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Local t regulatory cells depletion by an integrated nanodrug system for efficient chem-immunotherapy of tumor

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Science China Chemistry 2019年第9期62卷 1230-1244页

作者： Fan Gao Qian Cheng Miao-Deng Liu Lei Rong Chuan-Jun Liu Xian-Zheng Zhang Key Laboratory of Biomedical Polymers of Ministry of Education Department of ChemistryWuhan University

t regulatory(treg) cell is a major immunosuppressive factor that restrains the antitumor effect of immunotherapy, because it gets more after the immune activation and is hardly to be eliminated. Here, an acid-sensitive integrated nanodrug system is designed to activate antitumor immune response as well as locally deplete treg cells with low side effect. the nanosystem is synthetized by coordinating doxorubicin(DOX) and pentoxifylline(PtX) with Zn ions, then stabilized via liposome encapsulation(denoted as DtX@Lipo). DtX@Lipo can activate antitumor immune effect by chemotherapy of DOX. Besides, the release of PtX inhibits c-Rel expression, leading to the reduction of treg cells in tumor site. Owing to the good tumor accumulation and local drug release ability, DtX@Lipo exhibits better biosafety and convenience than traditional antibody blockade method for treg cells depletion. According to the results of in vivo experiments, the nanodrug system can significantly increase the ratio between effector t(teff) cells and treg cells locally, resulting in an immunoactivated tumor microenvironment. Importantly, it exhibits significant antitumor effect when combined with PD-1 blockade therapy, providing great potential for tumor therapy.

关键词： tumor t regulatory cell nanodrug system PD-1 immune response

Prediction Models on Distribution of Inherent Strains in t type Welding Structure

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Journal of Materials Science & technology 2003年第Z1期19卷 202-204页

作者： Peng HE Jicai FENG Jiecai HAN Yiyu QIAN National Key Laboratory of Advanced Welding Production technology HIT Harbin 150001 China National Key Laboratory of Advanced Welding Production Technology HIT Harbin 150001 China National Key Laboratory of Advanced Welding Production Technology HIT Harbin 150001 China National Key Laboratory of Advanced Welding Production Technology HIT Harbin 150001 China

A fundamental theory for the analysis of residual welding stresses and deformation based on the inherent strain distribution along the welded joint is introduced. the method of predicting maximum hardness Hv(y, z) and maximum inherent strain gmax is given. the model t.E.P-tav-hardness calculation is proposed to predict distribution of inherent strains in t type welding structure. By t.E.P-tav-hardness calculation, distribution of longitudinal inherent strains can be predicted in t type welding structure, and calculation and experimental results are consistent.

关键词： Inherent strain, Residual welding stresses, t type welding

Enhancement of t Follicular Helper Cell-Mediated Humoral Immunity Reponses During Development of Experimental Autoimmune Myasthenia Gravis

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维普期刊数据库

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Neuroscience Bulletin 2019年第3期35卷 507-518页

作者： Ying-Zhe Cui Si-Ying Qu Lu-Lu Chang Jia-Rui Zhao Lili Mu Bo Sun Hu-Lun Li tong-Shuai Zhang Guang-You Wang Qing-Fei Kong Department of Neurobiology Heilongjiang Provincial Key Laboratory of Neurobiology Harbin Medical University

Myasthenia gravis(MG) is a prototypical antibody-mediated neurological autoimmune disease with the involvement of humoral immune responses in its pathogenesis. t follicular helper(tfh) cells have been implicated in many autoimmune diseases. However, whether and how tfh cells are involved in MG remain ***, we established and studied a widely-used and approved animal model of human MG, the rat model with acetylcholine receptor alpha(AChRa) subunit(RAChR97–116)-induced experimental autoimmune myasthenia gravis(EAMG). this model presented mild bodyweight loss 10 days after the first immunization(representing the early stage of disease) and more obvious clinical manifestations and body-weight loss 7 days after the second immunization(representing the late stage of disease). AChR-specific pre-tfh cells and mature tfh cells were detected in these two stages, respectively. In cocultures of tfh cells and B cells, the number of IgG2 bsecreting B cells and the level of anti-AChR antibodies in the supernatant were higher in the cultures containing EAMG-derived tfh cells. In immunohistochemistry and immunofluorescence assays, a substantial number of CD4^+/Bcl-6^+ t cells and a greater number of larger germinal centers were observed in lymph node tissues resected from EAMG rats. Based on these results, wehypothesize that an AChR-specific tfh cell-mediated humoral immune response contributes to the development of EAMG.

关键词： Follicular helper t cells Experimental autoimmune myasthenia gravis Acetylcholine receptor Germinal center

Chimeric antigen receptor t cells in solid tumors: a war against the tumor microenvironment

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Science China(Life Sciences) 2020年第2期63卷 180-205页

作者： Zijun Zhao Xiaoyun Xiao Phei Er Saw Wei Wu Hongyan Huang Jiewen Chen Yan Nie Guangdong Provincial Key Laboratory of Malignant tumor Epigenetics and Gene Regulation Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Breast tumor Center Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Department of Ultrasound Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China

Chimeric antigen receptor(CAR) t cell is a novel approach, which utilizes anti-tumor immunity for cancer treatment. As compared to the traditional cell-mediated immunity, CAR-t possesses the improved specificity of tumor antigens and independent cytotoxicity from major histocompatibility complex molecules through a monoclonal antibody in addition to the tcell receptor. CAR-t cell has proven its effectiveness, primarily in hematological malignancies, specifically where the CD19 CAR-t cells were used to treat B-cell acute lymphoblastic leukemia and B-cell lymphomas. Nevertheless, there is little progress in the treatment of solid tumors despite the fact that many CAR agents have been created to target tumor antigens such as CEA,EGFR/EGFRvIII, GD2, HER2, MSLN, MUC1, and other antigens. the main obstruction against the progress of research in solid tumors is the tumor microenvironment, in which several elements, such as poor locating ability, immunosuppressive cells,cytokines, chemokines, immunosuppressive checkpoints, inhibitory metabolic factors, tumor antigen loss, and antigen heterogeneity, could affect the potency of CAR-t cells. to overcome these hurdles, researchers have reconstructed the CAR-t cells in various ways. the purpose of this review is to summarize the current research in this field, analyze the mechanisms of the major barriers mentioned above, outline the main solutions, and discuss the outlook of this novel immunotherapeutic modality.

关键词： chimeric antigen t cell solid tumor tumor microenvironment

Engineering t cells for immunotherapy of primary human hepatocellular carcinoma

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Journal of Genetics and Genomics 2020年第1期47卷 1-15页

作者： Leidy DCaraballo Galva Lun Cai Yanxia Shao Yukai He Georgia Cancer Center.Medical College of Georgia Augusta University.AugustaGA.30912USA Department of Medicine.Medical College of Georgia Augusta UniversityAugustaGA30912USA

Liver cancers, majority of which are primary hepatocellular carcinoma(HCC), continue to be on the rise in the world. Furthermore, due to the lack of effective treatments, liver cancer ranks the 4th most common cause of male cancer deaths. Novel therapies are urgently needed. Over the last few years,immunotherapies, especially the checkpoint blockades and adoptive cell therapies of engineered t cells,have demonstrated a great potential for treating malignant tumors including HCC. In this review, we summarize the current ongoing research of antigen-specific immunotherapies including cancer vaccines and adoptive cell therapies for HCC. We briefly discuss the HCC cancer vaccine and then focus on the antigen-specific t cells genetically engineered with the t cell receptor genes(tCRts) and the chimeric antigen receptor genes(CARts). We first review the current options of tCRts and CARts immunotherapies for HCC, and then analyze the factors and parameters that may help to improve the design of tCRts and CARts to enhance their antitumor efficacy and safety. Our goals are to render readers a panoramic view of the current stand of HCC immunotherapies and provide some strategies to design better tCRts and CARts to achieve more effective and durable antitumor effects.

关键词： Immunotherapy Hepatocellular carcinoma t cell receptor Chimeric antigen receptor t cell engineering Gene transfer

Panaxdiol Saponins Component Promotes Hematopoiesis and Modulates t Lymphocyte Dysregulation in Aplastic Anemia Model Mice

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Chinese Journal of Integrative Medicine 2019年第12期25卷 902-910页

作者： ZHENG Zhi-yin YU Xiao-ling DAI tie-ying YIN Li-ming ZHAO Yan-na XU Min ZHUANG Hai-feng Chong Beng Hock GAO Rui-lan Institution of Hematology Research the First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhou(310006)China Department of Hematology St George HospitalSt George Clinical SchoolUniversity of New South WalesKogarah(NSW 2217)Australia

Objective: to investigate the potential efficacy of panaxadiol saponins component(PDS-C) in the treatment of aplastic anemia(AA) model mice. Methods: totally 70 mice were divided into 7 groups as follows: normal, model, low-, medium-, high-dose PDS-C(20, 40, 80 mg/kg, namely L-, M-, H-PDS-C), cyclosporine(40 mg/kg), and andriol(25 mg/kg) groups, respectively. An immune-mediated AA mouse model was established in BALB/c mice by exposing to 5.0 Gy total body irradiation at 1.0 Gy/min, and injecting with lymphocytes from DBA mice. On day 4 after establishment of AA model, all drugs were intragastrically administered daily for 15 days, respectively, while the mice in the normal and model groups were administered with saline solution. After treatment, the peripheral blood counts, bone marrow pathological examination, colony forming assay of bone marrow culture, t lymphocyte subpopulation analysis, as well as t-bet, GAtA-3 and Fox P3 proteins were detected by flow cytometry and Western blot. Results: the peripheral blood of white blood cell(WBC), platelet, neutrophil counts and hemoglobin(Hb) concentration were significantly decreased in the model group compared with the normal group(all Pto 3 dose PDS-C treatment, the WBC, platelet, neutrophil counts were significantly increased at a dose-dependent manner compared with the model group(all Pthe myelosuppression status of AA was significantly reduced in M-, H-PDS-C groups, and hematopoietic cell quantity of bone marrow was more abundant than the model group. the colony numbers of myeloid, erythroid and megakaryocytic progenitor cells in the model group were less than those of the normal mice in bone marrow culture, while, PDS-C therapy enhanced proliferation of hematopoietic progenitor cells by significantly increasing colony numbers(all Pthermore,PDS-C therapy increased peripheral blood CD3^+ and CD3^+CD4^+ cells and reduced CD3^+CD8^+ cells(Ptreatme

关键词： Panaxadiol saponins component aplastic anemia hematopoiesis t lymphocyte

Regulation of Virus Replication and t Cell Homeostasis by N^6-Methyladenosine

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Virologica Sinica 2019年第1期34卷 22-29页

作者： Jing Yang Hong Wang Wenyan Zhang Institute of Virology and AIDS Research The First Hospital of Jilin University

RNA modifications are abundant in eukaryotes, bacteria, and archaea. N^6-methyladenosine(m^6A), a type of RNA modification mainly found in messenger RNA(mRNA), has significant effects on the metabolism and function of m RNAs. this modification is governed by three types of proteins, namely methyltransferases as ‘‘writers' ', demethylases as ‘‘erasers' ',and specific m^6A-binding proteins(YtHDF1-3) as ‘‘readers' '. Further, it is important for the regulation of cell fate and has a critical function in many biological processes including virus replication, stem cell differentiation, and cancer development, and exerts its effect by controlling gene expression. Herein, we summarize recent advances in research on m^6A in virus replication and t cell regulation, which is a rapidly emerging field that will facilitate the development of antiviral therapies and the study of innate immunity.

关键词： RNA modification N^6-methyladenosine (m^6A) Virus replication t cell homeostasis

Property t for Actions

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Acta Mathematica Sinica,English Series 2019年第11期35卷 1807-1816页

作者： Qing MENG Li Guang WANG School of Mathematical Sciences Qufu Normal University

We study property t for an action α of a discrete group Γ on a unital C~*-algebra A. Our main results improve some well-known results about property t for groups. Moreover, we introduce Hilbert A-module property t and show that the action α has property t if and only if the reduced crossed product ■has Hilbert A-module property t.

关键词： Property t α-positive definite α-negative definite

Regulatory t Cells and their Clinical Applications in Antitumor Immunotherapy

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Engineering 2019年第1期5卷 132-139页

作者： Feng Xie Rui Liang Dan Li Bin Li Shanghai Institute of Immunology Shanghai Jiao Tong University School of Medicine Shanghai 200025 China Department of Immunology and Microbiology Shanghai Jiao Tong University School of Medicine Shanghai 200025 China

Cancer is a potentially life-threatening disease characterized by the immortalization of tumor cells in the host. Immunotherapy has recently gained increasing interest among researchers due to its tremendous potential for preventing tumor progression and metastasis. Regulatory t cells (tregs) are a subgroup of suppressive CD4^+ t cells that play a vital role in the maintenance of host immune homeostasis. treg deficiency can induce severe autoimmune, hypersensitivity, and auto-inflammatory disorders, among other diseases. tregs are commonly enriched in a tumor microenvironment, and a greater number of immune-suppressive tregs often indicates a poorer prognosis;therefore, there is renewed interest in the function of tregs and in their clinical application in antitumor immunotherapy. Accumulating strategies that focus on the depletion of tregs have appeared to be effective in antitumor immunity. It is expected that treg-targeting strategies will provide great opportunities for improving antitumor efficiency in combination with other therapeutics (e.g., chimeric antigen receptor t cell (CAR-t)-based cell therapy or immune checkpoint blockading).

关键词： Regulatory t cells Cancer Immunotherapy