biology ,Natural killer T cell ,Antigen-presenting cell ,Molecular biology ,CD8 ,Interleukin 3 - Abstract
In contrast to thymic epithelial cells, which induce the positive selection of conventional CD8+ T cells, hematopoietic cells (HCs) select innate CD8+ T cells whose Ag specificity is not fully understood. Here we show that CD8+ T cells expressing an H-Y Ag-specific Tg TCR were able to develop in mice in which only HCs expressed MHC class I, when HCs also expressed the H-Y Ag. These HC-selected self-specific CD8+ T cells resemble innate CD8+ T cells in WT mice in terms of the expression of memory markers and effector functions, but are phenotypically distinct from the thymus-independent CD8+ T-cell population. The peripheral maintenance of H-Y-specific CD8+ T cells required presentation of the self-Ag and IL-15 on HCs. HC-selected CD8+ T cells in mice lacking the Tg TCR also showed these features. Furthermore, by using MHC class I tetramers with a male Ag peptide, we found that self-Ag-specific CD8+ T cells in TCR non-Tg mice could develop via HC-induced positive selection, supporting results obtained from H-Y TCR Tg mice. These findings indicate the presence of self-specific CD8+ T cells that are positively selected by HCs in the peripheral T-cell repertoire.
- Published
- 2013
55. C-type Lectin MCL Is an FcRγ-Coupled Receptor that Mediates the Adjuvanticity of Mycobacterial Cord Factor
- Author
-
Yasunobu Miyake, Kenji Toyonaga, Akiko Oyamada, Shou Yamasaki, Yoichiro Iwakura, Ken Ichiro Ono, Shigeru Kakuta, Mikita Suyama, Daiki Mori, Hisakata Yamada, Yasunobu Yoshikai, and Yoshihiko Hoshino
- Subjects
Encephalomyelitis, Autoimmune, Experimental ,Immunology ,Stimulation ,Biology ,Mice ,Immune system ,Adjuvants, Immunologic ,C-type lectin ,immune system diseases ,Adjuvanticity ,hemic and lymphatic diseases ,medicine ,Animals ,Immunology and Allergy ,Lectins, C-Type ,Receptor ,neoplasms ,Mice, Knockout ,Mycobacterium Infections ,Innate immune system ,Cord factor ,Macrophages ,Experimental autoimmune encephalomyelitis ,Receptors, IgG ,Membrane Proteins ,Mycobacterium tuberculosis ,Macrophage Activation ,medicine.disease ,Mycobacterium bovis ,Mice, Inbred C57BL ,Infectious Diseases ,Cancer research ,Cord Factors - Abstract
SummaryCord factor, also called trehalose-6,6′-dimycolate (TDM), is a potent mycobacterial adjuvant. We herein report that the C-type lectin MCL (also called Clec4d) is a TDM receptor that is likely to arise from gene duplication of Mincle (also called Clec4e). Mincle is known to be an inducible receptor recognizing TDM, whereas MCL was constitutively expressed in myeloid cells. To examine the contribution of MCL in response to TDM adjuvant, we generated MCL-deficient mice. TDM promoted innate immune responses, such as granuloma formation, which was severely impaired in MCL-deficient mice. TDM-induced acquired immune responses, such as experimental autoimmune encephalomyelitis (EAE), was almost completely dependent on MCL, but not Mincle. Furthermore, by generating Clec4egfp reporter mice, we found that MCL was also crucial for driving Mincle induction upon TDM stimulation. These results suggest that MCL is an FcRγ-coupled activating receptor that mediates the adjuvanticity of TDM.
- Published
- 2013
- Full Text
- View/download PDF
56. Ly6C+Ly6G−Myeloid-derived suppressor cells play a critical role in the resolution of acute inflammation and the subsequent tissue repair process after spinal cord injury
- Author
-
Takehiko Yokomizo, Hiromi Kumamaru, Yukihide Iwamoto, Kazu Kobayakawa, Yasuyuki Ohkawa, Hirokazu Saiwai, Hisakata Yamada, Seiji Okada, and Kensuke Kubota
- Subjects
Pathology ,medicine.medical_specialty ,Central nervous system ,Neovascularization, Physiologic ,Inflammation ,Biochemistry ,Antibodies ,Monocytes ,Immature Monocyte ,Mice ,Cellular and Molecular Neuroscience ,Animals ,Antigens, Ly ,Medicine ,Myeloid Cells ,Spinal cord injury ,Spinal Cord Injuries ,business.industry ,Monocyte ,medicine.disease ,Mice, Inbred C57BL ,Transplantation ,medicine.anatomical_structure ,Spinal Cord ,Myeloid-derived Suppressor Cell ,Female ,Receptors, Chemokine ,medicine.symptom ,business ,Infiltration (medical) ,Granulocytes - Abstract
Acute inflammation is a prominent feature of central nervous system (CNS) insult and is detrimental to the CNS tissue. Although this reaction spontaneously diminishes within a short period of time, the mechanism underlying this inflammatory resolution remains largely unknown. In this study, we demonstrated that an initial infiltration of Ly6C(+) Ly6G(-) immature monocyte fraction exhibited the same characteristics as myeloid-derived suppressor cells (MDSCs), and played a critical role in the resolution of acute inflammation and in the subsequent tissue repair by using mice spinal cord injury (SCI) model. Complete depletion of Ly6C(+) Ly6G(-) fraction prior to injury by anti-Gr-1 antibody (clone: RB6-8C5) treatment significantly exacerbated tissue edema, vessel permeability, and hemorrhage, causing impaired neurological outcomes. Functional recovery was barely impaired when infiltration was allowed for the initial 24 h after injury, suggesting that MDSC infiltration at an early phase is critical to improve the neurological outcome. Moreover, intraspinal transplantation of ex vivo-generated MDSCs at sites of SCI significantly reduced inflammation and promoted tissue regeneration, resulting in better functional recovery. Our findings reveal the crucial role of an Ly6C(+) Ly6G(-) fraction as MDSCs in regulating inflammation and tissue repair after SCI, and also suggests an MDSC-based strategy that can be applied to acute inflammatory diseases.
- Published
- 2013
57. Two Types of Interleukin 17A-Producing γδ T Cells in Protection Against Pulmonary Infection With Klebsiella pneumoniae
- Author
-
Yasunobu Yoshikai, Hisakata Yamada, Yoichiro Iwakura, Tesshin Murakami, and Shinya Hatano
- Subjects
0301 basic medicine ,Klebsiella pneumoniae ,T-Lymphocytes ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Interleukin 23 ,Pneumonia, Bacterial ,Immunology and Allergy ,Animals ,Receptor ,Mice, Knockout ,Lung ,biology ,CD69 ,Interleukin-17 ,Interleukin ,medicine.disease ,biology.organism_classification ,Klebsiella Infections ,Mice, Inbred C57BL ,Pneumonia ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Immunology ,Interleukin-23 Subunit p19 ,Female ,Interleukin 17 ,030215 immunology - Abstract
Background Klebsiella pneumoniae frequently causes life-threatening infection in children. Interleukin 17A (IL-17A) is known to be involved in protection against K. pneumoniae infection through activation of neutrophils. Methods and results We found that IL-17A-producing γδ T cells existed more frequently in younger mice on examination of IL-17A-producing lymphocytes in the lung of naive mice at various ages. We hence compared the protective role of IL-17A-producing γδ T cells against pulmonary K. pneumoniae infection in young (3 weeks old) and adult (8-12 weeks old) mice. IL-17A-deficient mice were susceptible to K. pneumonia regardless of age. Cγ-, Vγ4/6-, or Vδ1-deficient mice were susceptible to K. pneumonia at young age, while interleukin 23p19 (IL-23p19)-deficient mice were susceptible at adult age. IL-17A-producing Vγ1-Vγ4- γδ T cells expressing canonical Vγ6/Vδ1 genes were dominant over IL-17A-producing Vγ4+ γδ T cells in the lungs of young mice after infection. The IL-17A-producing Vγ1-Vγ4- γδ T cells expressed an activation marker, CD69, and proliferated in an IL-23-independent manner, while the IL-17A-producing Vγ4+ γδ T cells expressing IL-23 receptor but no CD69 proliferated in IL-23-dependent manner. Conclusions These results suggest that 2 types of IL-17A-producing γδ T cells are activated for host defense against K. pneumoniae infection by IL-23-dependent or independent mechanism.
- Published
- 2016
58. Additional file 1: Table S1. of Generation mechanism of RANKL+ effector memory B cells: relevance to the pathogenesis of rheumatoid arthritis
- Author
-
Ota, Yuri, Niiro, Hiroaki, Shun-Ichiro Ota, Ueki, Naoko, Tsuzuki, Hirofumi, Nakayama, Tsuyoshi, Mishima, Koji, Higashioka, Kazuhiko, Siamak Jabbarzadeh-Tabrizi, Mitoma, Hiroki, Mitsuteru Akahoshi, Yojiro Arinobu, Kukita, Akiko, Hisakata Yamada, Tsukamoto, Hiroshi, and Akashi, Koichi
- Abstract
Clinical characterization of patients with RA included in the study. (DOCX 18 kb)
- Published
- 2016
- Full Text
- View/download PDF
59. Additional file 2: Figure S1. of Generation mechanism of RANKL+ effector memory B cells: relevance to the pathogenesis of rheumatoid arthritis
- Author
-
Ota, Yuri, Niiro, Hiroaki, Shun-Ichiro Ota, Ueki, Naoko, Tsuzuki, Hirofumi, Nakayama, Tsuyoshi, Mishima, Koji, Higashioka, Kazuhiko, Siamak Jabbarzadeh-Tabrizi, Mitoma, Hiroki, Mitsuteru Akahoshi, Yojiro Arinobu, Kukita, Akiko, Hisakata Yamada, Tsukamoto, Hiroshi, and Akashi, Koichi
- Subjects
musculoskeletal diseases - Abstract
Analysis of osteoclast differentiation using RAW-Venus1. (A) Differentiation into Venus positive pre-osteoclasts and osteoclasts were induced by RANKL in a dose-dependent manner. TNF-α exerted synergistic effects on RANKL-induced osteoclast differentiation (magnification × 20). (B) Both anti-RANKL Ab and OPG strongly reduced the number of Venus positive cells, indicated the inhibition of osteoclast differentiation (magnification × 20). (C) Venus positive cells were tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (magnification × 40). Cells were stained using a commercial TRAP assay (Sigma-Aldrich, St Louis, MO, USA). (A-C) Cells were cultured at 4.5 × 104 cells/ml for 3 days in a 96-well plate. No stim No stimulation. (PDF 304 kb)
- Published
- 2016
- Full Text
- View/download PDF
60. Additional file 3: Figure S2. of Generation mechanism of RANKL+ effector memory B cells: relevance to the pathogenesis of rheumatoid arthritis
- Author
-
Ota, Yuri, Niiro, Hiroaki, Shun-Ichiro Ota, Ueki, Naoko, Tsuzuki, Hirofumi, Nakayama, Tsuyoshi, Mishima, Koji, Higashioka, Kazuhiko, Siamak Jabbarzadeh-Tabrizi, Mitoma, Hiroki, Mitsuteru Akahoshi, Yojiro Arinobu, Kukita, Akiko, Hisakata Yamada, Tsukamoto, Hiroshi, and Akashi, Koichi
- Subjects
musculoskeletal diseases ,hemic and lymphatic diseases ,hemic and immune systems - Abstract
Phenotypic analysis of RANKL+ and RANKL− effector memory B cells. Purified switched-memory B cells from HC were stimulated with BCR/CD40 and IFN-γ for 48 hours. RANKL+ and RANKL− cells were analyzed for expression of CD20, CD21, CD95, CD11c, CCR1 and CCR5 using respective Abs (all from BioLegend). Representative data are shown (n = 3–4). (PDF 177 kb)
- Published
- 2016
- Full Text
- View/download PDF
61. Age-related differences in cellular and molecular profiles of inflammatory responses after spinal cord injury
- Author
-
Yukihide Iwamoto, Yasuyuki Ohkawa, Hisakata Yamada, Hirokazu Saiwai, Hiromi Kumamaru, and Seiji Okada
- Subjects
Aging ,Chemokine ,Neutrophils ,Physiology ,Clinical Biochemistry ,Gene Expression ,Mice ,Animals ,Medicine ,Spinal cord injury ,Pathological ,Spinal Cord Injuries ,DNA Primers ,Base Sequence ,Microglia ,biology ,business.industry ,Cell Biology ,medicine.disease ,Spinal cord ,Immunity, Innate ,Mice, Inbred C57BL ,CXCL1 ,medicine.anatomical_structure ,Immunology ,biology.protein ,Cytokines ,Female ,Tumor necrosis factor alpha ,Chemokines ,Inflammation Mediators ,business ,Infiltration (medical) - Abstract
Previous experimental and clinical studies have suggested that the behavioral and pathological outcomes of spinal cord injury (SCI) are affected by the individual's age at the time of injury. However, the underlying mechanism responsible for these differences remains elusive because it is difficult to match injuries of similar severities between young and adult animals due to differences in the sizes of their respective spinal cords. In this study, the spinal cord size-matched young (4-week-old) and adult (10-week-old) mice were compared to evaluate their locomotor functions and inflammatory cellular/molecular responses after standardized contusion SCI. During the acute phase of SCI, young mice showed better functional recovery and lower pro-inflammatory cytokines/chemokines compared to adult mice. Flow-cytometric analysis revealed that the time courses of leukocyte infiltration were comparable between both groups, while the number of infiltrating neutrophils significantly decreased from 6 h after SCI in young mice. By combining flow-cytometric isolation and gene expression analysis of each inflammatory cell fraction, we found that microglial cells immediately initiate the production of several cytokines in response to SCI, which serve as major sources of IL-6, TNFa, and CXCL1 in injured spinal cord. Interestingly, the secretion of pro-inflammatory cytokines/chemokines but not anti-inflammatory cytokines by microglia was significantly lower in young mice compared to that in adult mice at 3 h after SCI, which will be attributed to the attenuation of the subsequent neutrophil infiltration. These results highlight age-related differences in pro-inflammatory properties of microglial cells that contribute to the amplification of detrimental inflammatory responses after SCI.
- Published
- 2012
62. Antitumor activity of recombinant Bacille Calmette-Guérin secreting interleukin-15-Ag85B fusion protein against bladder cancer
- Author
-
Keijiro Kiyoshima, Ryosuke Takahashi, Katsunori Tatsugami, Junichi Inokuchi, Masatoshi Eto, Masaki Shiota, Eiji Kashiwagi, Yoriyuki Kamiryo, Yasunobu Yoshikai, Hisakata Yamada, Ario Takeuchi, Naoya Ohara, Akira Yokomizo, and Takashi Dejima
- Subjects
0301 basic medicine ,Chemokine ,Neutrophils ,medicine.medical_treatment ,Recombinant Fusion Proteins ,Immunology ,Inflammation ,urologic and male genital diseases ,complex mixtures ,Lymphocyte Depletion ,Mycobacterium tuberculosis ,03 medical and health sciences ,Mice ,Bacterial Proteins ,Cell Movement ,medicine ,Immunology and Allergy ,Animals ,Humans ,Pharmacology ,Interleukin-15 ,Mycobacterium bovis ,Antigens, Bacterial ,Bladder cancer ,biology ,business.industry ,Immunity ,Interleukin ,Immunotherapy ,biology.organism_classification ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,Urinary Bladder Neoplasms ,Interleukin 15 ,biology.protein ,Female ,medicine.symptom ,business ,Genetic Engineering ,Acyltransferases - Abstract
Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is used for the treatment of bladder cancer. The recruitment of neutrophlis to the bladder after BCG instillation exerts anti-tumor activity against bladder tumor. We have recently demonstrated that interleukin (IL)-17A produced by γδ T cells played a role in the recruitment of neutrophlis to the bladder after BCG instillation. IL-15 is known to play an important role in neutrophil migration during inflammation. We previously constructed a recombinant BCG strain expressing the fusion protein of IL-15 and Ag85B (BCG-IL-15) for prevention of Mycobacterium tuberculosis infection. Here we compared the efficacy of the BCG-IL-15 in protection against bladder cancer with that of rBCG-Ag85B (BCG). Six-week-old female C57BL/6 mice were inoculated with MB49 bladder tumor cells in the bladder and subsequently intravesically inoculated with BCG or BCG-IL-15. BCG-IL-15 treatment significantly prolonged survival of mice inoculated with bladder cancer cells compared with BCG treatment. Infiltration of neutrophils was significantly elevated in BCGB-IL-15 treated mice accompanied by increased chemokines (MIP-2 and MIP-1α) in the bladder. Thus, BCG-IL-15 exerted additive effect on Infiltration of neutrophils in the bladder. BCG-IL-15 may be a promising drug for non-muscle invasive bladder cancer.
- Published
- 2015
63. Protective Role of Naturally Occurring Interleukin-17A-Producing γδ T Cells in the Lung at the Early Stage of Systemic Candidiasis in Mice
- Author
-
Kensuke Shibata, Takashi Dejima, Hiromitsu Hara, Yoichiro Iwakura, Seiji Naito, Yasunobu Yoshikai, and Hisakata Yamada
- Subjects
Neutrophils ,T cell ,Immunology ,Population ,Biology ,Interleukin-23 ,Microbiology ,Mice ,Antigen ,T-Lymphocyte Subsets ,medicine ,Animals ,education ,Candida albicans ,Lung ,Adaptor Proteins, Signal Transducing ,Mice, Knockout ,education.field_of_study ,Interleukin-17 ,Candidiasis ,Receptors, Antigen, T-Cell, gamma-delta ,medicine.disease ,biology.organism_classification ,Toll-Like Receptor 2 ,Specific Pathogen-Free Organisms ,CARD Signaling Adaptor Proteins ,Mice, Inbred C57BL ,TLR2 ,Infectious Diseases ,medicine.anatomical_structure ,Myeloid Differentiation Factor 88 ,Parasitology ,Interleukin 17 ,Systemic candidiasis ,Fungal and Parasitic Infections - Abstract
Interleukin-17A (IL-17A)-producing γδ T cells differentiate in the fetal thymus and reside in the peripheral tissues, such as the lungs of naïve adult mice. We show here that naturally occurring γδ T cells play a protective role in the lung at a very early stage after systemic infection with Candida albicans. Selective depletion of neutrophils by in vivo administration of anti-Ly6G monoclonal antibody (MAb) impaired fungal clearance more prominently in the lung than in the kidney 24 h after intravenous infection with C. albicans. Rapid and transient production of IL-23 was detected in the lung at 12 h, preceding IL-17A production and the influx of neutrophils, which reached a peak at 24 h after infection. IL-17A knockout (KO) mice showed reduced infiltration of neutrophils concurrently with impaired fungal clearance in the lung after infection. The major source of IL-17A was the γδ T cell population in the lung, and Cδ KO mice showed little IL-17A production and reduced neutrophil infiltration after infection. Early IL-23 production in a TLR2/MyD88-dependent manner and IL-23-triggered tyrosine kinase 2 (Tyk2) signaling were essential for IL-17A production by γδ T cells. Thus, our study demonstrated a novel role of naturally occurring IL-17A-producing γδ T cells in the first line of host defense against C. albicans infection.
- Published
- 2011
64. Innate memory phenotype CD4+ T cells play a role in early protection against infection by Listeria monocytogenes in a CD30L-dependent manner
- Author
-
Hisakata Yamada, Ying Guo, Kenji Umeda, Kensuke Shibata, Xun Sun, and Yasunobu Yoshikai
- Subjects
Immunology ,Wild type ,Interleukin ,Spleen ,Biology ,medicine.disease_cause ,biology.organism_classification ,Microbiology ,Peritoneal cavity ,medicine.anatomical_structure ,Listeria monocytogenes ,In vivo ,Virology ,medicine ,Listeria ,Tumor necrosis factor alpha - Abstract
CD30 ligand (CD30L, CD153) is a type II membrane-associated glycoprotein belonging to the tumor necrosis factor family. It is shown here that CD30L knock out (KO) mice are highly susceptible to primary infection with Listeria monocytogenes as assessed by the survival rate. There were significantly more bacteria on day 3 after infection in the peritoneal cavity, spleen and liver of CD30LKO mice than in wild type (WT) mice. The innate function of memory phenotype (MP) CD44+ CD4+ T cells for interferon-gamma production was significantly lower in CD30LKO mice than in WT mice in response to interleukin (IL)-12 and IL-15 in vitro. Depletion of CD4+ T cells by in vivo administration of anti-CD4 mAb at an early stage after infection hampered protection against Listeria. Furthermore, in vivo administration of agonistic anti-CD30 mAb restored protection against Listeria in CD30LKO mice, whereas treatment with soluble mCD30-Ig hampered protection in WT mice. Taken together, it appears that CD30L/CD30 signaling plays an important role in innate MPCD4+ T cell-mediated protection against infection with L. monocytogenes.
- Published
- 2011
65. Evaluation of cartilage degradation in arthritis using T1ρ magnetic resonance imaging mapping
- Author
-
Hiroshi Honda, Yasuharu Nakashima, Toshiaki Izawa, Hisakata Yamada, Yukihide Iwamoto, Yukihisa Takayama, Hidetoshi Tsushima, Masamitsu Hatakenaka, and Ken Okazaki
- Subjects
Cartilage, Articular ,Male ,medicine.medical_specialty ,Pathology ,Immunology ,Arthritis ,Osteoarthritis ,Severity of Illness Index ,Cartilage degradation ,Arthritis, Rheumatoid ,Rheumatology ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Aged ,Aged, 80 and over ,Fibrillation ,medicine.diagnostic_test ,business.industry ,Cartilage ,Magnetic resonance imaging ,Middle Aged ,Osteoarthritis, Knee ,medicine.disease ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,Rheumatoid arthritis ,Female ,Proteoglycans ,medicine.symptom ,business - Abstract
T1ρ magnetic resonance imaging (MRI) can be used to map proteoglycan (PG) loss in cartilage. Here, we used T1ρ MRI to map cartilage degradation in osteoarthritis (OA) and rheumatoid arthritis (RA). Tissue samples were obtained from five RA patients and 14 OA patients following total knee arthroplasty (TKA). Three parameters were measured: First, macroscopic grading of cartilage sample tissues was performed on a 5-grade scale (G0: normal, G1: swelling, G2: superficial fibrillation, G3: deep fibrillation, G4: subchondral bone exposure). Second, semi-quantitative values of PG were assessed by measuring the optical density of Safranin-O-stained paraffin sections that had been digitally photographed. Third, cartilage was divided into superficial and deep layers and the T1ρ values were quantified. T1ρ values of OA and RA in the superficial layers showed significant differences between groups (G0/1 and G0/2 for OA; G0/2 and G1/2 for RA). In the deep layers, T1ρ values of OA and RA also differed significantly between groups. In both the superficial and deep layers, there was a significant correlation between the mean T1ρ values and macroscopic grading (P < 0.01 for OA, P < 0.001 for RA). We found a negative correlation between the score of Safranin-O staining and T1ρ values (r = -0.61 for OA, r = -0.79 for RA). In addition, RA subjects had significantly higher T1ρ values than OA subjects of similar morphologic grade. In conclusion, T1ρ MRI is able to detect and map the early stages of cartilage degradation in OA and RA. This method is reliable and useful for the evaluation of macromolecular changes in arthritic cartilage.
- Published
- 2011
66. CD30 Ligand Is a Target for a Novel Biological Therapy against Colitis Associated with Th17 Responses
- Author
-
Kenzaburo Tani, Yoichiro Iwakura, Eckhard R. Podack, Hisakata Yamada, Xun Sun, Yasunobu Yoshikai, Hiromi Muta, and Kensuke Shibata
- Subjects
Male ,Recombinant Fusion Proteins ,Cellular differentiation ,Immunology ,Cell ,Immunoglobulins ,Ki-1 Antigen ,Cell Communication ,Mice, SCID ,Pathogenesis ,Mice ,Downregulation and upregulation ,Animals ,Humans ,Immunology and Allergy ,Medicine ,CD30 Ligand ,Colitis ,Acute colitis ,Mice, Knockout ,Mice, Inbred BALB C ,Lamina propria ,Mucous Membrane ,business.industry ,Dextran Sulfate ,Cell Differentiation ,medicine.disease ,medicine.anatomical_structure ,Acute Disease ,Chronic Disease ,Cancer research ,Cytokines ,Th17 Cells ,Female ,business ,Signal Transduction - Abstract
We have previously found that CD30 ligand (CD30L; CD153)/CD30 signaling executed by the T–T cell interaction plays a critical role in Th17 cell differentiation, at least partly via downregulation of IL-2 production. In this study, we investigated the role of CD30L in the development of colitis experimentally induced by dextran sulfate sodium (DSS), in which IL-17A is involved in the pathogenesis. CD30L−/− mice were resistant to both acute colitis induced by administration of 3 to ∼5% DSS and to chronic colitis induced by administration of 1.5% DSS on days 0–5, 10–15, and 20–25 as assessed by weight loss, survival rate, and histopathology. The levels of IFN-γ, IL-17A, and IL-10 were significantly lower but the IL-2 level higher in the lamina propria T lymphocytes of CD30L−/− mice than those in lamina propria T lymphocytes of wild-type mice after DSS administration. Soluble murine CD30-Ig fusion protein, which was capable of inhibiting Th17 cell differentiation in vitro, ameliorated both types of DSS-induced colitis in wild-type mice. Modulation of CD30L/CD30 signaling by soluble CD30 could be a novel biological therapy for inflammatory diseases associated with Th17 responses.
- Published
- 2010
67. IL-17 production by γδ T cells is important for the antitumor effect of Mycobacterium bovis bacillus Calmette-Guérin treatment against bladder cancer
- Author
-
Tatsuya Nakatani, Yasunobu Yoshikai, Takashi Dejima, Risa Nakamura, Kensuke Shibata, Hisakata Yamada, Masatoshi Eto, Seiji Naito, and Ario Takeuchi
- Subjects
Neutrophils ,T-Lymphocytes ,T cell ,Immunology ,urologic and male genital diseases ,complex mixtures ,Mice ,Antigen ,Cell Line, Tumor ,medicine ,Animals ,Immunology and Allergy ,Receptor ,Mice, Knockout ,Mycobacterium bovis ,Bladder cancer ,biology ,business.industry ,Interleukin-17 ,Receptors, Antigen, T-Cell, gamma-delta ,biology.organism_classification ,medicine.disease ,female genital diseases and pregnancy complications ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Urinary Bladder Neoplasms ,Cell culture ,CD4 Antigens ,Female ,Immunotherapy ,Interleukin 17 ,business ,Infiltration (medical) - Abstract
Intravesical inoculation of Mycobacterium bovis bacillus Calmette-Guérin (BCG) has been used for the treatment of bladder cancer. Recent studies implied the requirement of neutrophil infiltration for the antitumor effect. In this study, we found that IL-17 was produced in the bladder after BCG treatment, preceding the infiltration of neutrophils. Neutrophils in the bladder after BCG treatment were reduced in IL-17-deficient mice, in which BCG-induced antitumor effect against intravesically inoculated bladder cancer was abolished. Notably, the level of IL-17 production and the number of neutrophils in BCG-treated bladder was reduced in γδ T-cell-deficient mice but not in CD4-depleted mice. Survival of bladder cancer-inoculated γδ T-cell-deficient mice was not improved by BCG treatment. These results suggest that IL-17-producing γδ T cells play a key role in the BCG-induced recruitment of neutrophils to the bladder, which is essential for the antitumor activity against bladder cancer.
- Published
- 2010
68. Interleukin-15 Is Critical in the Pathogenesis of Influenza A Virus-Induced Acute Lung Injury
- Author
-
Kensuke Shibata, Tetsuo Kase, Risa Nakamura, Yasunobu Yoshikai, Naoyoshi Maeda, and Hisakata Yamada
- Subjects
Adoptive cell transfer ,Acute Lung Injury ,Immunology ,CD8-Positive T-Lymphocytes ,Lung injury ,Biology ,medicine.disease_cause ,Microbiology ,Virus ,Pathogenesis ,Mice ,Influenza A Virus, H1N1 Subtype ,Virology ,Influenza A virus ,medicine ,Animals ,Interleukin-15 ,Mice, Knockout ,Pneumonia ,medicine.disease ,Adoptive Transfer ,Interleukin 15 ,Insect Science ,Pathogenesis and Immunity ,Cytokine storm ,CD8 - Abstract
Highly pathogenic influenza A viruses cause acute severe pneumonia to which the occurrence of “cytokine storm” has been proposed to contribute. Here we show that interleukin-15 (IL-15) knockout (KO) mice exhibited reduced mortality after infection with influenza virus A/FM/1/47 (H1N1, a mouse-adapted strain) albeit the viral titers of these mice showed no difference from those of control mice. There were significantly fewer antigen-specific CD44 + CD8 + T cells in the lungs of infected IL-15 KO mice, and adoptive transfer of the CD8 + T cells caused reduced survival of IL-15 KO mice following influenza virus infection. Mice deficient in β 2 -microglobulin by gene targeting and those depleted of CD8 + T cells by in vivo administration of anti-CD8 monoclonal antibody displayed a reduced mortality rate after infection. These results indicate that IL-15-dependent CD8 + T cells are at least partly responsible for the pathogenesis of acute pneumonia caused by influenza A virus.
- Published
- 2010
69. Antibody-Mediated T-Cell Reduction or Increased Levels of Chimerism Overcome Resistance to Cyclophosphamide-Induced Tolerance in NKT-Deficient Mice
- Author
-
Shinji Okano, I Shimizu, Tatsushi Onzuka, Yukihiro Tomita, Hisakata Yamada, Yasunobu Yoshikai, and Ryuji Tominaga
- Subjects
T cell ,Immunology ,Spleen ,General Medicine ,Transplantation Chimera ,Biology ,Clonal deletion ,Immune tolerance ,Immunophenotyping ,medicine.anatomical_structure ,medicine ,biology.protein ,Central tolerance ,Antibody - Abstract
We reported that invariant NKT-cell knockout (iNKT KO) mice are resistant to the induction of intrathymic chimerism and clonal deletion in the cyclophosphamide (CP)-induced tolerance system (CPS). However, another report shows that clonal deletion with chimerism may be intact in iNKT KO recipients in a bone marrow transplantation model. We also reported that pretreatment with anti-Thy1.2 mAb, which reduces the number of T cells and iNKT cells, promotes allograft tolerance across H-2 barriers in the CPS. In this study, we evaluated the efficacy of T-cell depletion in the CPS, and the relationship between the role played by iNKT cells in central tolerance and mixed chimerism. BALB/c (H-2(d)) wild-type, or iNKT KO (Jalpha18(-/-)) mice were pretreated with 20-100 microg of anti-Thy1.2 mAb and given 10(8) donor DBA/2 (H-2(d)) spleen cells on Day 0, and 200 mg/kg CP on Day 2. Pretreatment with T-cell depletion resulted in higher levels of mixed chimerism, increased intrathymic clonal deletion of donor-reactive cells, and the induction of skin graft tolerance in iNKT KO recipients in CPS. This suggests that the high levels of mixed chimerism overcame the resistance to CP-induced tolerance in iNKT KO mice. Consistently, the enhancement of mixed chimerism by injection of tolerant donor spleen cells (SC) rendered iNKT KO recipients susceptible to CP-induced tolerance. These results suggest that iNKT-cell-mediated immunoregulation of central tolerance is evident at low levels of peripheral mixed chimerism in the CPS.
- Published
- 2010
70. Selective control of type I IFN induction by the Rac activator DOCK2 during TLR-mediated plasmacytoid dendritic cell activation
- Author
-
Akihiko Nishikimi, Naoyoshi Maeda, Yoshinori Fukui, Ryoichi Takayanagi, Yoshihiko Tanaka, Katsuaki Hoshino, Sadayuki Higashi, Munechika Enjoji, Tsuneyasu Kaisho, Yasunobu Yoshikai, Qinhong Cao, Takehito Uruno, Kazuhito Gotoh, Hisakata Yamada, Risa Nakamura, Yasushi Kawaguchi, and Takahiro Ishikawa
- Subjects
Male ,rac1 GTP-Binding Protein ,Herpesvirus 2, Human ,Interferon Regulatory Factor-7 ,IκB kinase ,Mice ,Guanine Nucleotide Exchange Factors ,Immunology and Allergy ,Phosphorylation ,Mice, Knockout ,Toll-like receptor ,Membrane Glycoproteins ,Interleukin-12 Subunit p40 ,Dock2 ,GTPase-Activating Proteins ,Toll-Like Receptors ,Imidazoles ,hemic and immune systems ,I-kappa B Kinase ,rac GTP-Binding Proteins ,Rac GTP-Binding Proteins ,Interleukin-1 Receptor-Associated Kinases ,STAT1 Transcription Factor ,Oligodeoxyribonucleotides ,Influenza A virus ,Interferon Type I ,Female ,Mitogen-Activated Protein Kinases ,Signal transduction ,Signal Transduction ,medicine.drug ,Immunology ,Endosomes ,Biology ,medicine ,Animals ,Plasmacytoid dendritic cell activation ,Neuropeptides ,Brief Definitive Report ,Interferon-alpha ,Dendritic Cells ,Interferon-beta ,TLR7 ,Actins ,Mice, Inbred C57BL ,Toll-Like Receptor 7 ,Toll-Like Receptor 9 ,Cancer research ,biology.protein ,Interferon type I - Abstract
Plasmacytoid dendritic cells (pDCs) play a key role in antiviral immunity, but also contribute to the pathogenesis of certain autoimmune diseases, by producing large amounts of type I IFNs. Although activation of pDCs is triggered by engagement of nucleotide-sensing toll-like receptors (TLR) 7 and 9, type I IFN induction additionally requires IkappaB kinase (IKK) alpha-dependent activation of IFN regulatory factor (IRF) 7. However, the signaling pathway mediating IKK-alpha activation is poorly defined. We show that DOCK2, an atypical Rac activator, is essential for TLR7- and TLR9-mediated IFN-alpha induction in pDCs. We found that the exposure of pDCs to nucleic acid ligands induces Rac activation through a TLR-independent and DOCK2-dependent mechanism. Although this Rac activation was dispensable for induction of inflammatory cytokines, phosphorylation of IKK-alpha and nuclear translocation of IRF-7 were impaired in Dock2-deficient pDCs, resulting in selective loss of IFN-alpha induction. Similar results were obtained when a dominant-negative Rac mutant was expressed in wild-type pDCs. Thus, the DOCK2-Rac signaling pathway acts in parallel with TLR engagement to control IKK-alpha activation for type I IFN induction. Owing to its hematopoietic cell-specific expression, DOCK2 may serve as a therapeutic target for type I IFN-related autoimmune diseases.
- Published
- 2010
71. Glucocorticoids Drive Diurnal Oscillations in T Cell Distribution and Responses by Inducing Interleukin-7 Receptor and CXCR4
- Author
-
Shizue Tani-ichi, Koichi Ikuta, Hitoshi Miyachi, Hisakata Yamada, Fumie Okazaki, Günther Schütz, Takashi Nagasawa, Makoto Ogawa, Guangwei Cui, Yasunobu Yoshikai, Satsuki Kitano, Shinya Abe, Akihiro Shimba, and Takahiro Hara
- Subjects
0301 basic medicine ,Male ,Receptors, CXCR4 ,T cell ,T-Lymphocytes ,Immunology ,Spleen ,Biology ,Lymphocyte Activation ,03 medical and health sciences ,Chemokine receptor ,Mice ,0302 clinical medicine ,Immune system ,Receptors, Glucocorticoid ,medicine ,Animals ,Immunology and Allergy ,Receptor ,Interleukin-7 receptor ,Glucocorticoids ,Cells, Cultured ,Receptors, Interleukin-7 ,Acquired immune system ,Chemokine CXCL12 ,Cell biology ,Circadian Rhythm ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Infectious Diseases ,030220 oncology & carcinogenesis ,Female ,Immunologic Memory ,Hormone - Abstract
Glucocorticoids are steroid hormones with strong anti-inflammatory and immunosuppressive effects that are produced in a diurnal fashion. Although glucocorticoids have the potential to induce interleukin-7 receptor (IL-7R) expression in T cells, whether they control T cell homeostasis and responses at physiological concentrations remains unclear. We found that glucocorticoid receptor signaling induces IL-7R expression in mouse T cells by binding to an enhancer of the IL-7Ra locus, with a peak at midnight and a trough at midday. This diurnal induction of IL-7R supported the survival of T cells and their redistribution between lymph nodes, spleen, and blood by controlling expression of the chemokine receptor CXCR4. In mice, T cell accumulation in the spleen at night enhanced immune responses against soluble antigens and systemic bacterial infection. Our results reveal the immunoenhancing role of glucocorticoids in adaptive immunity and provide insight into how immune function is regulated by the diurnal rhythm., ステロイドが免疫力を高める --免疫の新たな昼夜サイクルを解明--. 京都大学プレスリリース. 2018-01-24.
- Published
- 2018
72. Th17 cells and human arthritic diseases
- Author
-
Hisakata Yamada
- Subjects
business.industry ,Immunology ,Arthritis ,chemical and pharmacologic phenomena ,hemic and immune systems ,General Medicine ,medicine.disease ,Arthritis, Rheumatoid ,Clinical trial ,Mice ,Rheumatoid arthritis ,medicine ,Animals ,Humans ,Th17 Cells ,Immunology and Allergy ,business - Abstract
Th17 cells, though having been discovered just few years ago, is believed as the pathogenic T cells in many autoimmune diseases and chronic inflammatory diseases, such as rheumatoid arthritis (RA). Biologics targeting IL-17 have already been on clinical trial, and the results were recently reported. Although the importance of Th17 cells in animal models of arthritis is unquestionable, it is not recognized that there are only limited data on the role of Th17 cells and related cytokines in human arthritic diseases. In addition, the characteristics of human Th17 cells have not been fully defined, and there seem to be substantial differences between human and mouse Th17 cells. In this review, I will introduce and discuss about updated findings on human Th17 cells and its relation with human arthritic diseases.
- Published
- 2010
73. Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle
- Author
-
Hisakata Yamada, Eri Taniguchi Ishikawa, Taroh Kinoshita, Shizuo Akira, Yasu S. Morita, Kenji Toyonaga, Yasunobu Yoshikai, Tetsuaki Ishikawa, Osamu Takeuchi, and Sho Yamasaki
- Subjects
Lung Diseases ,medicine.medical_treatment ,Immunology ,Biology ,Ligands ,Proinflammatory cytokine ,chemistry.chemical_compound ,Mice ,Glycolipid ,Immune system ,C-type lectin ,medicine ,Immunology and Allergy ,Macrophage ,Animals ,Lectins, C-Type ,Cord factor ,Granuloma ,Receptors, IgG ,Brief Definitive Report ,Membrane Proteins ,Macrophage Activation ,Trehalose dimycolate ,Mice, Inbred C57BL ,Cytokine ,chemistry ,Myeloid Differentiation Factor 88 ,Cord Factors - Abstract
Tuberculosis remains a fatal disease caused by Mycobacterium tuberculosis, which contains various unique components that affect the host immune system. Trehalose-6,6′-dimycolate (TDM; also called cord factor) is a mycobacterial cell wall glycolipid that is the most studied immunostimulatory component of M. tuberculosis. Despite five decades of research on TDM, its host receptor has not been clearly identified. Here, we demonstrate that macrophage inducible C-type lectin (Mincle) is an essential receptor for TDM. Heat-killed mycobacteria activated Mincle-expressing cells, but the activity was lost upon delipidation of the bacteria; analysis of the lipid extracts identified TDM as a Mincle ligand. TDM activated macrophages to produce inflammatory cytokines and nitric oxide, which are completely suppressed in Mincle-deficient macrophages. In vivo TDM administration induced a robust elevation of inflammatory cytokines in sera and characteristic lung inflammation, such as granuloma formation. However, no TDM-induced lung granuloma was formed in Mincle-deficient mice. Whole mycobacteria were able to activate macrophages even in MyD88-deficient background, but the activation was significantly diminished in Mincle/MyD88 double-deficient macrophages. These results demonstrate that Mincle is an essential receptor for the mycobacterial glycolipid, TDM.
- Published
- 2009
74. Protective Role of Fas-FasL Signaling in Lethal Infection with Herpes Simplex Virus Type 2 in Mice
- Author
-
Takahiro Ishikawa, Akiko Oyamada, Hisakata Yamada, Yukihiro Nishiyama, Yasunobu Yoshikai, and Fumi Goshima
- Subjects
CD4-Positive T-Lymphocytes ,Cytotoxicity, Immunologic ,Adoptive cell transfer ,Fas Ligand Protein ,Herpesvirus 2, Human ,medicine.medical_treatment ,Immunology ,Biology ,medicine.disease_cause ,Microbiology ,Fas ligand ,Virus ,Mice ,Virology ,medicine ,Animals ,Cytotoxic T cell ,fas Receptor ,Mice, Knockout ,Herpes Simplex ,Mice, Inbred C57BL ,Herpes simplex virus ,Cytokine ,Apoptosis ,Insect Science ,Pathogenesis and Immunity ,Female ,CD8 ,Signal Transduction - Abstract
Herpes simplex virus type 2 (HSV-2) induces acute local infection followed by latent infection in the nervous system and often leads to the development of lethal encephalitis in immunocompromised hosts. The mechanisms of immune protection against lethal HSV-2 infection, however, have not been clarified. In this study, we examined the roles of Fas-Fas ligand (FasL) signaling in lethal infection with HSV-2 by using mice with mutated Fas (lpr) or FasL (gld) in C57BL/6 background. Bothlprandgldmice exhibited higher mortality than wild-type (WT) C57BL/6 mice after infection with virulent HSV-2 strain 186 and showed significantly increased viral titers in the spinal cord compared with WT mice 9 days after infection, just before the mice started to die. There were no differences in the numbers of CD4+and CD8+T cells infiltrated in the spinal cord or in the levels of HSV-2-specific gamma interferon produced by those cells in a comparison oflprand WT mice 9 days after infection. Adoptive transfer studies demonstrated that CD4+T cells from WT mice protectedgldmice from lethal infection by HSV-2. Furthermore, CD4+T cells infiltrated in the spinal cord of HSV-2-infected WT mice expressed functional FasL that induced apoptosis of Fas-expressing target cells in vitro. These results suggest that FasL-mediated cytotoxic activity of CD4+T cells plays an important role in host defense against lethal infection with HSV-2.
- Published
- 2009
75. IL-15 is critical for the maintenance and innate functions of self-specific CD8+T cells
- Author
-
Hisakata Yamada, Momoe Itsumi, and Yasunobu Yoshikai
- Subjects
medicine.medical_treatment ,Transgene ,Immunology ,Biology ,Interleukin 21 ,Cytokine ,Antigen ,Interleukin 15 ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,IL-2 receptor ,CD8 - Abstract
IL-15 is a pleiotropic cytokine involved in host defense as well as autoimmunity. IL-15-deficient mice show a decrease of memory phenotype (MP) CD8(+) T cells, which develop naturally in naive mice and whose origin is unclear. It has been shown that self-specific CD8(+) T cells developed in male H-Y antigen-specific TCR transgenic mice share many similarities with naturally occurring MP CD8(+) T cells in normal mice. In this study, we found that H-Y antigen-specific CD8(+) T cells in male but not female mice decreased when they were crossed with IL-15-deficient mice, mainly due to impaired peripheral maintenance. The self-specific TCR transgenic CD8(+) T cells developed in IL-15-deficient mice showed altered surface phenotypes and reduced effector functions ex vivo. Bystander activation of the self-specific CD8(+) T cells was induced in vivo during infection with Listeria monocytogenes, in which proliferation but not IFN-gamma production was IL-15-dependent. These results indicated important roles for IL-15 in the maintenance and functions of self-specific CD8(+) T cells, which may be included in the naturally occurring MP CD8(+) T-cell population in naive normal mice and participate in innate host defense responses.
- Published
- 2009
76. Donor CD4 T Cells Are Critical in Allogeneic Stem Cell Transplantation against Murine Solid Tumor
- Author
-
Katsunori Tatsugami, Yasunobu Yoshikai, Hisakata Yamada, Yoriyuki Kamiryo, Seiji Naito, Masahiko Harano, Toshiki Yajima, Masatoshi Eto, Masumitsu Hamaguchi, and Ario Takeuchi
- Subjects
CD4-Positive T-Lymphocytes ,Mice, Inbred C3H ,Cancer Research ,medicine.diagnostic_test ,Enzyme-Linked Immunosorbent Assay ,Spleen ,Neoplasms, Experimental ,Biology ,Flow Cytometry ,Lymphocyte Depletion ,Donor lymphocyte infusion ,Flow cytometry ,Transplantation ,Mice ,medicine.anatomical_structure ,Oncology ,In vivo ,Immunology ,medicine ,Animals ,Cytotoxic T cell ,Female ,Bone marrow ,Stem cell ,Stem Cell Transplantation - Abstract
Nonmyeloablative allogeneic stem cell transplantation (SCT) has been used for various malignancies, although detailed mechanisms of antitumor effects remain unclear. We showed that a nonmyeloablative allogeneic SCT regimen, which consists of mixed chimerism induced by an injection of donor spleen and bone marrow cells followed by cyclophosphamide treatment and a donor lymphocyte infusion (DLI), exerted antitumor effects on established murine bladder tumor, MBT-2. An expansion of donor CD4 T cells accompanied by transient but vigorous IFN-γ production was detected shortly after DLI. In vivo neutralization of IFN-γ or depletion of CD4 T cells from DLI abolished the antitumor effects, indicating an indispensable role of donor CD4 T cells producing IFN-γ. Donor as well as host CD8 T cells accumulated in the tumor region with time. Importantly, depletion of CD8 T cells from DLI did not reverse the suppression of tumor growth, indicating that CD4 T cells play a more essential role in mediating early antitumor effects. Furthermore, tumor-specific response of host CD8 T cells was suggested. These results not only provide the first evidence of nonmyeloablative allogeneic SCT for the treatment of bladder tumor but also elucidate detailed mechanisms of antitumor effects provoked by DLI. [Cancer Res 2009;69(12):5151–8]
- Published
- 2009
77. IL-15 protects antigen-specific CD8+ T cell contraction after Mycobacterium bovis bacillus Calmette-Guérin infection
- Author
-
Kensuke Shibata, Yasunobu Yoshikai, Ce Tang, Shin Ichi Yoshida, Worawidh Wajjwalku, and Hisakata Yamada
- Subjects
Immunology ,T-Cell Antigen Receptor Specificity ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Microbiology ,Mycobacterium tuberculosis ,Mice ,medicine ,Animals ,Tuberculosis ,Immunology and Allergy ,Cytotoxic T cell ,Lymphocyte Count ,Interleukin-15 ,Mycobacterium bovis ,biology ,Cell Biology ,biology.organism_classification ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Apoptosis ,Interleukin 15 ,BCG Vaccine ,BCG vaccine ,Memory T cell ,CD8 - Abstract
In vivo administration of IL-15 at the contraction phase in BCG infection inhibited apoptosis of effector CD8+ T cells resulting in the significant increase of Ag-specific memory CD8+ T cells. We reported previously that IL-15 plays a critical role in protecting effector CD8+ T cells from apoptosis during the contraction phase following acute infection with Listeria monocytogenes by inducing antiapoptotic molecules. In the present study, we examined the effects of in vivo administration of rIL-15 on contraction of CD8+ T cells after chronic infection with Mycobacterium bovis BCG and on the efficacy of BCG vaccination against Mycobacterium tuberculosis infection. Antigen-specific CD8+ T cells reached an expansion peak at approximately Day 21, followed by a contraction after inoculation with rBCG expressing OVA. In vivo administration of rIL-15 from Days 22 to 42 after BCG inoculation inhibited apoptosis of effector CD8+ T cells by up-regulating their Bcl-2 expression, resulting in a significant increase of antigen-specific memory CD8+ T cells producing IFN-γ. However, the IL-15 treatment did not elicit improved efficacy of BCG vaccination against M. tuberculosis. These results suggest that IL-15 plays a critical role in protecting activated CD8+ T cells from apoptosis during the contraction phase following BCG inoculation, although IL-15 administration alone at the contraction phase might not be sufficient to protect the efficient memory T cell responses against subsequent infection with M. tuberculosis.
- Published
- 2009
78. Tumor-specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti-tumor immunity
- Author
-
Yukari Shinozaki, Yasunobu Yoshikai, Hiroki Yoshida, Sean-Jiun Wang, Kohji Miyazaki, Yoshiyuki Miyazaki, Hiromitsu Hara, and Hisakata Yamada
- Subjects
Cancer Research ,Cellular immunity ,Ovalbumin ,Melanoma, Experimental ,Angiogenesis Inhibitors ,chemical and pharmacologic phenomena ,Mice ,Neuroblastoma ,Neoplasms ,Animals ,Cytotoxic T cell ,RNA, Neoplasm ,Receptors, Cytokine ,Interleukin 27 ,Antigen-presenting cell ,Melanoma ,Mice, Knockout ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Interleukin-17 ,hemic and immune systems ,Dendritic Cells ,Receptors, Interleukin ,Dendritic cell ,Th1 Cells ,CTL ,Oncology ,Perforin ,Immunology ,Cancer research ,biology.protein ,Interleukin-2 ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
Interleukin (IL-) 27 is a member of IL-12 cytokine family with Th1-promoting and anti-inflammatory effects. IL-27 has been shown to facilitate tumor-specific cytotoxic T lymphocyte (CTL) induction against various tumors. However, IL-27 suppresses cytokine production of lymphocytes and antigen-presenting function of dendritic cells (DCs). To examine the in vivo role of IL-27 in generation of anti-tumor immunity, we examined IL-27-mediated antitumor-effects using WSX-1 (IL-27 receptor alpha chain)-deficient (WSX-1(-/-)) mice. In WSX-1(-/-) mice inoculated with B16 melanoma cells, tumor growth was higher than in wild-type (WT) mice. Accordingly, tumor-specific CTL generation was lower in WSX-1(-/-) mice than in WT mice. CTL induction in WSX-1(-/-) mice was not restored by transfer of WT DCs pulsed with TRP2 peptide, indicating that IL-27 is directly required for generation of tumor-specific CTLs. However, when transferred into tumor-bearing mice, WSX-1(-/-) DCs pulsed with TRP2 peptide was more potent than WT DCs in tumor growth inhibition and generation of CTLs, indicating suppressive effects of IL-27 on DC function. Finally, the combination of WT CD8(+) T cells and KO DCs is more potent in generation of antigen-specific CTLs than any other combinations. Expression of perforin gene and percentages of tumor-specific CD8(+) T cells were also the highest in the combination of WT CD8+ T cells and WSX-1(-/-) DCs. It was thus revealed that IL-27 promotes CTL generation while suppressing DC function during generation of tumor immunity. The combination of WT T cells and IL-27 signal-defective DCs may have therapeutic potential against tumors.
- Published
- 2009
79. Role of the Cytokine Profiles Produced by Invariant Natural Killer T Cells in the Initial Phase of Cyclophosphamide-Induced Tolerance
- Author
-
Yasunobu Yoshikai, Shinji Okano, I Shimizu, Tatsushi Onzuka, Ryuji Tominaga, Yukihiro Tomita, and Hisakata Yamada
- Subjects
medicine.medical_treatment ,Galactosylceramides ,Biology ,Immune tolerance ,Interferon-gamma ,Mice ,Chimera (genetics) ,Immune Tolerance ,medicine ,Animals ,Interferon gamma ,Cyclophosphamide ,Interleukin 4 ,Immunosuppression Therapy ,Mice, Knockout ,Mice, Inbred BALB C ,Transplantation ,Dose-Response Relationship, Drug ,Chimera ,Skin Transplantation ,Natural killer T cell ,Interleukin-10 ,Interleukin 10 ,Tolerance induction ,Cytokine ,Mice, Inbred DBA ,Immunology ,Natural Killer T-Cells ,Interleukin-4 ,Immunosuppressive Agents ,Spleen ,medicine.drug - Abstract
Background Cyclophosphamide (CP)-induced tolerance is a mixed chimerism-based tolerance induction protocol. Recently, we reported that invariant natural killer T (iNKT) cells were essential for the tolerance induction in this system. In this study, we evaluated the roles of the cytokines produced by iNKT cells. Methods DBA/2 (H-2d) mice and BALB/c (H-2d) wild-type (WT) or iNKT knock out (KO) mice were used as donors and recipients. WT recipients received three doses (days -7, -4, -1 or 35, 38, 41) or a single dose (day -1 or 0) of alpha-galactosylceramide (GC) in conjunction with our conditioning regimen that consisted of 10(8) donor spleen cells on day 0 and 200 mg/kg CP on day 2. To investigate the iNKT cell function, iNKT KO recipients were reconstituted with cytokine (interferon-gamma, interleukin [IL]-4, or IL-10) KO iNKT cells and received donor spleen cells and CP. Results Mixed chimerism was observed in WT recipients, but was reduced in iNKT KO recipients. However, mixed chimerism was absent in WT recipients given GC on days -7, -4, -1, but not in WT recipients given GC on day 35, 38, 41. Donor skin grafts were chronically rejected when mixed chimerism was diminished. Skin grafts were accepted in iNKT KO recipients reconstituted with iNKT cells from interferon-gamma, IL-4, or IL-10 KO mice and receiving our conditioning regimen. Conclusions Invariant NKT cells were required in the initial phase of the induction of chimerism. Our results indicated that known major cytokines produced by iNKT cells were dispensable for the regulatory function of iNKT cells.
- Published
- 2008
80. A Novel Role of CD30L/CD30 Signaling by T-T Cell Interaction in Th1 Response against Mycobacterial Infection
- Author
-
Yasunobu Yoshikai, Ce Tang, Kensuke Shibata, Worawidh Wajjwalku, Hiromi Muta, Eckhard R. Podack, and Hisakata Yamada
- Subjects
T cell ,CD3 ,Immunology ,Cell ,Ki-1 Antigen ,Spleen ,Cell Communication ,Interferon-gamma ,Mice ,Interleukin 21 ,T-Lymphocyte Subsets ,Cell Line, Tumor ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,Genetic Predisposition to Disease ,Tuberculosis, Pulmonary ,Cells, Cultured ,Mice, Knockout ,Mice, Inbred BALB C ,Mycobacterium Infections ,biology ,CD44 ,Th1 Cells ,Mycobacterium bovis ,Virology ,Molecular biology ,Coculture Techniques ,Mice, Inbred C57BL ,medicine.anatomical_structure ,biology.protein ,CD30 Ligand ,CD8 ,Signal Transduction - Abstract
A CD30 ligand (CD30L, CD153) is a type II membrane-associated glycoprotein belonging to the TNF family. To illustrate the potential role of CD30L in CD4(+) Th1 cell responses, we investigated the fate of Ag-specific CD4(+) T cells in CD30L-deficient (CD30L(-/-)) mice after Mycobacterium bovis bacillus Calmette-Guérin (BCG) infection. The number of bacteria was significantly higher in organs of CD30L(-/-) mice than in wild-type (WT) mice 4 wk postinfection. The numbers of purified protein derivative- or Ag85B-specific-IFN-gamma-producing-CD4(+) T cells in spleen, lung, or peritoneal exudate cells were significantly fewer in CD30L(-/-) mice than in WT mice. During the infection, CD30L was expressed mainly by CD44(+)CD3(+)CD4(+) T cells but not by CD3(+)CD8(+) T cells, B cells, dendritic cells, or macrophages. Costimulation with agonistic anti-CD30 mAb or coculturing with CD30L-transfected P815 cells restored IFN-gamma production by CD4(+) T cells from BCG-infected CD30L(-/-) mice. Coculturing with CD30L(+/+)CD4(+) T cells from BCG-infected WT mice also restored the number of IFN-gamma(+)CD30L(-/-)CD4(+) T cells. When transferred into the CD30L(+/+) mice, Ag-specific donor CD30L(-/-) CD4(+) T cells capable of producing IFN-gamma were restored to the compared level seen in CD30L(+/+) CD4(+) T cells on day 10 after BCG infection. When naive CD30L(+/+) T cells were transferred into CD30L(-/-) mice, IFN-gamma-producing-CD4(+) Th1 cells of donor origin were normally generated following BCG infection, and IFN-gamma-producing-CD30L(-/-)CD4(+) Th1 cells of host origin were partly restored. These results suggest that CD30L/CD30 signaling executed by CD30(+) T-CD30L(+) T cell interaction partly play a critical role in augmentation of Th1 response capable of producing IFN-gamma against BCG infection.
- Published
- 2008
81. The Cytokine RANKL Produced by Positively Selected Thymocytes Fosters Medullary Thymic Epithelial Cells that Express Autoimmune Regulator
- Author
-
Izumi Ohigashi, Yu Hikosaka, Yoshio Hayashi, Yoshifumi Yokota, Hisakata Yamada, Yasunobu Yoshikai, Naozumi Ishimaru, Taishin Akiyama, Yousuke Takahama, Takeshi Nitta, Hiroshi Takayanagi, Mitsuru Matsumoto, Jun-ichiro Inoue, Josef M. Penninger, Kouta Yano, and Koichi Matsuo
- Subjects
musculoskeletal diseases ,medicine.medical_specialty ,Medullary cavity ,medicine.medical_treatment ,Immunology ,RANK Ligand ,Biology ,Autoimmune regulator ,Cell biology ,Infectious Diseases ,Cytokine ,Endocrinology ,Osteoprotegerin ,CELLIMMUNO ,RANKL ,Internal medicine ,medicine ,biology.protein ,Immunology and Allergy ,Central tolerance ,MOLIMMUNO ,Gene - Abstract
SummaryThe thymic medulla provides a microenvironment where medullary thymic epithelial cells (mTECs) express autoimmune regulator and diverse tissue-restricted genes, contributing to launching self-tolerance. Positive selection is essential for thymic medulla formation via a previously unknown mechanism. Here we show that the cytokine RANK ligand (RANKL) was produced by positively selected thymocytes and regulated the cellularity of mTEC by interacting with RANK and osteoprotegerin. Forced expression of RANKL restored thymic medulla in mice lacking positive selection, whereas RANKL perturbation impaired medulla formation. These results indicate that RANKL produced by positively selected thymocytes is responsible for fostering thymic medulla formation, thereby establishing central tolerance.
- Published
- 2008
82. Th1 but not Th17 cells predominate in the joints of patients with rheumatoid arthritis
- Author
-
Yasunobu Yoshikai, Hisakata Yamada, Yukihide Iwamoto, Ken Okazaki, Taro Mawatari, Jun Ichi Fukushi, Nobutaka Kaibara, Yasuharu Nakashima, and Akiko Hori
- Subjects
Adult ,Male ,Immunology ,Arthritis ,Severity of Illness Index ,General Biochemistry, Genetics and Molecular Biology ,Arthritis, Rheumatoid ,Interferon-gamma ,Interleukin 21 ,Rheumatology ,T-Lymphocyte Subsets ,Humans ,Immunology and Allergy ,Medicine ,Synovial fluid ,Cells, Cultured ,Interleukin 4 ,Aged ,Aged, 80 and over ,business.industry ,Interleukin-17 ,Synovial Membrane ,hemic and immune systems ,T-Lymphocytes, Helper-Inducer ,Middle Aged ,Th1 Cells ,medicine.disease ,medicine.anatomical_structure ,Antirheumatic Agents ,Leukocytes, Mononuclear ,Interleukin 12 ,Female ,Tumor necrosis factor alpha ,IL17A ,Synovial membrane ,business - Abstract
Objectives: Recent animal studies have revealed critical roles of interleukin (IL)17, which is produced by a newly identified subset of helper T cells, Th17 cells, in the development of autoimmune diseases including arthritis. However, in human rheumatoid arthritis (RA), detailed characteristics and the prevalence of Th17 cells are unclear. Methods: Peripheral blood mononuclear cells (PBMC) were obtained from 123 patients with RA and 28 healthy controls. Mononuclear cells were also prepared from synovial membrane or synovial fluid of 12 patients with RA. IL17 (IL17A) positive T cells were identified by a flow cytometer after ex vivo stimulation with phorbol myristate acetate and ionomycin. Disease activity was assessed with the 28-joint Disease Activity Score (DAS28). Results: IL17 positive cells were detected in CD45RO+ CD4 T cells. Most IL17 positive T cells produced neither interferon (IFN)γ nor IL4, but tumour necrosis factor (TNF)α similar to murine Th17 cells. The frequency of Th17 cells was neither increased in RA nor correlated with DAS28. Unexpectedly, the frequency of Th17 cells was significantly decreased in the joints compared with PBMC of the same patients with RA, whereas Th1 cells were more abundant in the joints than in PBMC. Conclusions: We could not obtain evidence that positively supports predominance of Th17 cells in RA. Further careful investigation is necessary before clinical application of IL17-targeting therapy.
- Published
- 2007
83. IL-15 exacerbates collagen-induced arthritis with an enhanced CD4+ T cell response to produce IL-17
- Author
-
Hisakata Yamada, Yasunobu Yoshikai, Akiko Hori, Toshiki Yajima, Kazufumi Yoshihara, and Chiharu Kubo
- Subjects
CD4-Positive T-Lymphocytes ,Male ,musculoskeletal diseases ,medicine.medical_specialty ,Immunology ,Epitopes, T-Lymphocyte ,Arthritis ,Mice, Transgenic ,Biology ,Lymphocyte Activation ,medicine.disease_cause ,Autoimmunity ,Pathogenesis ,Mice ,Internal medicine ,medicine ,Animals ,Immunology and Allergy ,Collagen Type II ,Cells, Cultured ,Interleukin-15 ,Mice, Knockout ,Cd4 t cell ,Interleukin-17 ,medicine.disease ,Arthritis, Experimental ,In vitro ,Mice, Inbred C57BL ,Endocrinology ,Interleukin 15 ,Rheumatoid arthritis ,Interleukin 17 - Abstract
IL-15 is thought to be involved in the pathogenesis of rheumatoid arthritis (RA). We found that IL-15 plays an important role in the development of murine collagen-induced arthritis (CIA). The incidence and severity of CIA were slightly decreased in IL-15 KO mice but were increased in IL-15 Tg mice compared with wild-type (WT) mice. The levels of type II collagen (CII)-specific IL-17 production were significantly increased in IL-15 Tg mice compared with WT mice with CIA. Expression of IL-23R was up-regulated in CD4(+) T cells in IL-15 Tg mice but down-regulated in IL-15 KO mice compared with WT mice. In correlation with the expression levels of IL-23R, IL-17 production by CD4(+) T cells in response to exogenous IL-23 was increased in IL-15 Tg mice compared with WT mice. Furthermore, exogenous IL-15 synergized with IL-23 to induce CII-specific IL-17 production by CD4(+) T cells in vitro. Taken together, these results indicate that IL-15 plays an important role in the progression of CIA through increasing antigen-specific IL-17 production by CD4(+) T cells.
- Published
- 2007
84. Interleukin-15 selectively expands CD57+CD28−CD4+ T cells, which are increased in active rheumatoid arthritis
- Author
-
Takeshi Maeda, Nobutaka Kaibara, Yukihide Iwamoto, Yasuharu Nakashima, Shinji Okano, Toshihide Shuto, Hisakata Yamada, and Ken Okazaki
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Male ,Adolescent ,medicine.medical_treatment ,Immunology ,chemical and pharmacologic phenomena ,Lymphocyte Activation ,Arthritis, Rheumatoid ,TCIRG1 ,Interleukin 21 ,CD57 Antigens ,CD28 Antigens ,Humans ,Immunology and Allergy ,Medicine ,Cytotoxic T cell ,IL-2 receptor ,Cells, Cultured ,Aged ,Cell Proliferation ,Interleukin-15 ,Tumor Necrosis Factor-alpha ,business.industry ,ZAP70 ,CD28 ,hemic and immune systems ,Middle Aged ,Molecular biology ,Cytokine ,Interleukin 15 ,Female ,business - Abstract
Proinflammatory cytokines as well as CD4(+) T cells play critical roles in the pathogenesis of rheumatoid arthritis (RA). Recently, an increase of CD57(+) or CD28(-)CD4(+) T cells was demonstrated in RA, although the mechanism of the increase of these T cells is unclear. In this study, we first examined the relationship between CD57(+)CD4(+) T cells and CD28(-)CD4(+) T cells and found CD57(+)CD28(-)CD4(+) T cells, but neither CD57(+)CD28(+) nor CD57(-)CD28(+) cells, expanded in the peripheral blood of active RA. In vitro experiments revealed that CD57(+)CD28(-)CD4(+) T cells selectively expanded in response to IL-15. Furthermore IL-15-stimulated CD57(+)CD28(-)CD4(+) T cells induced TNF-alpha production from monocytes. These results suggest that CD57(+)CD28(-)CD4(+) T cells are involved in the pathogenesis of RA by responding to IL-15.
- Published
- 2007
85. H2-M3-Restricted CD8+ T Cells Induced by Peptide-Pulsed Dendritic Cells Confer Protection against Mycobacterium tuberculosis
- Author
-
Toshiki Yajima, Worawidh Wajjwalku, Takehiko Doi, Yasunobu Yoshikai, Hisakata Yamada, and Toshiro Hara
- Subjects
Immunology ,Bone Marrow Cells ,Spleen ,Peptide ,CD8-Positive T-Lymphocytes ,Mycobacterium tuberculosis ,Mice ,MHC class I ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,Tuberculosis, Pulmonary ,chemistry.chemical_classification ,Antigens, Bacterial ,biology ,Histocompatibility Antigens Class I ,Vaccination ,Dendritic Cells ,Dendritic cell ,biology.organism_classification ,Molecular biology ,medicine.anatomical_structure ,Immunization ,chemistry ,biology.protein ,Female ,Peptides ,CD8 - Abstract
One of the oligopolymorphic MHC class Ib molecules, H2-M3, presents N-formylated peptides derived from bacteria. In this study, we tested the ability of an H2-M3-binding peptide, TB2, to induce protection in C57BL/6 mice against Mycobacterium tuberculosis. Immunization with bone marrow-derived dendritic cell (BMDC) pulsed with TB2 or a MHC class Ia-binding peptide, MPT64190–198 elicited an expansion of Ag-specific CD8+ T cells in the spleen and the lung. The number of TB2-specific CD8+ T cells reached a peak on day 6, contracted with kinetics similar to MPT64190–198-specific CD8+ T cells and was maintained at an appreciable level for at least 60 days. The TB2-specific CD8+ T cells produced less effector cytokines but have stronger cytotoxic activity than MPT64190–198-specific CD8+ T cells. Mice immunized with TB2-pulsed BMDC as well as those with MPT64190–198-pulsed BMDC showed significant protection against an intratracheal challenge with M. tuberculosis H37Rv. However, histopathology of the lung in mice immunized with TB2-pulsed BMDC was different from mice immunized with MPT64190–198-pulsed BMDC. Our results suggest that immunization with BMDC pulsed with MHC class Ib-restricted peptides would be a useful vaccination strategy against M. tuberculosis.
- Published
- 2007
86. Requirement of CD30 expression on CD4 T cells in the pathogenesis of experimental autoimmune encephalomyelitis
- Author
-
Xun Sun, Jun Ichi Kira, Hisakata Yamada, Akiko Oyamada, Yasunobu Yoshikai, and Koji Shinoda
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,Encephalomyelitis, Autoimmune, Experimental ,Time Factors ,CD30 ,Immunology ,Ki-1 Antigen ,Biology ,Tritium ,03 medical and health sciences ,Interleukin 21 ,Mice ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,IL-2 receptor ,Mice, Knockout ,integumentary system ,Dose-Response Relationship, Drug ,ZAP70 ,Experimental autoimmune encephalomyelitis ,Th1 Cells ,medicine.disease ,Flow Cytometry ,Peptide Fragments ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Spinal Cord ,Cancer research ,Interleukin 12 ,Cytokines ,Th17 Cells ,Myelin-Oligodendrocyte Glycoprotein ,Neurology (clinical) ,Bone marrow ,030215 immunology ,Thymidine - Abstract
CD30, a member of the tumor necrosis factor receptor superfamily, is expressed preferentially by effector or memory helper T cells. Here we show that experimental autoimmune encephalomyelitis (EAE) is ameliorated with markedly reduced induction of antigen-specific Th1 and Th17 cells in CD30 knockout mice. Passive EAE indicated that CD30 on non-hematopoietic parenchymal cell is not required and mixed bone marrow chimera experiments revealed that CD30 signaling on CD4 T cells amplified the development of antigen-specific and encephalitogenic CD4 T cells. Thus, CD30 expression on CD4 T cells is critically involved in the pathogenesis of central nervous system autoimmunity.
- Published
- 2015
87. Outcome of Joint-Preserving Arthroplasty for Rheumatoid Forefoot Deformities
- Author
-
Taro Mawatari, Akiko Oyamada, Jun Ichi Fukushi, Yukio Akasaki, Masanobu Ohishi, Yukihide Iwamoto, Ken Okazaki, Hisakata Yamada, and Yasuharu Nakashima
- Subjects
musculoskeletal diseases ,Male ,Metatarsophalangeal Joint ,medicine.medical_specialty ,medicine.medical_treatment ,Pharmacological management ,Arthrodesis ,Arthroplasty ,Arthritis, Rheumatoid ,03 medical and health sciences ,0302 clinical medicine ,Resection arthroplasty ,medicine ,Humans ,Orthopedics and Sports Medicine ,Aged ,Pain Measurement ,Retrospective Studies ,030203 arthritis & rheumatology ,030222 orthopedics ,business.industry ,Foot Deformities, Acquired ,Forefoot ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Surgery ,Patient Satisfaction ,Rheumatoid arthritis ,Physical therapy ,Female ,business - Abstract
Background: Along with the recent advances in the pharmacological management of rheumatoid arthritis, there is a trend toward the use of joint-preserving surgery in the treatment of rheumatoid forefoot deformities. However, the clinical outcomes of joint-preserving surgery for rheumatoid forefoot deformities have not been assessed in comparison to resection arthroplasty. Methods: We retrospectively evaluated 23 feet in 17 patients with rheumatoid forefoot deformities who underwent surgery between January 2010 and December 2013. The patients included 1 male (1 foot) and 16 females (22 feet), with a mean age of 62 years. The mean length of follow-up was 28 months. The patients were treated by 3 surgeons. One surgeon performed joint-preserving procedures (JP group) to the feet in which (1) no pain with motion existed, and (2) the range of motion in the first metatarsophalangeal (MTP) joint was greater than 30 degrees (n = 10); otherwise, resection arthroplasty with arthrodesis of the first MTP joint was performed (n = 3). The other surgeons performed resection arthroplasty in all cases (n = 10) (RA group, n = 13 in total). The clinical outcomes of the patients were evaluated using the Japanese Society for Surgery of the Foot (JSSF) hallux and lesser toe scales. Results: There were no significant differences in the preoperative total JSSF scores for either the hallux (54.5 and 61.4 points) or the lesser toe (45.2 and 57.4 points) between the RA and JP groups, respectively. Postoperatively, the total JSSF scores for both the hallux (79.4 and 88.2 points) and lesser toes (73.6 and 87.7 points) showed significant improvement in both the RA and JP groups, respectively; however, the JP group showed a greater postoperative improvement. The scores relating to the function category on the hallux scale and the alignment category on the lesser toe scale were significantly higher in the JP group. Conclusion: With regard to the function of the hallux and the alignment of the lesser toes, the joint-preserving procedures for rheumatoid forefoot deformities resulted in better clinical outcomes than resection arthroplasty. Level of Evidence: Level III, comparative case series.
- Published
- 2015
88. Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes
- Author
-
Daiki Miyakawa, Yoshiyuki Niho, Akari Inada, Kanako Hirakawa, Miho Teshima, Shuji Fujimoto, Yuji Kai, Shuichiro Ogawa, Hitoshi Katsuta, Seiho Nagafuchi, Kazuya Shimoda, Keiichiro Mine, Hiroko Minagawa, Kenichi Izumi, Yoshitaka Inoue, Hisakata Yamada, Hironori Kurisaki, Yasunobu Yoshikai, Teruo Yamashita, Toshinobu Kurafuji, Koichi Akashi, Takashi Kobayashi, Keisuke Ina, Haruka Ikeda, Manami Hara, and Keizo Anzai
- Subjects
Mutant ,Gene Expression ,General Physics and Astronomy ,Mice, Inbred Strains ,Biology ,Gene mutation ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,Virus ,Diabetes Mellitus, Experimental ,Mice ,Interferon ,Insulin-Secreting Cells ,Gene expression ,Cardiovirus Infections ,medicine ,Animals ,Genetic Predisposition to Disease ,RNA, Messenger ,Encephalomyocarditis virus ,Gene ,Mice, Knockout ,TYK2 Kinase ,Mutation ,Multidisciplinary ,General Chemistry ,Virology ,Molecular biology ,Mice, Inbred C57BL ,Tyrosine kinase 2 ,Interferon Type I ,medicine.drug - Abstract
Accumulating evidence suggests that viruses play an important role in the development of diabetes. Although the diabetogenic encephalomyocarditis strain D virus induces diabetes in restricted lines of inbred mice, the susceptibility genes to virus-induced diabetes have not been identified. We report here that novel Tyrosine kinase 2 (Tyk2) gene mutations are present in virus-induced diabetes-sensitive SJL and SWR mice. Mice carrying the mutant Tyk2 gene on the virus-resistant C57BL/6 background are highly sensitive to virus-induced diabetes. Tyk2 gene expression is strongly reduced in Tyk2-mutant mice, associated with low Tyk2 promoter activity, and leads to decreased expression of interferon-inducible genes, resulting in significantly compromised antiviral response. Tyk2-mutant pancreatic β-cells are unresponsive even to high dose of Type I interferon. Reversal of virus-induced diabetes could be achieved by β-cell-specific Tyk2 gene expression. Thus, reduced Tyk2 gene expression in pancreatic β-cells due to natural mutation is responsible for susceptibility to virus-induced diabetes., Diabetes can be caused by viral infections in humans and some inbred mice, suggesting genetic predisposition. Here the authors show that mutations in Tyk2 gene underlie susceptibility to virus-induced diabetes in mice, due to Tyk2 requirement for antiviral response in insulin-producing cells.
- Published
- 2015
89. Prevalence of dyslipidemia in Japanese patients with rheumatoid arthritis and effects of atorvastatin treatment
- Author
-
Ken Okazaki, Yasuharu Nakashima, Chinami Hashimura, Jun Ichi Fukushi, Yukihide Iwamoto, Taro Mawatari, Junji Kishimoto, Masakazu Kondo, Mio Akiyama, Hisaaki Miyahara, and Hisakata Yamada
- Subjects
Male ,medicine.medical_specialty ,Atorvastatin ,Population ,Gastroenterology ,Efficacy ,Arthritis, Rheumatoid ,chemistry.chemical_compound ,Rheumatology ,Asian People ,Japan ,Risk Factors ,Internal medicine ,medicine ,Humans ,education ,Triglycerides ,Aged ,Dyslipidemias ,Retrospective Studies ,education.field_of_study ,biology ,Cholesterol ,business.industry ,Cholesterol, HDL ,nutritional and metabolic diseases ,General Medicine ,Cholesterol, LDL ,Middle Aged ,medicine.disease ,Prognosis ,Endocrinology ,Logistic Models ,Treatment Outcome ,chemistry ,Rheumatoid arthritis ,HMG-CoA reductase ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Female ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business ,Dyslipidemia ,medicine.drug - Abstract
Few studies have examined dyslipidemia in patients with rheumatoid arthritis (RA), especially in Japanese cohorts. The aims of this study were to investigate the lipid profiles of RA patients, to assess the relationships between lipid profiles and RA activity and treatment, and to elucidate the effects of HMG-CoA reductase inhibitors (statins) in Japanese patients with RA. A multicenter observational study was conducted in 488 patients with RA. Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels, and RA activity as assessed by disease activity score 28 (DAS28), and treatment for RA were analyzed retrospectively. In statin-treated patients, drug efficacy was also analyzed. The prevalence of hyper LDL-C, hyper TG, and hypo HDL-C were 29.3, 24.2, and 10.2 %, respectively, and the overall prevalence of dyslipidemia was 56.5 %. The level of HDL-C was inversely correlated with DAS28. Patients treated with low-dose glucocorticoids showed significantly higher levels of HDL-C and lower TC/HDL-C ratios compared with patients not receiving glucocorticoid treatment. Conversely, patients treated with biologic agents showed significantly higher levels of LDL-C, lower levels of HDL-C, and higher TC/HDL-C ratios. Atorvastatin significantly improved lipid profiles after a few months of treatment. The prevalence of dyslipidemia in Japanese patients with RA is higher than that in the non-RA population. Our result suggests that controlling RA disease activity might improve lipid profiles and eventually lower cardiovascular risk. Low-dose atorvastatin was effective for treatment of dyslipidemia in RA patients but had no apparent effect on RA disease activity.
- Published
- 2015
90. Pristane, a Non-Antigenic Adjuvant, Induces MHC Class II-Restricted, Arthritogenic T Cells in the Rat
- Author
-
Jonatan Tuncel, Shemin Lu, Hisakata Yamada, Jens Holmberg, Peter Olofsson, and Rikard Holmdahl
- Subjects
CD4-Positive T-Lymphocytes ,Male ,Receptors, Antigen, T-Cell, alpha-beta ,Immunology ,CD1 ,Arthritis ,Biology ,Lymphocyte Activation ,Interferon-gamma ,Adjuvants, Immunologic ,Antigen ,Animals, Congenic ,T-Lymphocyte Subsets ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,MHC class II ,Terpenes ,Tumor Necrosis Factor-alpha ,Histocompatibility Antigens Class II ,Rats, Inbred Strains ,MHC restriction ,medicine.disease ,Adoptive Transfer ,Arthritis, Experimental ,In vitro ,Rats ,Disease Models, Animal ,biology.protein ,Syngenic ,Female - Abstract
Pristane-induced arthritis (PIA) in rats, a model for rheumatoid arthritis (RA), is a T cell-dependent disease. However, pristane itself is a lipid and unable to form a stable complex with a MHC class II molecule. Therefore, the specificity and function of the T cells in PIA are as unclear as in rheumatoid arthritis. In this study, we show that activated CD4+ αβT cells, which target peripheral joints, transfer PIA. The pristane-primed T cells are of oligo or polyclonal origin as determined by their arthritogenicity after stimulation with several mitogenic anti-TCRVβ and anti-TCRVα mAbs. Arthritogenic cells secreted IFN-γ and TNF-α (but not IL-4) when stimulated with Con A in vitro, and pretreatments of recipient rats with either anti-IFN-γ or a recombinant TNF-α receptor before transfer ameliorated arthritis development. Most importantly, we show that these T cells are MHC class II restricted, because treatment with Abs against either DQ or DR molecules ameliorates arthritis development. The MHC class II restriction was confirmed by transferring donor T cells to irradiated recipients that were syngenic, semiallogenic, or allogenic to MHC class II molecules, in which only syngenic and semiallogenic recipients developed arthritis. These data suggest that the in vivo administration of a non-antigenic adjuvant, like pristane, activates CD4+ αβT cells that are MHC class II restricted and arthritogenic.
- Published
- 2006
91. A genome-wide analysis identifies a notch-RBP-Jκ-IL-7Rα axis that controls IL-17-producing γδ T cell homeostasis in mice
- Author
-
Masataka Nakamura, Kensuke Shibata, Yasunobu Yoshikai, Yasuyuki Ohkawa, Hisakata Yamada, Tetsuya Sato, Koichi Ikuta, and Shinya Hatano
- Subjects
T cell ,Receptors, Antigen, T-Cell, alpha-beta ,T-Lymphocytes ,Immunology ,Regulator ,Notch signaling pathway ,Biology ,Antibodies ,Interferon-gamma ,Mice ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Immunology and Allergy ,Animals ,Homeostasis ,HES1 ,Receptor, Notch1 ,Gene ,Cell Proliferation ,Homeodomain Proteins ,Mice, Knockout ,Receptors, Interleukin-7 ,Interleukin-7 ,Interleukin-17 ,Receptors, Antigen, T-Cell, gamma-delta ,In vitro ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Immunoglobulin J Recombination Signal Sequence-Binding Protein ,Transcription Factor HES-1 ,Interleukin 17 ,Genome-Wide Association Study ,Signal Transduction - Abstract
Notch signaling is an important regulator for the development and function of both αβ and γδ T cells, whereas roles of Notch signaling in T cell maintenance remain unclear. We reported previously that the Notch–Hes1 pathway was involved in the intrathymic development of naturally occurring IL-17–producing (IL-17+) γδ T cells. To gain insight into additional roles for the Notch axis in the homeostasis of γδ T cells, we performed a genome-wide analysis of Notch target genes and identified the novel promoter site of IL-7Rα driven by the Notch–RBP-Jκ pathway. Constitutive Notch signaling had the potential to induce IL-7Rα expression on γδ T cells in vivo, as well as in vitro, whereas conditional deletion of RBP-Jκ abrogated IL-7Rα expression, but not Hes1 expression, by γδ T cells and selectively reduced the pool size of IL-7Rαhigh IL-17+ γδ T cells in the periphery. In the absence of IL-7Rα–mediated signaling, IL-17+ γδ T cells were barely maintained in adult mice. Addition of exogenous IL-7 in vitro selectively expanded IL-17+ γδ T cells. Thus, our results revealed a novel role for the Notch–RBP-Jκ–IL-7Rα axis that is independent of Hes1 for homeostasis of IL-17+ γδ T cells.
- Published
- 2014
92. Cutting Edge: B Cells Expressing Cyclic Citrullinated Peptide-Specific Antigen Receptor Are Tolerized in Normal Conditions.
- Author
-
Yasunobu Yoshikai, Hisakata Yamada, Seiji Okada, Yasuharu Nakashima, Tatsuhiko Ozawa, Hiroyuki Kishi, and Atsushi Muraguchi
- Abstract
Generation of neoantigens by citrullination is implicated in the production of anti-citrullinated protein Abs in rheumatoid arthritis, but citrullination is also a physiological process. To verify whether citrullin-specific B cells are immunologically ignorant or tolerant in normal conditions, transgenic (Tg) mice expressing IgM with the V region of an anti-cyclic citrullinated peptide (CCP) mAb cloned from a rheumatoid arthritis patient were generated. CCP-specific B cells developed in the anti-CCP IgM Tg mice with an alteration of bone marrow B cell fractions, and the number of mature B cells decreased compared with wild-type or the control anti-influenza nucleoprotein-specific IgM Tg mice. In addition, B cells in anti-CCP IgM Tg mice are functionally anergic. Thus, tolerance is induced in CCP-specific B cells in vivo, suggesting that the immune systems are naturally exposed to citrullinated Ags, and anti-CCP Ab production requires additional steps beyond the generation of neoantigens by citrullination. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
93. The molecular pathogenesis of collagen-induced arthritis in mice—a model for rheumatoid arthritis
- Author
-
Rikard Holmdahl, Hisakata Yamada, Robert Bockermann, and Johan Bäcklund
- Subjects
musculoskeletal diseases ,Aging ,T-Lymphocytes ,Genes, MHC Class II ,Type II collagen ,Arthritis ,Disease ,medicine.disease_cause ,Major histocompatibility complex ,Biochemistry ,Autoimmunity ,Arthritis, Rheumatoid ,Pathogenesis ,Mice ,Animals ,Humans ,Medicine ,Molecular Biology ,biology ,business.industry ,medicine.disease ,Disease Models, Animal ,Neurology ,Rheumatoid arthritis ,Immunology ,biology.protein ,Tumor necrosis factor alpha ,Collagen ,business ,Biotechnology - Abstract
The most widely used model for rheumatoid arthritis is the collagen-induced arthritis (CIA) in mice. This model has gained acceptance since it is reproducible, well defined and has proven useful for development of new therapies for rheumatoid arthritis, as exemplified by the most recent advancement using TNFalpha neutralization treatment. The collagen-induced arthritis model, however, represents only certain pathways leading to arthritis and there is no consensus on how they operate. Nevertheless, we are beginning to understand the immune recognition structures, such as MHC molecules, lymphocyte receptors and type II collagen epitopes, which are of crucial importance for the development of this disease. These provide useful tools for further investigations of the pathogenesis of CIA as well as for understanding the pathogenesis of rheumatoid arthritis.
- Published
- 2002
94. Involvement of CD4+,CD57+ T cells in the disease activity of rheumatoid arthritis
- Author
-
Yukihide Iwamoto, Ryuji Nagamine, Yasuharu Nakashima, Hisakata Yamada, Toshihide Shuto, Go Hirata, and Takeshi Maeda
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Health Status ,medicine.medical_treatment ,CD3 ,Immunology ,Antigen presentation ,Blood Sedimentation ,Arthritis, Rheumatoid ,Interferon-gamma ,CD57 Antigens ,Immune system ,Rheumatology ,Interferon ,Humans ,Immunology and Allergy ,Medicine ,Pharmacology (medical) ,Aged ,Aged, 80 and over ,medicine.diagnostic_test ,biology ,business.industry ,T lymphocyte ,Middle Aged ,Flow Cytometry ,Cytokine ,Erythrocyte sedimentation rate ,biology.protein ,Interleukin-4 ,business ,CD8 ,medicine.drug - Abstract
Objective To evaluate the relationship between the frequency of peripheral CD57+ T cells and the physical status of rheumatoid arthritis (RA) patients, and to perform cytokine analysis of these CD57+ T cells. Methods Four-color fluorescence-activated cell sorter analysis was performed to detect both cell surface antigens and intracellular cytokines in peripheral blood leukocytes, using monoclonal antibodies against CD3, CD4, CD8, CD57, interferon-γ (IFNγ), and interleukin-4 (IL-4). RA patients were clinically evaluated with a modified Health Assessment Questionnaire (M-HAQ), joint score, face scale, and visual analog scale (VAS) assessing pain and disease activity. Results There was a significant correlation between the frequency of CD4+,CD57+ T cells and erythrocyte sedimentation rate (ESR), whereas a correlation was not found between the frequency of CD8+,CD57+ T cells and ESR. The frequency of CD4+,CD57+ T cells also showed a significant correlation with the mHAQ score, VAS, and face scale. Again, there was no significant correlation between the above-mentioned clinical scores and the frequency of CD8+,CD57+ T cells. Flow cytometric analysis of intracellular cytokines revealed that 14.5% of the CD57+ T cells produced IFNγ, whereas only 2.8% of the CD57+ T cells produced IL-4 in RA patients. Conclusion Evidence showing that the frequency of CD4+,CD57+ T cells among CD3+ cells of RA patients had a significant correlation not only with ESR but also with the physical status of the patients, and that a large proportion of the CD4+,CD57+ T cells had the capacity to produce IFNγ, strongly suggests that these CD4+,CD57+ T cells are involved in the immunopathogenesis of RA.
- Published
- 2002
95. Th1 is the predominant helper T cell subset that produces GM-CSF in the joint of rheumatoid arthritis
- Author
-
Koji Sakuraba, Jun Ichi Fukushi, Masakazu Kondo, Hisakata Yamada, Hisaaki Miyahara, Yasuharu Nakashima, Kenjiro Fujimura, Hideki Mizu-uchi, Akihisa Haraguchi, Yasunobu Yoshikai, Yukio Akasaki, Ken Okazaki, Satoshi Kamura, and Yukio Esaki
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Immunology ,Rheumatoid Arthritis ,03 medical and health sciences ,Interleukin 21 ,0302 clinical medicine ,Rheumatology ,medicine ,Immunology and Allergy ,Macrophage ,Synovial fluid ,t cells ,030203 arthritis & rheumatology ,biology ,business.industry ,GATA3 ,medicine.disease ,cytokines ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Rheumatoid arthritis ,biology.protein ,Synovial membrane ,Antibody ,business - Abstract
Granulocyte macrophage colony-stimulating factor (GM-CSF), an immunomodulatory cytokine, is an emerging therapeutic target of rheumatoid arthritis (RA).1 Although GM-CSF is produced by various types of cells, including synovial fibroblasts, the importance of GM-CSF-producing CD4 T cells in the pathogenesis of RA was reported.2 Moreover, GM-CSF has been shown to be the critical effector cytokine produced by interleukin (IL)-23-stimulated Th17 cells in mice, leading to the prevailing notion that GM-CSF is a Th17-related cytokine.3 However, in humans, a distinct subset of CD4 T cells that produce only GM-CSF has recently been identified.4 The ‘GM-CSF-only’ T cells are characterised by the lack of lineage defining cytokines (interferon (IFN)-γ, IL-17 and IL-4) and are regulated independently of the master transcriptional regulators, T-bet, RORγt or GATA3. Furthermore, in contrast to mice, GM-CSF production by human CD4 T cells was promoted in Th1 conditions and was also detected in Th1 cells. At present, it is unclear which helper CD4 T cell subsets produce GM-CSF in human RA joints. Therefore, in this study, we performed multicolour flow cytometric analysis of cytokine production in CD4 T cells from patients with RA. Lymphocytes in the peripheral blood (PB) and in joints from the same patients were analysed to compare the profiles of cytokine production. Synovial fluid (SF) samples were obtained from seven patients by arthrocentesis, while synovial membrane (SM) samples were obtained from seven other patients who underwent joint replacement surgery. The mean age and disease duration of the patients was 63.5±15.5 and 16.5±10.1 years, respectively. Twelve patients (86%) were positive for RF and/or anti-CCP2 antibody, and the mean C reactive protein level was 1.2±1.1 mg/dL. In total, 11 (79%), 10 (71%) and 4 (29%) patients received …
- Published
- 2017
96. Brief report: successful in vitro culture of rheumatoid arthritis synovial tissue explants at the air-liquid interface
- Author
-
Koji, Sakuraba, Kenjiro, Fujimura, Yasuharu, Nakashima, Ken, Okazaki, Jun-ichi, Fukushi, Masanobu, Ohishi, Akiko, Oyamada, Yukio, Esaki, Hisaaki, Miyahara, Yukihide, Iwamoto, Yasunobu, Yoshikai, and Hisakata, Yamada
- Subjects
Arthritis, Rheumatoid ,Tissue Culture Techniques ,Mice ,Synovial Membrane ,Animals ,Humans ,Middle Aged ,Aged - Abstract
To establish a method to culture synovial tissue explants from patients with rheumatoid arthritis (RA).Synovial tissue explants obtained from 10 patients with RA were cultured at the air-liquid interface or were submerged in culture medium. As a control, synovial explants were engrafted subcutaneously into SCID mice. The synovial explants were harvested at different time points, and histologic or flow cytometric analysis was performed. Cytokine levels in the culture supernatants were measured by enzyme-linked immunosorbent assay. Infliximab was added to the air-liquid interface culture to evaluate the effect of tumor necrosis factor α blockade on inflammatory cytokine production.The histologic features of RA synovitis, including a hyperplastic lining layer and the presence of cellular infiltrate in the sublining layer, were maintained in synovial tissue explants in air-liquid interface culture. In synovial grafts harvested from SCID-HuRAg mice, the cellular infiltrate was well maintained in the sublining, but the lining layer was lost. Viable CD4+ T cells and macrophages were abundant after air-liquid interface culture but were virtually absent after submerged culture. Furthermore, synovial tissue explants in air-liquid interface culture produced interleukin-6 (IL-6) and IL-8 for a prolonged period of time. The addition of infliximab effectively reduced cytokine production.RA synovial explants can be maintained for weeks using an air-liquid interface culture. This simple culture system might be useful for analyzing the pathogenesis of RA synovitis and for developing antirheumatic drugs.
- Published
- 2014
97. Effects of adalimumab administration in bio-naïve and bio-switch rheumatoid arthritis patients in daily clinical practice : two-year results from single center
- Author
-
Yasutaka, Tashiro, Yasuharu, Nakashima, Ken, Okazaki, Taro, Mawatari, Jun-Ichi, Fukushi, Masanobu, Ohishi, Akiko, Oyamada, Hisakata, Yamada, and Yukihide, Iwamoto
- Subjects
Adult ,Male ,Time Factors ,Drug Substitution ,Injections, Subcutaneous ,Remission Induction ,Adalimumab ,Antibodies, Monoclonal ,Middle Aged ,Antibodies, Monoclonal, Humanized ,Infliximab ,Arthritis, Rheumatoid ,Methotrexate ,Treatment Outcome ,Antirheumatic Agents ,Humans ,Drug Therapy, Combination ,Arthrography ,Aged - Abstract
To investigate the impact of adalimumab on the biologic-naive (bio-naïve) and bio-switch rheumatoid arthritis (RA) patients, and to clarify the appropriate indications for adalimumab treatment.The retention rate, efficacy and safety of adalimumab in twenty-one RA patients were analyzed. Fourteen of the patients were bio-naive and seven were bio-switched from other biologics. Concomitant methotrexate was used in 85% of the bio-naive and 71% of the bio-switch patients. The radiographic findings before and after the 1 year and the two years treatment were also surveyed.In the bio-naive group, 63% of patients continued adalimumab for 2 years, and remission was achieved in approximately 50% of patients. The mean 28-joint Disease Activity Scores improved from 5.2 to 2.6. Radiographically, the joint damage did not progress in either erosions or joint space narrowing. In the bio-switch group, the retention rate was 29%, and only patients who were switched from infliximab showed responses to the treatment. Herpes zoster requiring hospitalization occurred in two cases and injection site reactions were noted in other two cases.Adalimumab combined with methotrexate would be a useful first choice biologic regimen in bio-naïve RA patients. As a second biologic, adalimumab could be useful only when treatments are switched from infliximab.
- Published
- 2014
98. CYCLOPHOSPHAMIDE-INDUCED TOLERANCE IN RAT ORTHOTOPIC LIVER TRANSPLANTATION1
- Author
-
Kenichi Nomoto, Masatoshi Eto, Kikuo Nomoto, Yukihiro Tomita, Hisakata Yamada, Tomoharu Yoshizumi, Ryosuke Minagawa, Shinji Okano, and Keizo Sugimachi
- Subjects
Interleukin 2 ,Transplantation ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Mixed lymphocyte reaction ,Immune tolerance ,Andrology ,medicine.anatomical_structure ,Immunology ,medicine ,Skin grafting ,Bone marrow ,business ,human activities ,Interleukin 4 ,medicine.drug - Abstract
BACKGROUND We previously established a cyclophosphamide (CP)-induced tolerance system in rodent skin graft models. In this study, we applied this system to rat liver transplantation. METHODS Lewis recipients were inoculated on day -2 with spleen and bone marrow cells (SC+BMC) from Dark Agouti (DA) donors, followed by 100 mg/kg CP on day 0. On day 25, DA livers were orthotopically grafted. We assessed the alloresponses to the donors of the long-term surviving recipients, using the second skin grafting and in vitro assay. RESULTS The recipients that had been treated with SC+BMC and CP survived for more than 165 days. None of control group that received SC+BMC alone (mean survival times [MST]=13.8 days), CP alone (MST=40.0), SC+BMC from third-party PVG rats and CP (MST=45.0), or no treatment (MST=13.8) survived over 50 days. The donor-specific tolerance was confirmed by second skin grafts onto recipients with permanent DA liver grafts, which accepted DA skins (MST>75) but not PVG (MST=8.3). However, the lymphocytes from the tolerant recipients showed alloresponse to DA in vitro. To investigate whether the T helper type 2 deviation contributed to this "split tolerance," we assessed the production of cytokines in mixed lymphocyte reaction. Interleukin 2 and interferon-gamma were detected but interleukin 4 was not. CONCLUSIONS These data showed that this protocol induced split tolerance in rat liver transplantation and, furthermore, the mechanism of split tolerance was not due to T helper 2 deviation.
- Published
- 2001
99. Persistent infection withListeria monocytogenesin the kidney induces anti-inflammatory invariant fetal-type γδ T cells
- Author
-
Hiroaki Takimoto, Kikuo Nomoto, T Nakamura, Hisakata Yamada, H. Ikebe, M. Nomoto, and K.-H. Sonoda
- Subjects
Kidney ,T cell ,Immunology ,T-cell receptor ,chemical and pharmacologic phenomena ,hemic and immune systems ,Inflammation ,Biology ,medicine.disease_cause ,Molecular biology ,stomatognathic diseases ,Peritoneal cavity ,medicine.anatomical_structure ,Listeria monocytogenes ,Antigen ,medicine ,Immunology and Allergy ,medicine.symptom ,Receptor - Abstract
After intraperitoneal inoculation with Listeria monocytogenes, gammadelta T cells appear in the peritoneal cavity preceding the appearance of alphabeta T cells. Such gammadelta T cells predominantly express T-cell receptor (TCR)Vgamma1/Vdelta6, develop through an extrathymic pathway, and contribute to host defence against the bacteria. We have observed a gradual increase in gammadelta T cells in kidneys of mice after intrarenal inoculation with L. monocytogenes, which resulted in an unusually long-lasting local infection. In this study, we examined the characteristics and the roles of the gammadelta T cells induced in this model. It was found that these gammadelta T cells predominantly expressed TCRVgamma6/Vdelta1 with canonical junctional sequences identical to those expressed on fetal thymocytes. Although depletion of such gammadelta T cells in vivo did not affect the number of bacteria, it resulted in histologically exacerbated inflammation in the kidneys. These results indicate that a persistent infection with L. monocytogenes in kidneys induces a different kind of gammadelta T cell from that induced after intraperitoneal infection. The former expresses invariant fetal-type Vgamma6/Vdelta1+TCR and plays a regulatory role in resolution of inflammation.
- Published
- 2001
100. Toll-like receptors, session 1 (WS-001a)
- Author
-
A. Watanabe, M. Colonna, Cevayir Coban, C. E. McCoy, X. Cao, Mitsuru Matsumoto, Shizuo Akira, Gabriel Núñez, F. Takeshita, A. Nishikimi, I. Matos, Yoshinori Fukui, Y. Igari, Mark J. Shlomchik, A. Salazar, Gerd-Rüdiger Burmester, C. Kluger, Zoltán Konthur, T. Häupl, R. Nakamura, Tsuneyasu Kaisho, P. Longhi, Tsukasa Seya, Katsuaki Hoshino, Karl Skriner, N. Li, Hisakata Yamada, Yasunobu Yoshikai, B. Marklein, Ralph M. Steinman, Luke A. J. O'Neill, K. Gotoh, Toshihiro Horii, M. Yagi, H. Liu, T. Tsukui, Kazunari Ishii, Yoshiya Tanaka, T. Reimer, C. Han, J. Idiyaga, J. Jin, Christine Trumpfheller, M. Caskey, and K. Ohata
- Subjects
biology ,Toll ,Immunology ,biology.protein ,Immunology and Allergy ,General Medicine ,Session (computer science) ,Psychology ,Receptor ,Neuroscience - Published
- 2010
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.