Hitoshi Kohsaka

RIKEN, Вако, Saitama, Japan

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Publications (144)535.98 Total impact

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    ABSTRACT: Objective: C protein-induced myositis (CIM) is a mouse model of polymyositis, in which activated antigen-specific CD8+ T cells injure the muscles. Autoimmune animal models examined in the past for the effects of type-1 and type-2 cytokines, interferon (IFN) -γ and interleukin (IL) -4, are all mediated by pathogenic CD4+ T cells. In those models, the disruption of IFNγ leads to upregulation of IL-17A, exacerbating the diseases with neutrophil infiltration into the inflammatory sites. The purpose of the study is to study the roles of IFN-γ and IL-4 as well as IL-17A in the absence of IFN-γ in the CD8 T cell-mediated CIM. Methods: IFNγ-null, anti-IL-17A antibody-treated IFNγ-null, IFNγ/IL-17A double-null, IL-4-null, and wild-type C57BL/6 mice were immunized with skeletal muscle C protein fragments to provoke CIM. The muscle tissues were examined histologically. Results: IFNγ-null mice developed myositis with the higher incidence and severity than wild-type mice. Unlike the wild-type mice, they had infiltration of neutrophils into the endomysial sites of the affected muscles. IFNγ-null mice treated with anti-IL-17A antibodies and IFNγ/IL-17A double-null mice developed myositis with the incidence and severity comparable to those of the IFNγ-null mice. Neutrophils infiltrated as in the IFNγ-null mice. IL-4-null mice developed CIM comparable to that of the wild-type mice. Conclusion: IFNγ but not IL-4 has a suppressive role in the development of CIM. Unlike CD4 T cell-mediated autoimmune disease models, IFNγ prevents factors other than IL-17A from exacerbating myositis and neutrophil infiltration. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Arthritis and Rheumatology
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    ABSTRACT: Synovial fibroblasts play crucial roles in inflammation and joint destruction in rheumatoid arthritis (RA). How they accumulate in the RA joints remains unclear. This study was conducted to discern whether cellular influx from the outside of the joints and local proliferation are responsible for synovial fibroblast accumulation in an animal model of RA. We found that synovial fibroblasts were identified as GFP+ cells using collagen type I alpha 2 (Col1a2)-GFP transgenic reporter mice. Then, bone marrow transplantation and parabiosis techniques were utilized to study the cellular influx. Irradiated wild-type mice were transplanted with bone marrow from Col1a2-GFP mice. Col1a2-GFP and wild-type mice were conjoined for parabiosis. The transplanted mice and the were subjected to collagen antibody-induced arthritis (CAIA). We found no GFP+ cells in the hyperplastic synovial tissues from the transplanted mice with CAIA and from the wild-type with CAIA. Furthermore, normal and CAIA synovial tissues from Col1a2-GFP mice and from fluorescent -based cell cycle indicator () transgenic mice, in which cells in S/G2/M phases of the cell cycle express -Green, were studied for Ki67, a cellular proliferation marker, and , a fibroblast marker, expression. The percentages of Ki67+/GFP+ and -Green+/+ cells in the CAIA synovial tissues were higher than those in the untreated synovial tissues (34% vs. 0.40% and 19% vs. 0.26%, respectively). These findings indicate that local fibroblast proliferation but not cellular influx is responsible for the synovial hyperplasia in CAIA. Suppression of proliferation of the local synovial fibroblasts should be a promising treatment for RA.
    No preview · Article · Jan 2016 · Biochemical and Biophysical Research Communications
  • Y Tagawa · T Saito · K Takada · K Kawahata · H Kohsaka
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    ABSTRACT: Systemic lupus erythematosus-related hepatitis, known as lupus hepatitis, is a rare manifestation of systemic lupus erythematosus, and is usually subclinical with mild abnormalities of serum liver enzymes. While cases with clinically significant and refractory lupus hepatitis are uncommon, treatment options for lupus hepatitis are to be established. Here, we report the case of a 45-year-old man with progressive lupus hepatitis accompanied by autoimmune haemolytic anaemia. Lupus hepatitis of this patient was refractory to tacrolimus, azathioprine and cyclophosphamide, but was successfully treated by mycophenolate mofetil. Mycophenolate mofetil might be an effective therapeutic option for refractory lupus hepatitis.
    No preview · Article · Jan 2016 · Lupus
  • Hirokazu Sasaki · Hayato Yamazaki · Hitoshi Kohsaka

    No preview · Article · Jan 2016 · The Journal of Rheumatology
  • Takumi Matsumoto · Tetsuya Saito · Hitoshi Kohsaka
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    ABSTRACT: Chronic myelomonocytic leukemia (CMML), a clonal hematopoietic stem cell disorder with myelodysplastic and myeloproliferative overlap feature, is frequently associated with autoimmune diseases, such as vasculitis, polyarthritis, and neutrophilic dermatosis. We herein report the first case of CMML complicated with spondyloarthritis (SpA). A 64-year-old female patient, admitted to our hospital with buttock pain alternating left and right, was found to have sacroiliitis and spondylitis by contrast magnetic resonance imaging (MRI). Peripheral blood test and bone marrow biopsy revealed an increase of monocytes with trilineage dysplasia. We made a diagnosis of CMML. Although arthritic symptoms and imaging findings initially improved by azacitidine, CMML was thereafter transformed into acute myeloid leukemia (AML). She is scheduled to hematopoietic stem cell transplantation. The concomitant onset of sacroiliitis with CMML suggested that her SpA feature was a paraneoplastic phenomenon of CMML. Thus, we must be aware that myelodysplastic syndrome (MDS) including CMML can manifest as SpA.
    No preview · Article · Sep 2015 · Modern Rheumatology
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    ABSTRACT: Objectives: This study aimed to investigate the clinical characteristics of polymyositis/dermatomyositis (PM/DM) in Japan by analyzing data from the nationwide registration system. Methods: The data of the registration system in 2009 were analyzed to investigate patient numbers, sex, clinical symptoms, therapies, complications and prognosis of PM/DM. Results: The total number of PM/DM cases was approximately 17,000, and the female/male sex ratio was 2.7:1. Almost all patients improved as a result of therapy, but many suffered from sequelae such as muscle weakness. Conclusions: The results characterize significant aspects of Japanese PM/DM patients. However, a further prospective survey is required to clarify the true epidemiology and natural history of PM/DM.
    No preview · Article · Sep 2015 · Modern Rheumatology
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    ABSTRACT: A 30-year-old woman had suffered from recurrent and self-limiting fevers since childhood. Although she had no mutations in the exons or introns of the tumor necrosis factor (TNF) receptor superfamily member 1A gene, her clinical characteristics were consistent with those of TNF receptor-associated periodic syndrome (TRAPS). She did not respond to treatment with etanercept, although tocilizumab therapy was successful, subsequently ameliorating her symptoms and preventing further inflammatory attacks. Interleukin-6 blocking therapy should be considered as a new alternative treatment in patients with TRAPS who do not respond to etanercept.
    Full-text · Article · Aug 2015 · Internal Medicine
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    ABSTRACT: Background Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction. MTX and biological DMARDs (bDMARDs) have revolutionized treatment of RA and clinical remission and structural remission are now realistic targets. However, we still experience patients with joint destruction by the retardation of appropriate treatments. Thereby, treatment strategy targeting structural remission in patients with early RA is prerequisite. Objectives The ZERO-J study (UMIN000001281) was undertaken to clarify strategic treatments that successfully reduce and stop joint destruction in ERA. Methods 162 patients who meet all of the following criteria were registered from 10: diagnosed with the 2010 ACR/EULAR criteria, MTX-naïve, ACPA-positive, disease duration <2Y (mean=7.4M) and bone erosion in hands and feet <3. The treatment was initialized with MTX 6-8 mg/w and the dose was increased by the maximum in each patient within 3M. At M3, if patients fulfilled DAS28(ESR) <3.2 and no new bone erosion, MTX was continued for further 1Y as high responders (HR group). If not, they were treated with the combination of MTX and TNF-inhibitors (TNFi group) or MTX and DMARDs (DMARDs group) for further 1Y. The primary end points at M15 were the mean changes from baseline in the Sharp-van der Heijde score (SHS). Results DAS28 (from 4.8 to 3.7), SDAI (20.4 to 12.2) and SHS (5.7 to 6.0) changed by MTX for 3 months (means 12.0 mg/w) and 151 patients were divided to 3 groups based on investigator and/or patient decision; TNFi-group (N=35, DAS28=5.6, SDAI=28.6 at M3), DMARDs-group (N=29, DAS28=4.0, SDAI=12.2) and HR-group (N=87, DAS28=2.8, SDAI=5.2). Thus, 58% of them were high responders to 3M-treatment with MTX. At M15, DAS28 (TNFi=2.7, DMARDs=2.9, HR=2.7) and SDAI (TNFi=5.5, DMARDs=5.9, HR=5.3) were comparable among groups (LOCF). However, changes in SHS from BL to M15 were significantly higher in TNFi group (1.0) than DMARDs group (0.7) and HR group (0.5), structural remission rate was observed significantly lower in a TNFi group (65%) than those in DMARDs group (74%) and HR-group (87%), and clinical relevant radiographic progression was observed in 6% of TNFi, 5% of DMARDs and 3% of HR-group. Conclusions About 60% of early RA patients were high responders to MTX within 3 months and structural as well as clinical remission was sustained for further 12 months in the majority of the HR group, indicating that bDMARDs may not be required to these MTX-HR patients. In contrast, less proportion of patient revealed structural remission in TNFi group, about 20% of ERA patients, 3-months retardation of intervention with bDMARDs resulted in progress in joint damages in the population. These results indicated that substantial proportions of patients have benefited from induction with MTX and bDMARDs to target joint damage to ZERO. Disclosure of Interest Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Chugai, MSD, Astellas, Novartis, Speakers bureau: Abbvie, Chugai, Astellas, Takeda, Santen, Mitsubishi-Tanabe, Pfizer, Janssen, Eisai, Daiichi-Sankyo, UCB, GlaxoSmithKline, Bristol-Myers, S. Hirata: None declared, K. Amano Grant/research support from: Astellas, Chugai, Pfizer, Tanabe-Mitsubishi, Paid instructor for: Chugai, Tanabe-Mitsubishi, Pfizer, Santen, Speakers bureau: AbbVie, Actellion, Astellas, Bristol-Myers-Squibb, Chugai, Diichi-Sankyo, Eisai, Pfizer, Tanabe-Mitsubishi, T. Atsumi Grant/research support from: Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Bristol-Myers Squibb Co., Astellas Pharma Inc., Daiichi Sankyo Co. Ltd., Mitsubishi Tanabe Pharma Co, Speakers bureau: Astellas Pharma Inc., Mitsubishi Tanabe Pharma Co., K. Yamamoto Grant/research support from: Astellas, AbbVie, Takeda, TEIJIN, Pfizer, Bristol-Myers, DAIICHI SANKYO, Mitsubishi-Tanabe, Chugai, Janssen, Eisai, Speakers bureau: Astellas, abbvie, Eisai, Pfizer, Bristol-Myers, Janssen, UCB, Asahi Kasei, Santen, ONO, Taisho Toyama, DAIICHI SANKYO, AstraZeneca, Chugai, TEIJIN PHARMA, Mitsubishi-Tanabe, Boehringer Ingelheim, Nippon Kayaku, Takeda, T. Sumida: None declared, T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., and Taisho Toyama Pharmaceutical Co., Ltd.,SymBio Pharmaceuticals Ltd., Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical K.K.,abbivie GK, Daiichi Sankyo Co.,Ltd., Bristol–Myers K.K., Nipponkayaku Co.Ltd., Paid instructor for: Mitsubishi Tanabe Pharma Co., Eisai Co., Ltd., Abbivie GK, Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Astellas Pharma, and Diaichi Sankyo Co.,Ltd., Celtrion, Nipponkayaku Co.Ltd, H. Kohsaka Grant/research support from: Mitsubishi Tanabe Pharma Corporation Takeda Pharmaceutical Company Limited Bristol-Myers Squibb Eisai Co.,Ltd. Teijin Pharma Limited Pfizer Inc. Actelion Pharmaceuticals Japan Ltd. Santen Pharmaceutical Co,.Ltd. Ono Pharmaceutical Co., Ltd. Daiichi Sankyo Company.,Limited. Nippon Kayaku Co.,Ltd. Abbie Inc. AstraZeneca plc., Paid instructor for: Teijin Pharma Limited Chugai Pharmaceutical Co., LTD., Speakers bureau: Mitsubishi Tanabe Pharma Corporation Takeda Pharmacentical Company Limite Abbie Inc. Ono Pharmaceutical Co.,LTD. UCB Japan Co. Ltd. Astellas Pharma Inc. Chugai Pharmaceutical Co.,LTD. Japan Blood Products Organization Asahi Kasei Corporation, T. Mimori: None declared, A. Kawakami Grant/research support from: Abbvie GK, Eisai Co., Mitsubishi Tanabe Pharma Co., Pfizer Japan, Janssen Pharmaceutical K. K., Takeda Pharmaceutical Company Astellas Pharma Inc., Speakers bureau: Abbvie GK, Eisai Co., Mitsubishi Tanabe Pharma Co., Pfizer Japan, Janssen Pharmaceutical K. K., Takeda Pharmaceutical Company Astellas Pharma Inc., N. Nishimoto: None declared, E. Tanaka: None declared, Y. Kaneko Consultant for: Abbvie, Paid instructor for: Eisai Pharmaceutical, Chugai Pharmaceutical, Astellas Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Pfizer, Speakers bureau: Abbvie, Eisai Pharmaceutical, Chugai Pharmaceutical, Bristol Myers Squibb, Astellas Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Pfizer, Janssen, UCB, H. Yasuoka Consultant for: AbbVie Inc, S. Fukuyo: None declared, K. Saito: None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Objective To investigate whether leucine-rich alpha-2 glycoprotein (LRG) could be a disease activity biomarker of rheumatoid arthritis (RA) during IL-6 blockade.Methods Serum LRG levels in RA patients treated with tocilizumab for 24 weeks (n=59) were determined by ELISA. RA disease activity was evaluated by the Clinical Disease Activity Index (CDAI). Receiver operating characteristics (ROC) curve analysis was used to examine diagnostic performance of LRG and other biomarkers. Monkeys with experimental autoimmune arthritis were treated by anti-IL-6 receptor antibody and their swollen joint counts, joint pathological changes, and blood levels of CRP and LRG were evaluated.ResultsAmong tocilizumab-treated RA patients, patients with active disease (CDAI > 2.8) had significantly high serum LRG levels compared to those in remission. ROC curve analysis suggests that LRG is more useful than CRP, ESR or MMP-3 in discriminating between CDAI remission and active disease during therapy with tocilizumab. In arthritic monkeys with IL-6 blockade, LRG levels correlated with joint scores better than CRP. Histological analysis of joints revealed that LRG levels correlated significantly with granulomatous tissue formation, cartilage degeneration and bone destruction in CRP-low monkeys during IL-6 blockade.Conclusion Under IL-6 inhibition, LRG was more useful than other biomarkers for discriminating active disease in human RA and detecting joint inflammation in arthritic animals. LRG may serve as a convenient biomarker for RA during IL-6 blockade. This article is protected by copyright. All rights reserved.
    No preview · Article · Apr 2015 · Arthritis and Rheumatology
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    ABSTRACT: To evaluate the efficacy and safety of switching from intravenous (IV) tocilizumab (TCZ) to subcutaneous (SC) TCZ monotherapy in rheumatoid arthritis patients. Patients who had completed 24 weeks' TCZ-SC (162 mg/2 weeks) or TCZ-IV (8 mg/kg/4 weeks) monotherapy in the MUSASHI study double-blind period were enrolled in an 84-week open-label extension period (OLE). All received TCZ-SC (162 mg/2 weeks) monotherapy. Effects of the IV-to-SC switch were evaluated at week 36 (12 weeks after switching). Overall, 319 patients received at least one dose of TCZ-SC during OLE; 160 switched from TCZ-IV to TCZ-SC (TCZ IV/SC) and 159 continued TCZ-SC (TCZ SC/SC). DAS28-ESR clinical remission rates were 62.5% (100/160) for TCZ IV/SC and 50.0% (79/158) for TCZ SC/SC at week 24, and were maintained at 62.5% (100/160) and 57.0% (90/158), respectively, at week 36. In the TCZ IV/SC group, 9% (9/100) of patients who had achieved remission at week 24 could not maintain remission at week 36. In TCZ IV/SC patients weighing ≥ 70 kg, the percentage with sufficient serum TCZ concentration (≥1 μg/mL) decreased from 90.9% (10/11) at week 24 to 45.5% (5/11) at week 36. Overall safety profiles were similar in TCZ IV/SC and TCZ SC/SC except for mild injection site reactions in TCZ IV/SC. Efficacy is adequately maintained in most patients switching from TCZ-IV (8 mg/kg/4 weeks) to TCZ-SC (162 mg/2 weeks) monotherapy. Patients receiving TCZ-IV can switch to TCZ-SC without serious safety concerns. Clinical efficacy may be reduced after switching in some high-body-weight patients. This article is protected by copyright. All rights reserved. © 2015 American College of Rheumatology.
    Full-text · Article · Apr 2015
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    ABSTRACT: Pulmonary infections (PI) are leading causes of death in patients with connective tissue diseases (CTD). The PREVENT study (Pulmonary infections in patients receiving immunosuppressive treatment for CTD) assessed risk of PI in patients with active CTD in the contemporary era of advanced immunosuppressive therapy. In patients who started corticosteroids (n = 763), conventional immunosuppressants or biologics for active CTD were enrolled. Clinical and laboratory data, usage of drugs, and occurrence of PI were collected for 12 months. Baseline risk factors were investigated using Cox regression analysis. A nested case-control (NCC) study was performed with 1:2 matched case-control pairs to assess the risk for each drug category. During the observation period, 32 patients died (4.2%) and 66 patients were lost to followup (8.6%). Patients with PI (n = 61, 8%) had a significantly worse accumulated survival rate than patients without (p < 0.01). Cox hazard regression analysis using baseline data showed that these factors were significantly associated with PI: age ≥ 65 years (HR 3.87, 95% CI 2.22-6.74), ≥ 20 pack-years of smoking (2.63, 1.37-5.04), higher serum creatinine level (1.21, 1.05-1.41 per 1.0 mg/dl increase), and maximum prednisolone (PSL) dose during the first 2 weeks of treatment (2.81, 1.35-5.86 per 1.0 mg/kg/day increase). Logistic regression analysis by an NCC study revealed that maximum PSL dose within 14 days before PI (OR 4.82, 95% CI 1.36-17.01 per 1.0 mg/dl increase; 2.57, 1.28-5.16 if ≥ 0.5 mg/kg/day) was significantly associated with the events, while other immunosuppressants were not. Physicians should be aware of the higher risks for corticosteroids of PI than other immunosuppressants and assess these risk factors before immunosuppressive treatment, to prevent PI.
    No preview · Article · Feb 2015 · The Journal of Rheumatology
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    ABSTRACT: It is suggested that polymyositis, an autoimmune inflammatory myopathy, is mediated by autoaggressive CD8 T cells. Skeletal muscle C protein is a self-antigen that induces C protein-induced myositis, a murine model of polymyotitis. To establish a new murine model of myosits inducible with a single CD8 T cell epitope peptide that derives from the C protein, 3 internet-based prediction systems were employed to identify 24 candidate peptides of the immunogenic fragment of the C protein and bind theoretically to major histocompatibility complex (MHC) class I molecules of C57BL/6 (B6) mice. RMA-S cell assay revealed that a HILIYSDV peptide, amino acid position 399 - 406 of the C protein, had the highest affinity to the H2-K(b) molecules. Transfer of mature bone marrow-derived dendritic cells pulsed with HILIYSDV induced myositis in naïve B6 mice. This myositis was suppressed by anti-CD8 depleting antibodies but not by anti-CD4 depleting antibodies. Because this myositis model is mediated by CD8 T cells independently of CD4 T cells, it should be a useful tool to investigate pathology of polymyositis and develop therapies targeting CD8 T cells. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Full-text · Article · Jan 2015 · International Immunology
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    ABSTRACT: Objective: To determine whether injury and regeneration of the skeletal muscles induce an inflammatory milieu that facilitates the development and relapse of autoimmune myositis. Methods: The quadriceps of C57BL/6 mice were injured with bupivacaine hydrochloride (BPVC) and evaluated histologically. Macrophages and regenerating myofibers in the treated muscles and differentiating C2C12 myotubes were examined for cytokine expression. Mice were immunized with C protein fragments at the base of the tail and in the right hind footpads (day 0) to evoke systemic anti-C protein immunity and to induce local myositis in the right hind limbs. The contralateral quadriceps muscles were injured with BPVC or phosphate buffered saline (PBS) on day 7 or after spontaneous regression of myositis (day 42). The quadriceps muscle in nonimmunized mice was injured with BPVC on day 7. The muscles were examined histologically 14 days after treatment. Results: The BPVC-injured muscles had macrophage infiltration most abundantly at 3 days after the injection, with emergence of regenerating fibers from day 5. The macrophages expressed inflammatory cytokines, including tumor necrosis factor α, interleukin-1β, and CCL2. Regenerating myofibers and C2C12 myotubes also expressed the cytokines. The BPVC-injected muscles from nonimmunized mice had regenerating myofibers with resolved cell infiltration 14 days after treatment. In mice preimmunized with C protein fragments, the muscles injected with BPVC on day 7 as well as on day 42, but not those injected with PBS, had myositis accompanied by CD8+ T cell infiltration. Conclusion: Injury and regeneration could set up an inflammatory milieu in the muscles and facilitate the development and relapse of autoimmune myositis.
    No preview · Article · Jan 2015 · Arthritis and Rheumatology
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    ABSTRACT: In this study, we investigated the relationship between several growth factors and inflammation development. Serum concentrations of epiregulin, amphiregulin, betacellulin, TGF-α, fibroblast growth factor 2, placental growth factor (PLGF), and tenascin C were increased in rheumatoid arthritis patients. Furthermore, local blockades of these growth factors suppressed the development of cytokine-induced arthritis in mice by inhibiting chemokine and IL-6 expressions. We found that epiregulin expression was early and followed by the induction of other growth factors at different sites of the joints. The same growth factors then regulated the expression of epiregulin at later time points of the arthritis. These growth factors were increased in patients suffering from multiple sclerosis (MS) and also played a role in the development of an MS model, experimental autoimmune encephalomyelitis. The results suggest that the temporal expression of growth factors is involved in the inflammation development seen in several diseases, including rheumatoid arthritis and MS. Therefore, various growth factor pathways might be good therapeutic targets for various inflammatory diseases. Copyright © 2015 by The American Association of Immunologists, Inc.
    Full-text · Article · Jan 2015 · The Journal of Immunology
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    ABSTRACT: A 59-year-old man, who suffered from periodic fever with continuous elevation of the C-reactive protein (CRP) level was referred to our hospital. He had frequent respiratory infections and diarrhea since his childhood. The serum immunoglobulin (Ig) G level was low (537 mg/dl) while IgA and IgE were undetectable. The serum IgM level was elevated (737 mg/dl). Based on these clinical features, he was diagnosed with primary immune deficiency, hyper IgM syndrome. He had past histories of aortic aneurysm, which had been repaired surgically in his fifties. His persistent proteinuria made us to perform renal biopsy, which revealed nephrosclerotic changes. During the hospitalization, multiple events of subcortical brain hemorrhage, subarachnoid hemorrhage, and pulmonary alveolar hemorrhage occurred. Bleeding time and coagulation tests were normal. Antinuclear antibody, anti-neutrophil cytoplasmic antibody, or anti-cardiolipin antibody was absent. Herein, we described the first case of the immune deficiency associated with severe arteriosclerosis and hemorrhage.
    Preview · Article · Jan 2015 · Japanese Journal of Clinical Immunology
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    ABSTRACT: IntroductionBiological drugs are effective in patients with rheumatoid arthritis (RA), but increase severe infections. The CC chemokine receptor (CCR) 9 antagonist was effective for Crohn¿s disease without critical adverse effects including infections in clinical trials. The present study was carried out to explore the pathogenic roles of chemokine (C-C motif) ligand (CCL) 25 and its receptor, CCR9 in autoimmune arthritis and to study if the CCR9 antagonist could be a new treatment for RA.MethodsCCL25 and CCR9 expression was examined with immunohistochemistry and Western blotting. Concentration of interleukin (IL)-6, matrix metalloproteinase (MMP)-3 and tumor necrosis factor (TNF)-¿ was measured with enzyme-linked immunosorbent assays. Effects of abrogating CCR9 on collagen-induced arthritis (CIA) was evaluated using CCR9-deficient mice or the CCR9 antagonist, CCX8037. Fluorescence labeled-CD11b+ splenocytes from CIA mice were transferred to recipient CIA mice and those infiltrating into the synovial tissues of the recipient mice were counted.ResultsCCL25 and CCR9 proteins were found in the RA synovial tissues. CCR9 was expressed on macrophages, fibroblast-like synoviocytes (FLS) and dendritic cells in the synovial tissues. Stimulation with CCL25 increased IL-6 and MMP-3 production from RA FLS, and IL-6 and TNF-¿ production from peripheral blood monocytes. CIA was suppressed in CCR9-deficient mice. CCX8037 also inhibited CIA and the migration of transferred CD11b+ splenocytes into the synovial tissues.Conclusion The interaction between CCL25 and CCR9 may play important roles in cell infiltration into the RA synovial tissues and inflammatory mediator production. Blocking CCL25 or CCR9 may represent a novel safe therapy for RA.
    Full-text · Article · Sep 2014 · Arthritis Research & Therapy
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    ABSTRACT: Objective Biological disease-modifying antirheumatic drugs (DMARDs) that inhibit aberrant immune reactions in rheumatoid arthritis (RA) cannot induce complete remission in all patients. Combination therapies using two biological DMARDs have failed to exert additive effects and increased serious infections. We have found that cell cycle inhibition of synovial fibroblasts with cyclin-dependent kinase (CDK) inhibitors ameliorated the disease in animal models of RA without attenuating acquired immunity. The objective of this study was to determine whether a clinically well-tolerated selective CDK 4/6 inhibitor (CDKI), palbociclib, is effective and whether combination with cytokine blockers acts additively without enhancing immune suppression. Methods The effects of CDKI on haematopoiesis and physical and behavioural findings in mice were evaluated. Mice with collagen-induced arthritis (CIA) were treated with CDKI, etanercept or anti-interleukin (IL)-6 receptor antibody (MR16-1) alone or with a combination of CDKI with etanercept or MR16-1. Their clinical, histological and radiographic scores, serum anti-(type II collagen (CII)) antibody levels and proliferative responses of lymph node cells to CII were determined. Results Although CDKI induced marginal myelosuppression, it was well tolerated and ameliorated CIA dose-dependently. The combinations of low-dose CDKI and either tumour necrosis factor-α or IL-6 blocker enhanced the antiarthritic effects additively. The addition of CDKI to either cytokine blocker did not affect the levels of anti-CII antibodies and proliferative responses of lymphocytes to CII. Conclusions A clinically well-tolerated CDK4/6 inhibitor exerted antiarthritic effects in this mouse model. By combining therapeutic agents targeting immune reaction and synovial proliferation, we have demonstrated for the first time that two molecular targeting treatments act additively and may not increase immune suppression.
    Full-text · Article · Aug 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Some of cannabinoids, which are chemical compounds contained in marijuana, are immunosuppressive. One of the receptors, CB receptor 1 (CB1), is expressed predominantly by the cells in the central nervous system, whereas CB receptor 2 (CB2) is expressed primarily by immune cells. Theoretically, selective CB2 agonists should be devoid of psychoactive effects. In this study, we investigated therapeutic effects of a selective CB2 agonist on arthritis. Methods The expression of CB2 was analyzed with immunohistochemistry and Western blotting. Interleukin (IL)-6, matrix metalloproteinase-3 (MMP-3), and chemokine (C-C motif) ligand 2 (CCL2) were quantified with enzyme-linked immunosorbent assays (ELISA). Osteoclastogenesis was assessed with tartrate-resistant acid phosphatase staining and the resorption of coated-calcium phosphate. Effect of JWH133, a selective CB2 agonist, on murine collagen type II (CII)-induced arthritis (CIA) was evaluated with arthritis score, and histological and radiographic changes. IFN-γ and IL-17 production by CII-stimulated splenocytes and serum anti-CII Ab were analyzed by ELISA. Results Immunohistochemistry showed that CB2 was expressed more in the synovial tissues from the rheumatoid joints than in those from the osteoarthritis joints. CB2 expression on RA FLS was confirmed with Western blot analysis. JWH133 inhibited IL-6, MMP-3, and CCL2 production from tumor necrosis factor-α-stimulated fibroblast-like synoviocytes (FLS) derived from the rheumatoid joints, and osteoclastogenesis of peripheral blood monocytes. Administration of JWH133 to CIA mice reduced the arthritis score, inflammatory cell infiltration, bone destruction, and anti-CII IgG1 production. Conclusion The present study suggests that a selective CB2 agonist could be a new therapy for RA that inhibits production of inflammatory mediators from FLS, and osteoclastogenesis.
    Preview · Article · Aug 2014 · BMC Musculoskeletal Disorders
  • Waka Yokoyama · Kazuki Takada · Nobuyuki Miyasaka · Hitoshi Kohsaka
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    ABSTRACT: A 64-year-old woman presented with an acute onset of myelitis and optic neuritis after 47 months of etanercept use for rheumatoid arthritis. Etanercept was discontinued and pulse methylprednisolone therapy (1000 mg/day for 3 days) was started, followed by a quick and complete resolution. Demyelination associated with antitumor necrosis factor agents, reported to develop mostly from 1 week to 12 months after the initiation of the agents, could develop after a few years and thus warrants vigilant monitoring.
    No preview · Article · Aug 2014 · Case Reports
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    ABSTRACT: Objective: To investigate the role of adhesion molecules in C protein-induced myositis (CIM), a murine model of polymyositis (PM). Methods: CIM was induced in wild-type mice, L-selectin-deficient (L-selectin(-/-) ) mice, intercellular adhesion molecule 1 (ICAM-1)-deficient (ICAM-1(-/-) ) mice, and mice deficient in both L-selectin and ICAM-1 (L-selectin(-/-) ICAM-1(-/-) mice). Myositis severity, inflammatory cell infiltration, and messenger RNA expression in the inflamed muscles were analyzed. The effect of dendritic polyglycerol sulfate, a synthetic inhibitor that suppresses the function of L-selectin and endothelial P-selectin, was also examined. Results: L-selectin(-/-) mice and L-selectin(-/-) ICAM-1(-/-) mice developed significantly less severe myositis compared to wild-type mice, while ICAM-1 deficiency did not inhibit the development of myositis. L-selectin(-/-) mice that received wild-type T cells developed myositis. Treatment with dendritic polyglycerol sulfate significantly diminished the severity of myositis in wild-type mice compared to treatment with control. Conclusion: These data indicate that L-selectin plays a major role in the development of CIM, whereas ICAM-1 plays a lesser role, if any, in the development of CIM. L-selectin-targeted therapy may be a candidate for the treatment of PM.
    Full-text · Article · Jul 2014 · Arthritis and Rheumatology

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2k Citations
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Institutions

  • 2007-2015
    • RIKEN
      Вако, Saitama, Japan
    • Japan Clinical Research Support Unit
      Edo, Tōkyō, Japan
  • 1989-2015
    • Tokyo Medical and Dental University
      • • Department of Medicine and Rheumatology
      • • Graduate School of Medical and Dental Sciences
      • • Department of Dermatology
      • • Department of Medicine
      • • Department of Internal Medicine
      • • Medical Research Institute
      Edo, Tōkyō, Japan
    • The University of Tokyo
      Tōkyō, Japan
  • 2014
    • Tazuke Kofukai Medical Research Institute, Kitano Hospital
      Ōsaka, Ōsaka, Japan
  • 1996
    • National Cheng Kung University
      臺南市, Taiwan, Taiwan
  • 1993-1994
    • University of California, San Diego
      • Department of Medicine
      San Diego, California, United States
    • National University (California)
      San Diego, California, United States