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Natural killer cells in liver diseases

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《医学前沿（英文）》 2018年第12卷第3期页码 269-279 doi: 10.1007/s11684-018-0621-4

摘要：

The liver has been characterized as a frontline lymphoid organ with complex immunological features such as liver immunity and liver tolerance. Liver tolerance plays an important role in liver diseases including acute inflammation, chronic infection, autoimmune disease, and tumors. The liver contains a large proportion of natural killer (NK) cells, which exhibit heterogeneity in phenotypic and functional characteristics. NK cell activation, well known for its role in the immune surveillance against tumor and pathogen-infected cells, depends on the balance between numerous activating and inhibitory signals. In addition to the innate direct “killer” functions, NK cell activity contributes to regulate innate and adaptive immunity (helper or regulator). Under the setting of liver diseases, NK cells are of great importance for stimulating or inhibiting immune responses, leading to either immune activation or immune tolerance. Here, we focus on the relationship between NK cell biology, such as their phenotypic features and functional diversity, and liver diseases.

关键词： natural killer cell phenotype immune activation immune tolerance liver diseases

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NKT cells in liver diseases

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《医学前沿（英文）》 2018年第12卷第3期页码 249-261 doi: 10.1007/s11684-018-0622-3

摘要：

Natural killer T cells are innate-like and tissue-resident lymphocytes, which recognize lipid antigens and are enriched in the liver. Natural killer T cells play important roles in infections, tumors, autoimmune diseases, and metabolic diseases. In this study, we summarize recent findings on biology of natural killer T cells and their roles in hepatitis B virus and hepatitis C virus infection, autoimmune liver diseases, alcoholic liver disease, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Controversial results from previous studies are discussed, and indicate the dynamic alteration in the role of natural killer T cells during the progression of liver diseases, which might be caused by changes in natural killer T subsets, factors skewing cytokine responses, and intercellular crosstalk between natural killer T cells and CD1d-expressing cells or bystander cells.

关键词： natural killer T cells hepatitis B virus and hepatitis C virus infection autoimmune liver diseases alcoholic liver disease nonalcoholic fatty liver disease hepatocellular carcinoma

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Natural killer cells in hepatocellular carcinoma: current status and perspectives for future immunotherapeutic

null

《医学前沿（英文）》 2017年第11卷第4期页码 509-521 doi: 10.1007/s11684-017-0546-3

摘要：

Hepatocellular carcinoma (HCC) is currently the fifth most common malignancy and the third leading cause of cancer-related mortalities worldwide. In the last few years, treatments for HCC have significantly improved from a mere surgical resection to a series of minimally invasive therapies and targeted drugs. However, recurrence frequently occurs even upon curative therapeutics, and drug therapies generally produce disappointing results, with the overall prognosis dismal. This challenging clinical scenario warrants new effective and life-prolonging strategies for patients with HCC. Compelling evidence suggests that NK cells play a critical role in the immune function of the liver and in the immune defenses against HCC, indicating that HCC might be an ideal target for NK cell-based immunotherapies. To obtain comprehensive insights into the putative influence of NK cells on HCC, this paper summarizes current knowledge on NK cells in HCC and discusses the usefulness and prospects of NK cell-based immunotherapies. Critical issues that require consideration for the successful clinical translation of NK cell-based therapies are also addressed. If appropriately used and further optimized, NK cell-based therapies could dominate important roles in the future immunotherapeutic market of HCC.

关键词： natural killer cell hepatocellular carcinoma immunotherapy

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Astragaloside IV suppresses post-ischemic natural killer cell infiltration and activation in the brain

Baokai Dou, Shichun Li, Luyao Wei, Lixin Wang, Shiguo Zhu, Zhengtao Wang, Zunji Ke, Kaixian Chen, Zhifei Wang

《医学前沿（英文）》 2021年第15卷第1期页码 79-90 doi: 10.1007/s11684-020-0783-8

摘要： Natural killer (NK) cells, a type of cytotoxic lymphocytes, can infiltrate into ischemic brain and exacerbate neuronal cell death. Astragaloside IV (ASIV) is the major bioactive ingredient of , a Chinese herbal medicine, and possesses potent immunomodulatory and neuroprotective properties. This study investigated the effects of ASIV on post-ischemic brain infiltration and activation of NK cells. ASIV reduced brain infarction and alleviated functional deficits in MCAO rats, and these beneficial effects persisted for at least 7 days. Abundant NK cells infiltrated into the ischemic hemisphere on day 1 after brain ischemia, and this infiltration was suppressed by ASIV. Strikingly, ASIV reversed NK cell deficiency in the spleen and blood after brain ischemia. ASIV inhibited astrocyte-derived CCL2 upregulation and reduced CCR2 NK cell levels in the ischemic brain. Meanwhile, ASIV attenuated NK cell activating receptor NKG2D levels and reduced interferon-γ production. ASIV restored acetylation of histone H3 and the p65 subunit of nuclear factor-κB in the ischemic brain, suggesting inhibition of histone deacetylase (HDAC). Simultaneously, ASIV prevented p65 nuclear translocation. The effects of ASIV on reducing CCL2 production, restoring acetylated p65 levels and preventing p65 nuclear translocation were mimicked by valproate, an HDAC inhibitor, in astrocytes subjected to oxygen-glucose deprivation. Our findings suggest that ASIV inhibits post-ischemic NK cell brain infiltration and activation and reverses NK cell deficiency in the periphery, which together contribute to the beneficial effects of ASIV against brain ischemia. Furthermore, ASIV’s effects on suppressing NK cell brain infiltration and activation may involve HDAC inhibition.

关键词： astragaloside IV brain ischemia natural killer cells histone deacetylase nuclear factor-κB

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Natural killer cell lines in tumor immunotherapy

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《医学前沿（英文）》 2012年第6卷第1期页码 56-66 doi: 10.1007/s11684-012-0177-7

摘要：

Natural killer (NK) cells are considered to be critical players in anticancer immunity. However, cancers are able to develop mechanisms to escape NK cell attack or to induce defective NK cells. Current NK cell-based cancer immunotherapy is aimed at overcoming NK cell paralysis through several potential approaches, including activating autologous NK cells, expanding allogeneic NK cells, usage of stable allogeneic NK cell lines and genetically modifying fresh NK cells or NK cell lines. The stable allogeneic NK cell line approach is more practical for quality-control and large-scale production. Additionally, genetically modifying NK cell lines by increasing their expression of cytokines and engineering chimeric tumor antigen receptors could improve their specificity and cytotoxicity. In this review, NK cells in tumor immunotherapy are discussed, and a list of therapeutic NK cell lines currently undergoing preclinical and clinical trials of several kinds of tumors are reviewed.

关键词： natural killer cell natural killer cell line tumor immunotherapy genetic modification

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Challenges of NK cell-based immunotherapy in the new era

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《医学前沿（英文）》 2018年第12卷第4期页码 440-450 doi: tzg@ustc.edu.cn

摘要：

Natural killer cells (NKs) have a great potential for cancer immunotherapy because they can rapidly and directly kill transformed cells in the absence of antigen presensitization. Various cellular sources, including peripheral blood mononuclear cells (PBMCs), stem cells, and NK cell lines, have been used for producing NK cells. In particular, NK cells that expanded from allogeneic PBMCs exhibit better efficacy than those that did not. However, considering the safety, activities, and reliability of the cell products, researchers must develop an optimal protocol for producing NK cells from PBMCs in the manufacture setting and clinical therapeutic regimen. In this review, the challenges on NK cell-based therapeutic approaches and clinical outcomes are discussed.

关键词： natural killer cells immunotherapy adoptive transfer genetic modification immune checkpoint inhibitor

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Study of recombinant human IFN-α-2b bacilli Calmette–Guerin activated killer cells and against bladder

FAN Xiaodong, HAN Ruifa

《医学前沿（英文）》 2007年第1卷第4期页码 377-380 doi: 10.1007/s11684-007-0073-8

摘要： Presently, one of the most potent immunotherapies is the application of bacillus Calmette Guerin (BCG) to prevent recurrences of the superficial bladder cancer. Despite its successful use, nonresponders and certain side effects remain a major obstacle. Therefore, current studies aim at developing recombinant BCG (rBCG) strains secreting Th1-like cytokines to improve the effectiveness of the therapy. In this study, a new type of rBCG strain constructed by Tianjin institute of Urology was tested for its immunostimulatory capacity . Peripheral blood monocytes (PBMC) were stimulated by recombinant BCG and transformed into bacilli Calmette–Guerin activated killer (BAK) cells, and the effect of anticancer BAK cells was studied. Recombinant IFN--2b-BCG, wild-type BCG (wBCG), wild-type BCG and IFN--2b were coincubated with PBMCs respectively , and the proliferation of PBMC was detected with MTT in different time. BAK cells have the ability to kill bladder tumor cells, and the antitumor activity of effecter cells was determined by LDH release assay. The result of MTT showed that the proliferation of PBMC in the recombinant BCG group was more powerful than in the other two groups (<0.05). The result of LDH release assay showed that the antitumor activity of BAK cells stimulated by Recombinant BCG was the highest in all groups. We conclude that the recombinant BCG can activate more PBMCs to anti-bladder cancer than wild-type BCG does.

关键词： Urology powerful 2b-BCG Tianjin institute wild-type

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Innate and adaptive T cells in influenza disease

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《医学前沿（英文）》 2018年第12卷第1期页码 34-47 doi: 10.1007/s11684-017-0606-8

摘要：

Influenza is a major global health problem, causing infections of the respiratory tract, often leading to acute pneumonia, life-threatening complications and even deaths. Over the last seven decades, vaccination strategies have been utilized to protect people from complications of influenza, especially groups at high risk of severe disease. While current vaccination regimens elicit strain-specific antibody responses, they fail to generate cross-protection against seasonal, pandemic and avian viruses. Moreover, vaccines designed to generate influenza-specific T-cell responses are yet to be optimized. During natural infection, viral replication is initially controlled by innate immunity before adaptive immune responses (T cells and antibody-producing B cells) achieve viral clearance and host recovery. Adaptive T and B cells maintain immunological memory and provide protection against subsequent infections with related influenza viruses. Recent studies also shed light on the role of innate T-cells (MAIT cells, gd T cells, and NKT cells) in controlling influenza and linking innate and adaptive immune mechanisms, thus making them attractive targets for vaccination strategies. We summarize the current knowledge on influenza-specific innate MAIT and gd T cells as well as adaptive CD8⁺ and CD4⁺ T cells, and discuss how these responses can be harnessed by novel vaccine strategies to elicit cross-protective immunity against different influenza strains and subtypes.

关键词： influenza innate T cells CD4⁺ and CD8⁺ T cells vaccination

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γδ T cells in liver diseases

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《医学前沿（英文）》 2018年第12卷第3期页码 262-268 doi: 10.1007/s11684-017-0584-x

摘要：

γδ T cells display unique developmental, distributional, and functional patterns and can rapidly respond to various insults and contribute to diverse diseases. Different subtypes of γδ T cells are produced in the thymus prior to their migration to peripheral tissues. γδ T cells are enriched in the liver and exhibit liver-specific features. Accumulating evidence reveals that γδ T cells play important roles in liver infection, non-alcoholic fatty liver disease, autoimmune hepatitis, liver fibrosis and cirrhosis, and liver cancer and regeneration. In this study, we review the properties of hepatic γδ T cells and summarize the roles of γδ T cells in liver diseases. We believe that determining the properties and functions of γδ T cells in liver diseases enhances our understanding of the pathogenesis of liver diseases and is useful for the design of novel γδ T cell-based therapeutic regimens for liver diseases.

关键词： γδT cells liver infection non-alcoholic fatty liver disease autoimmune hepatitis liver fibrosis and cirrhosis liver cancer liver regeneration

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基于自然杀伤细胞的癌症免疫疗法的进展和前景 Review

胡渊, 田志刚, 张彩

《工程（英文）》 2019年第5卷第1期页码 106-114 doi: 10.1016/j.eng.2018.11.015

摘要：

自然杀伤（natural killer，NK）细胞是重要的先天免疫细胞，位于机体抵御病毒感染和癌症的第一道防线。

关键词：自然杀伤细胞免疫疗法癌症临床试验嵌合抗原受体

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New nanostructured sorbents for desulfurization of natural gas

Lifeng WANG, Ralph T. YANG

《化学科学与工程前沿（英文）》 2014年第8卷第1期页码 8-19 doi: 10.1007/s11705-014-1411-4

摘要： Desulfurization of natural gas is achieved commercially by absorption with liquid amine solutions. Adsorption technology could potentially replace the solvent extraction process, particularly for the emerging shale gas wells with production rates that are generally lower than that from the large conventional reservoirs, if a superior adsorbent (sorbent) is developed. In this review, we focus our discussion on three types of sorbents: metal-oxide based sorbents, Cu/Ag-based and other commercial sorbents, and amine-grafted silicas. The advantages and disadvantages of each type are analyzed. Possible approaches for future developments to further improve these sorbents are suggested, particularly for the most promising amine-grafted silicas.

关键词： desulfurization natural gas desulfurization hydrogen sulfide sorbent amine-silica sorbent

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High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells

Synat Kang, Yanyan Li, Yifeng Bao, Yi Li

《医学前沿（英文）》 2019年第13卷第1期页码 69-82 doi: 10.1007/s11684-018-0677-1

摘要：

Cytokine-activated T cells (CATs) can be easily expanded and are widely applied to cancer immunotherapy. However, the good efficacy of CATs is rarely reported in clinical applications because CATs have no or very low antigen specificity. The low-efficacy problem can be resolved using T cell antigen receptor-engineered CAT (TCR-CAT). Herein, we demonstrate that NY-ESO-1_157–165 HLA-A*02:01-specific high-affinity TCR (HAT)-transduced CATs can specifically kill cancer cells with good efficacy. With low micromolar range dissociation equilibrium constants, HAT-transduced CATs showed good specificity with no off-target killing. Furthermore, the high-affinity TCR-CATs delivered significantly better activation and cytotoxicity than the equivalent TCR-engineered T cells (TCR-Ts) in terms of interferon-g and granzyme B production and in vitro cancer cell killing ability. TCR-CAT may be a very good alternative to the expensive TCR-T, which is considered an effective personalized cyto-immunotherapy.

关键词： cytokine-activated T cells high-affinity T cell receptor cancer immunotherapy TCR-CAT

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Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system

Xiaohui Wang, Zhiqiang Wu, Wei Qiu, Ping Chen, Xiang Xu, Weidong Han

《医学前沿（英文）》 2020年第14卷第6期页码 726-745 doi: 10.1007/s11684-020-0746-0

摘要： Chimeric antigen receptor (CAR) T cells have been indicated effective in treating B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma and have shown encouraging results in preclinical and clinical studies. However, CAR T cells have achieved minimal success against solid malignancies because of the additional obstacles of their insufficient migration into tumors and poor amplification and persistence, in addition to antigen-negative relapse and an immunosuppressive microenvironment. Various preclinical studies are exploring strategies to overcome the above challenges. Mobilization of endogenous immune cells is also necessary for CAR T cells to obtain their optimal therapeutic effect given the importance of the innate immune responses in the elimination of malignant tumors. In this review, we focus on the recent advances in the engineering of CAR T cell therapies to restore the immune response in solid malignancies, especially with CAR T cells acting as cellular carriers to deliver immunomodulators to tumors to mobilize the endogenous immune response. We also explored the sensitizing effects of conventional treatment approaches, such as chemotherapy and radiotherapy, on CAR T cell therapy. Finally, we discuss the combination of CAR T cells with biomaterials or oncolytic viruses to enhance the anti-tumor outcomes of CAR T cell therapies in solid tumors.

关键词： CAR T cells immunoregulatory molecules endogenous immune response solid malignancies

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调节性T细胞及其在抗肿瘤免疫疗法中的临床应用 Review

解丰, 梁瑞, 李丹, 李斌

《工程（英文）》 2019年第5卷第1期页码 132-139 doi: 10.1016/j.eng.2018.12.002

摘要：调节性T 细胞（Treg）是对维持宿主免疫稳态起重要作用的抑制性CD4+ T 细胞的一个亚群。调节性T 细胞缺陷可引起严重的自身免疫、过敏和自身炎症等疾病。调节性T 细胞通常富集在肿瘤微环境中，而大量免疫抑制调节性T细胞往往表明预后较差。因此，人们对调节性T 细胞的功能及其在抗肿瘤免疫疗法中的临床应用再次产生了兴趣。越来越多的策略关注调节性T 细胞的消耗，这在抗肿瘤免疫方面似乎有效。预计调节性T 细胞靶向策略与其他疗法（如嵌合抗原受体T 细胞疗法或免疫检查点阻断）联用将为提高抗肿瘤疗效带来重大机遇。

关键词：调节性T细胞癌症免疫疗法

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CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies

《医学前沿（英文）》 2021年第15卷第6期页码 783-804 doi: 10.1007/s11684-021-0904-z

摘要： The current standard of care in hematological malignancies has brought considerable clinical benefits to patients. However, important bottlenecks still limit optimal achievements following a current medical practice. The genetic complexity of the diseases and the heterogeneity of tumor clones cause difficulty in ensuring long-term efficacy of conventional treatments for most hematological disorders. Consequently, new treatment strategies are necessary to improve clinical outcomes. Chimeric antigen receptor T-cell (CAR T) immunotherapy opens a new path for targeted therapy of hematological malignancies. In this review, through a representative case study, we summarize the current experience of CAR T-cell therapy, the management of common side effects, the causative mechanisms of therapy resistance, and new strategies to improve the efficacy of CAR T-cell therapy.

关键词： CAR T cells hematological malignancies review