PD-1 Inhibits Antiviral Immunity at the Effector Phase in the Liver

Unlike naive T cells, effector T cells can be activated by either T cell receptor signal or costimulatory signal alone and therefore the absence of costimulatory molecules on tissue cells cannot explain the tolerance mechanism at the effector phase. Here we report that PD-L1, the ligand for the immunoinhibitory receptor PD-1, was expressed on vascular endothelium in peripheral tissues. Liver nonparenchymal cells including sinusoidal endothelial cells and Kupffer cells constitutively expressed PD-L1 and inhibited proliferation and cell division of activated T cells expressing PD-1. The absence of PD-1 induced proliferation of effector T cells in the adenovirus-infected liver and resulted in rapid clearance of the virus. These results indicate that PD-1 plays an important role in T cell tolerance at the effector phase and the blockade of the PD-1 pathway can augment antiviral immunity

Activation of fibroblast-like synoviocytes derived from rheumatoid arthritis via lysophosphatidic acid-lysophosphatidic acid receptor 1 cascade

INTRODUCTION: Lysophosphatidic acid (LPA) is a bioactive lipid that binds to G protein–coupled receptors (LPA(1–6)). Recently, we reported that abrogation of LPA receptor 1 (LPA(1)) ameliorated murine collagen-induced arthritis, probably via inhibition of inflammatory cell migration, Th17 differentiation and osteoclastogenesis. In this study, we examined the importance of the LPA–LPA(1) axis in cell proliferation, cytokine/chemokine production and lymphocyte transmigration in fibroblast-like synoviocytes (FLSs) obtained from the synovial tissues of rheumatoid arthritis (RA) patients. METHODS: FLSs were prepared from synovial tissues of RA patients. Expression of LPA(1–6) was examined by quantitative real-time RT-PCR. Cell surface LPA(1) expression was analyzed by flow cytometry. Cell proliferation was analyzed using a cell-counting kit. Production of interleukin 6 (IL-6), vascular endothelial growth factor (VEGF), chemokine (C-C motif) ligand 2 (CCL2), metalloproteinase 3 (MMP-3) and chemokine (C-X-C motif) ligand 12 (CXCL12) was measured by enzyme-linked immunosorbent assay. Pseudoemperipolesis was evaluated using a coculture of RA FLSs and T or B cells. Cell motility was examined by scrape motility assay. Expression of adhesion molecules was determined by flow cytometry. RESULTS: The expression of LPA(1) mRNA and cell surface LPA(1) was higher in RA FLSs than in FLSs from osteoarthritis tissue. Stimulation with LPA enhanced the proliferation of RA FLSs and the production of IL-6, VEGF, CCL2 and MMP-3 by FLSs, which were suppressed by an LPA(1) inhibitor (LA-01). Ki16425, another LPA(1) antagonist, also suppressed IL-6 production by LPA-stimulated RA FLSs. However, the production of CXCL12 was not altered by stimulation with LPA. LPA induced the pseudoemperipolesis of T and B cells cocultured with RA FLSs, which was suppressed by LPA(1) inhibition. In addition, LPA enhanced the migration of RA FLSs and expression of vascular cell adhesion molecule and intercellular adhesion molecule on RA FLSs, which were also inhibited by an LPA(1) antagonist. CONCLUSIONS: Collectively, these results indicate that LPA–LPA(1) signaling contributes to the activation of RA FLSs

Quantification of Cell Migration and Invasion, and Their Association with Periostin in Anaplastic Thyroid Cancer, Using a Real-time Cell Analyzer

Anaplastic thyroid cancer (ATC) is known to be a highly malignant cancer of the thyroid with a high mortality rate. In a previous study, we used real-time cell analysis (RTCA) to analyze cell migration and invasion of oral squamous cell carcinomas (OSCCs) of the tongue and floor of the mouth. In the present study, we investigated cell migration and invasion of ATC using RTCA, as well as their association with periostin, matrix metalloproteinases (MMPs), and integrins. Experiments were performed on TCO-1 and HTC/C3 cells, which are human ATC cell lines. OSCC cell lines were used for comparison. Using the cell analysis system, cell migration was assessed on fibronectin-coated CIM-Plates, whereas invasion was assessed on fibronectin- and matrigel-coated CIM-Plates. SCC-4 cells exhibited high cell migration and invasion activity compared with other OSCC cell lines. TCO-1 cells exhibited equivalent cell invasion but stronger migration than SCC-4 cells. Although TCO-1 cells had strong invasive activity, they did not express MMP-9, unlike SCC-4 cells. Conversely, periostin expression was high in TCO-1 cells. Therefore, periostin expression appears to be associated with the cell migration and invasion activity of ATC. The RTCA system will be useful for the analysis of the metastatic characteristics of ATC in head and neck cancer

An IFN-γ-IL-18 Signaling Loop Accelerates Memory CD8+ T Cell Proliferation

Rapid proliferation is one of the important features of memory CD8+ T cells, ensuring rapid clearance of reinfection. Although several cytokines such as IL-15 and IL-7 regulate relatively slow homeostatic proliferation of memory T cells during the maintenance phase, it is unknown how memory T cells can proliferate more quickly than naïve T cells upon antigen stimulation. To examine antigen-specific CD8+ T cell proliferation in recall responses in vivo, we targeted a model antigen, ovalbumin(OVA), to DEC-205+ dendritic cells (DCs) with a CD40 maturation stimulus. This led to the induction of functional memory CD8+ T cells, which showed rapid proliferation and multiple cytokine production (IFN-γ, IL-2, TNF-α) during the secondary challenge to DC-targeted antigen. Upon antigen-presentation, IL-18, an IFN-γ-inducing factor, accumulated at the DC:T cell synapse. Surprisingly, IFN-γ receptors were required to augment IL-18 production from DCs. Mice genetically deficient for IL-18 or IFN-γ-receptor 1 also showed delayed expansion of memory CD8+ T cells in vivo. These results indicate that a positive regulatory loop involving IFN-γ and IL-18 signaling contributes to the accelerated memory CD8+ T cell proliferation during a recall response to antigen presented by DCs

ミンカン ノ ヤクブツイソンショウ リハビリテーション シセツ ニオケル ケイジショブンレキ ノ アル ヤクブツイションショウシャ ノ ジッタイ ト サイハンボウシ ニ カンスル イチコウサツ

背景：薬物依存症者の刑務所への再入所率は非常に高い。目的：民間の薬物依存症リハビリテーション施設に在籍している刑事処分歴のある薬物依存症者の実態を調査し、再犯を防止するための若干の提言を示すことを本研究の目的とした。方法：13の民間の薬物依存症リハビリテーション施設において、刑事処分歴のある薬物依存症者112名を調査した。結果：112名の刑務所入所回数は、平均2.0回であった。また、平均2.7回目の刑務所入所の後に薬物依存症リハビリテーション施設に入寮していた。保釈後、あるいは刑務所出所から再逮捕までの期間は、1年以内が55.3％であった。結論：刑事処分歴のある薬物依存症者は、少なくとも刑務所出所後の1年間は薬物依存症の治療プログラムが必要であると思われた。Background:The percentage of drug-addicts re-entering prison are very high.Objective:We examined drug addicts who were admitted to private drug-rehabilitation institutions with a history of criminal offences/incarcerations. The goal would be to minimize or prevent, even by little, the re-occurrence of criminal offences/incarceration.Methods:This survey was conducted on 112 drug-addicts with a history of criminal offences/incarceration, at 13 various private drug-rehabilitation institutions.Results:The average prison incarceration rate was two times. The drug-addicts were admitted to drug-rehabilitation institutions after an average of 2.7 prison terms. Fromthe time of release, be it released on bail or released from prison, 55.3％ were re-arrested within one year.Conclusion:These results suggest that it is necessary for drug-addicts with a history of criminal offences/incarcerations to receive at least one year of drug-addiction treatment

Cutting: Traditions in anatomy and Thanksgiving

"Synapsis: A Health Humanities Journal" was founded in 2017 by Arden Hegele, a literary scholar, and Rishi Goyal, a physician. Its mission is to develop conversations among diverse people thinking about medical and humanistic ways of knowing ... as a “Department Without Walls” that connects scholars and thinkers from different spheres

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京都大学0048新制・課程博士博士(医学)甲第9469号医博第2482号新制||医||797(附属図書館)UT51-2002-G227京都大学大学院医学研究科分子医学系専攻(主査)教授 湊 長博, 教授 坂口 志文, 教授 本庶 佑学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA