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| 1 | Molecular mechanisms of liver ischemia reperfusion injury:Insights from transgenic knockout models显示文摘Ischemia reperfusion injury is a major obstacle in liver resection and liver transplantation surgery.Understanding the mechanisms of liver ischemia reperfusion injury(IRI) and developing strategies to counteract this injury will therefore reduce acute complications in hepatic resection and transplantation,as well as expanding the potential pool of usable donor grafts.The initial liver injury is initiated by reactive oxygen species which cause direct cellular injury and also activate a cascade of molecular mediators leading to microvascular changes,increased apoptosis and acute inflammatory changes with increased hepatocyte necrosis.Some adaptive pathways are activated during reperfusion that reduce the reperfusion injury.IRI involves a complex interplay between neutrophils,natural killer T-cells cells,CD4+ T cell subtypes,cytokines,nitric oxide synthases,haem oxygenase-1,survival kinases such as the signal transducer and activator of transcription,Phosphatidylinositol 3-kinases/Akt and nuclear factor κβ pathways.Transgenic animals,particularly genetic knockout models,have become a powerful tool at elucidating mechanisms of liver ischaemia reperfusion injury and are complementary to pharmacological studies.Targeted disruption of the protein at the genetic level is more specific and maintained than pharmacological inhibitors or stimulants of the same protein.This article reviews the evidence from knockout models of liver IRI about the cellular and molecular mechanisms underlying liver IRI. | Gourab Datta Barry J Fuller Brian R Davidson | 2013 | World Journal of Gastroenterology2013，19，11： | 50 |
| 2 | Restoring the Treg cell to Th17 cell ratio may alleviate HBV-related acute-on-chronic liver failure显示文摘AIM: To investigate the role of T helper 17 cells (Th17) and regulatory T cells (Treg) in hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF).METHODS: We enrolled 79 patients with HBV infection into the study, 50 patients with HBV-related ACLF and 29 patients with chronic hepatitis B (CHB), from the First Affiliated Hospital of Medical College from January 2009 to June 2012. The ACLF patients were diagnosed according to the criteria recommended by The 19th Conference of the Asian Pacific Association for the Study of the Liver in 2009. Twenty healthy individuals with a similar gender and age structures to the two patient groups were also included as the normal controls (NC). Of the 50 ACLF patients, 28 were subsequently classified as non-survivors: 19 patients died from multiorgan failure, 3 underwent liver transplantation, and 6 discontinued therapy during follow-up because of financial reasons. The remaining 22 ACLF patients whose liver and anticoagulation function recovered to nearly normal levels within the next 6 mo were classified as survivors. The number of circulating Treg and Th17 cells was determined upon diagnosis and during the 8th week of follow-up through flow cytometry. RESULTS: The percentage of circulating Treg cells in the ACLF group was significantly higher than that in the CHB group (5.50% ± 1.15% vs 3.30% ± 1.13%, P < 0.01). The percentages of circulating Th17 cells in the ACLF and the CHB groups were significantly higher than that in the NC group (6.32% ± 2.22% vs 1.56% ± 0.44%, P < 0.01; 3.53% ± 1.65% vs 1.56% ± 0.44%, P < 0.01). No significant difference in Treg cell to Th17 cell ratio was observed between the ACLF group and the CHB group (0.98 ± 0.44 vs 1.12 ± 0.64, P = 0.991), whereas those in the two HBV infection groups were significantly lower than that in the NC group (1.85 ± 1.22; both P < 0.01). The percentage of Treg cells in the survivors during the 8th week of follow-up was significantly lower than that during peak ACLF severity [total bilirubin (TBIL) peak] (3.45% ± 0.97% vs 5.18% ± 1.02%, P < 0.01). The percentage of Th17 cells in survivors during the 8th week of follow-up was significantly lower than that during the peak TBIL (2.89% ±0.60% vs 5.24% ± 1.46%; P < 0.01). The Treg cell to Th17 cell ratio during the 8 th week of follow-up was significantly higher than that during the TBIL peak (1.22 ± 0.36 vs 1.10 ± 0.54; P < 0.05). CONCLUSION: Restoring the Treg cell to Th17 cell ratio during the follow-up phase of ACLF could maintain the immune system at a steady state, which favours good prognosis. | Ying-Hua Niu Dong-Lin Yin Hong-Li Liu Rui-Tian Yi Yu-Cong Yang Hong-An Xue Tian-Yan Chen Shu-Lin Zhang Shu-Mei Lin Ying-Ren Zhao | 2013 | World Journal of Gastroenterology2013，19，26： | 36 |
| 3 | Th17 plasticity and its changes associated with inflammatory bowel disease显示文摘CD4 T helper(Th) cell differentiation into distinct T cell subsets is critical to the normal function of the immune system. Until recently,the paradigm held that na?ve T cells differentiated into distinct subsets under the guidance of environmental cues(e.g.,cytokines) and that once polarized,these cells were committed to a particular functional state. However,the existence of transdifferentiated T cell populations,which express signature transcription factors and cytokines associated with more than one Th subset,challenges the immutability of T helper subsets and suggests that plasticity is a feature of multifaceted immune responses. How this process impacts immune dysregulation in diseases such as inflammatory bowel diseases(IBD) and the machinery that underlies this process is far from fully understood. Interleukin(IL)-17 secreting helper T(Th17) cells have been heavily implicated in tissue-specific immune pathology including murine models of IBD,human Crohn's disease and ulcerative colitis. Plasticity within this subset is suggested by the existence of IL-17 secreting cells,which,can also secrete interferon-γ,the signature cytokine for Th1 cells or,can co-express the anti-inflammatory transcription factor forkhead box p3,a signature transcription factor of regulatory T cells. In this review we mainly discuss evidence for Th17 plasticity,mechanisms,which govern it,and highlight the potential to therapeutically target this process in human IBD. | Aito Ueno Abhisek Ghosh Daniel Hung Ji Li Humberto Jijon | 2015 | World Journal of Gastroenterology2015，21，43： | 23 |
| 4 | Management of cytokine release syndrome related to CAR-T cell therapy显示文摘Chimeric antigen receptor T (CAR-T) cell therapy is a novel cellular immunotherapy that is widely used to treat hematological malignancies, including acute leukemia, lymphoma, and multiple myeloma. Despite its remarkable clinical effects, this therapy has side effects that cannot be underestimated. Cytokine release syndrome (CRS) is one of the most clinically important and potentially life-threatening toxicities. This syndrome is a systemic immune storm that involves the mass cytokines releasing by activated immune cells. This phenomenon causes multisystem damages and sometimes even death. In this study, we reported the management of a patient with recurrent and refractory multiple myeloma and three patients with acute lymphocytic leukemia who suffered CRS during CAR-T treatment. The early application of tocilizumab, an anti-IL-6 receptor antibody, according to toxicity grading and clinical manifestation is recommended especially for patients who suffer continuous hyperpyrexia, hypotensive shock, acute respiratory failure, and whose CRS toxicities deteriorated rapidly. Moreover, low doses of dexamethasone (5-10 mg/day) were used for refractory CRS not responding to tocilizumab. The effective management of the toxicities associated with CRS will bring additional survival opportunities and improve the quality of life for patients with cancer. | Hongli Chen Fangxia Wang Pengyu Zhang Yilin Zhang Yinxia Chen Xiaohu Fan Xingmei Cao Jie Liu Yun Yang Baiyan Wang Bo Lei Liufang Gu Ju Bai Lili Wei Ruili Zhang Qiuchuan Zhuang Wanggang Zhang Wanhong Zhao Aili He | 2019 | Frontiers of Medicine2019，13，5： | 21 |
| 5 | Impaired balance of T helper 17/T regulatory cells in carbon tetrachloride-induced liver fibrosis in mice显示文摘AIM:To investigate the effect of T helper(Th)17/T regulatory(Treg)cells on hepatic fibrosis in mice and its possible mechanism.METHODS:Hepatic fibrosis was induced by intraperitoneal injection of carbon tetrachloride.Hepatic pathological changes were observed by hematoxylin and eosin staining;the protein levels of interleukin(IL)-6,transforming growth factor(TGF)-βandα-smooth muscle actin(SMA)in liver tissue were determined by Western blotting;and the frequency of Th17 and Treg cells in the liver was estimated by flow cytometry.In addition,hepatic stellate cells were isolated from healthy mouse liver and co-cultured with Th17 or Treg cells.Immunofluorescence staining and Western blotting were performed to determine the change in HSC activation.RESULTS:In the model group,there were different degrees of fibroplasia,degeneration and necrosis.The protein levels of IL-6,TGF-βandα-SMA in liver tissue were significantly higher than those in the control group at 12 wk(P<0.05).Compared with the control group,the frequency of Th17 cells in the model group was increased but the frequency of Treg cells decreased gradually.Furthermore,at 4,8 and 12 wk,there were significant differences in the number of Th17 cells(0.52%±0.16%,1.46%±0.24%,and2.60%±0.41%,respectively,P<0.05)and Treg cells(2.99%±0.40%,2.16%±0.50%,and 1.49%±0.34%,respectively,P<0.05).In vitro,Th17 cells promoted,whereas Treg cells inhibited the expression ofα-SMA,both in a dose-dependent manner,compared with the control group.CONCLUSION:Th17/Treg imbalance exists in mice with liver fibrosis,which potentially promotes liver fibrosis via HSC activation. | Xiao-Fei Sun Lei Gu Wen-Sheng Deng Qing Xu | 2014 | World Journal of Gastroenterology2014，20，8： | 20 |
| 6 | Clostridium butyricum alleviates intestinal low-grade inflammation in TNBS-induced irritable bowel syndrome in mice by regulating functional status of lamina propria dendritic cells显示文摘BACKGROUND Irritable bowel syndrome (IBS) is one of the most common functional gastroenterological diseases characterized by abnormal visceral sensitivity and lowgrade inflammation. The role of Clostridium butyricum (C. butyricum) in reducing intestinal low-grade inflammation via immune pathways has been well defined. However, the detailed mechanisms of the effects of C. butyricum on intestinal mucosal immunity, especially on immune cells of the lamina propria, remain unclear. Dendritic cells (DCs), which are important immune cells, secrete proinflammatory cytokines (IL-1β, IL-6, and others) and express T cell immunoglobulin and mucin domain-3 (TIM3), promoting proliferation and activation of DCs, and mediating Th1 and Th17 inflammatory responses. AIM To investigate the role of DCs in the development of IBS in a rat model and to understand the regulation of DCs after C. butyricum intervention. METHODS An IBS animal model was established using C57BL/6 mice, and C. butyricum was continuously administered via the intragastric route to simulate different intestinal immune states. Intestinal visceral hypersensitivity and histopathology were assessed using the abdominal withdrawal reflex (AWR) test and hematoxylin & eosin (H&E) staining, respectively. The expression of proinflammatory cytokines (IL-1β and IL-6) and TIM3 was analyzed by Western blot analysis and real-time PCR. Flow cytometry was applied to analyze the quantity, function, and membrane molecule TIM3 of the lamina propria dendritic cells (LPDCs). The regulatory effect of C. butyricum was verified in bone marrowderived dendritic cells by in vitro experiments. RESULTS The secretion of proinflammatory cytokines (IL-1β and IL-6) in mice with IBS was significantly increased compared with that of the control group, which suggested that the intestinal mucosa in mice with IBS was in a low-grade inflammatory state. The expression of CD11C+CD80+ and CD11c+TIM3+ in intestinal LPDCs in mice with IBS increased significantly. Meanwhile, the cytokines (IL-1β and IL-6) were significantly reduced after the intervention with probiotic C. butyricum. The amount and function of LPDCs and the TIM3 on the surface of the LPDCs were decreased with the alleviation of the intestinal inflammatory response. CONCLUSION The results suggest that C. butyricum regulates the amount and functional status of LPDCs in the intestinal mucosa of mice with IBS, and therefore modulates the local immune response in the intestine. | Qin Zhao Wen-Rong Yang Xiao-Hong Wang Gai-Qin Li Lei-Qi Xu Xiao Cui Yang Liu Xiu-Li Zuo | 2019 | World Journal of Gastroenterology2019，25，36： | 20 |
| 7 | Adoptive cell transfer therapy for hepatocellular carcinoma显示文摘Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. This malignancy is associated with poor prognosis and high mortality. Novel approaches for prolonging the overall survival of patients with advanced HCC are urgently needed. The antitumor activities of adoptive cell transfer therapy (ACT), such as strategies based on tumor-infiltrating lymphocytes and cytokine-induced killer cells, are more effective than those of traditional strategies. Currently, chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved numerous breakthroughs in the treatment of hematological malignancies, including relapsed or refractory lymphoblastic leukemia and refractory large B-cell lymphoma? Nevertheless, this approach only provides a modest benefit in the treatment of solid tumors. The clinical results of CAR-T immunotherapy for HCC that could be obtained at present are limited. Some published studies have demonstrated that CAR-T could inhibit tumor growth and cause severe side effects. In this review, we summarized the current application of ACT, the challenges encountered by CAR-T technology in HCC treatment, and some possible strategies for the future direction of immunotherapeutic research. | Renyu Zhang Zhao Zhang Zekun Liu Ding Wei Xiaodong Wu Huijie Bian Zhinan Chen | 2019 | Frontiers of Medicine2019，13，1： | 17 |
| 8 | Aberrant TGF-β1 signaling contributes to the development of primary biliary cirrhosis in murine model显示文摘AIM:To investigate whether transforming growth factor-β1(TGF-β1)signaling pathway is involved in the pathogenesis of primary biliary cirrhosis(PBC).METHODS:A murine model of PBC was developed by injection of polyinosinic polycytidylic acids(polyⅠ:C)in C57BL/6 mice,and the liver expressions of TGFβ1,TGF-βreceptorⅠ(TβRⅠ),TGF-βreceptorⅡ(TβRⅡ),p-Smad2/3,monoclonalα-smooth muscle actin antibody(α-SMA)andα1(Ⅰ)collagen in the mouse model and control mice were evaluated by immunohistochemistry,immunoblotting and real-time polymerase chain reaction(RT-PCR).Lymphocyte subsets in liver were analyzed using flow cytometry.RESULTS:The mouse model had several key phenotypic features of human PBC,including elevated levels of alkaline phosphatase,antimitochondrial antibodies,portal bile ducts inflammation,and progressive collagen deposition.Compared with control mice,protein and mRNA levels of TGFβ1,TβRⅠ,TβRⅡ,p-Smad2/3,α-SMA andα1(Ⅰ)collagen in liver(1.7±0.4 vs 8.9±1.8,0.8±0.2 vs 5.1±1.5,0.6±0.01 vs5.1±0.1,0.6±0.3 vs 2.0±0.3,0.9±0.4 vs 3.4±0.6,0.8±0.4 vs 1.7±0.3,1.1±1.2 vs 11.8±0.6,P<0.05),and the total number and percentage of CD4+CD25+FOXP3+and CD8+lymphocytes(0.01±0.001vs 0.004±0.00,0.12±0.04 vs 0.52±0.23,P<0.01)were higher in the mouse model.CONCLUSION:TGFβ1 might play a dual role in the development of PBC:it suppresses inflammatory response but operates to enhance fibrogenesis.The aberrant activity of TGF-β1 signaling contributes to the development of PBC. | Bin Liu Xuan Zhang Feng-Chun Zhang Jin-Bao Zong Wen Zhang Yan Zhao | 2013 | World Journal of Gastroenterology2013，19，35： | 14 |
| 9 | Bone metastases:When and how lung cancer interacts with bone显示文摘Bone metastasis is a common and debilitating consequence of lung cancer:30%-40% of patients with nonsmall cell lung cancer develop bone metastases during the course of their disease. Lung cancer cells find a favorable soil in the bone microenvironment due to factors released by the bone matrix, the immune system cells, and the same cancer cells. Many aspects of the cross-talk among lung tumor cells, the immune system,and bone cells are not clear, but this review aims to summarize the recent findings in this field, with particular attention to studies conducted to identify biomarkers for early detection of lung cancer bone metastases. | Ilaria Roato | 2014 | World Journal of Clinical Oncology2014，5，2： | 14 |
| 10 | Emergence of immunotherapy as a novel way to treat hepatocellular carcinoma显示文摘Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC. | Naofumi Mukaida Yasunari Nakamoto | 2018 | World Journal of Gastroenterology2018，24，17： | 13 |
| 11 | Protective Effect of Ganshuang Granules(肝爽颗粒)on Liver Cirrhosis by Suppressing Regulatory T Cells in Mouse Model显示文摘Objective: To investigate the potential antifibrotic mechanisms of Chinese medicine Ganshuang Granules(肝爽颗粒, GSG) and to provide clinical therapeutic evidence of its effects. Methods: A cirrhotic mouse model was established by intraperitoneally injecting a mixture of CCl_4(40%) and oil(60%) at 0.2 mL per 100 g of body weight twice a week for 12 weeks. After 12-week modeling, GSG was intragastric administrated to the mice for 2 weeks, and the mice were divided into low-, medium-and high-dose groups at doses of 1, 2 and 4 g/(kg·day), respectively. Liver morphology changes were observed using Masson's trichrome staining and B-ultrasound. The levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST) and hyaluronic acid(HA) in serum were detected using an automatic biochemistry analyzer. The expressions of desmin, smooth muscle actin(SMA) and Foxp3 in liver were detected by immunofluorescence. The regulatory T cell(Treg) frequency was determined through flow cytometry analysis. Collagen-Ⅰ, SMA, IL-6, tumor necrosis factor α(TNF-α), interleukin(IL)-1β and transforming growth factor β1(TGF-β1) expression levels were measured using quantitative polymerase chain reaction(qPCR). Results: Masson's staining result showed fewer pseudolobule structures and fibrous connective tissue in the GSG-treatment groups than in the spontaneous recovery group. Ultrasonography showed that GSG treatment reduced the number of punctate hyperechoic lesions in mice cirrhotic livers. The serum ALT, AST, HA levels were significantly ameliorated by GSG treatment(ALT: F=8.104, P=0.000; AST: F=7.078, P=0.002; and HA: F=7.621, P=0.001). The expression levels of collagen-Ⅰ and SMA in the cirrhotic livers were also attenuated by GSG treatment(collagen-Ⅰ: F=3.938, P=0.011; SMA: F=4.115, P=0.009). Tregs, which were elevated in the fibrotic livers, were suppressed by GSG treatment(F=8.268, P=0.001). The expressions of IL-6, TNF-α and IL-1β increased, and TGF-β levels decreased in the cirrhotic livers after GSG treatment(IL-6: F=5.457, P=0.004; TNF-α: F=6.023, P=0.002; IL-1β: F=6.658, P=0.001; and TGF-β1: F=11.239, P=0.000). Conclusions: GSG promoted the resolution/regression of cirrhosis and restored liver functions in part by suppressing Treg cell differentiation, which may be mediated by hepatic stellate cells. | LIU Yan-min SHI Hong-bo LIU Yi-rong SHI Hong-lin REN Feng CHEN Yu CHEN De-xi LOU Jin-li DUAN Zhong-ping | 2019 | Chinese Journal of Integrative Medicine2019，25，1： | 12 |
| 12 | Immune therapy for human papillomaviruses-related cancers显示文摘Human papillomaviruses(HPVs) are a large family of double strand DNA viruses comprising more than 180 types. Infection with HPV is very common and it is associated with benign and malignant proliferation of skin and squamous mucosae. Many HPVs, considered lowrisk such as HPV 6 and 11, produce warts; while highrisk viruses, such as HPVs 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, and 58, induce tumors. About 5% of all cancers in men and women are associated with HPV infection. Because there are not antiviral drugs for HPV infection, current therapies for low-risk HPV infections involve physical removal of the lesion by cryotherapy, trichloracetic acid, laser, or surgical removal. Surgical procedures are effective in the treatment of precancerous lesions, however after these procedures, many recurrences appear due to new re-infections, or to failure of the procedure to eliminate the HPV. In addition, HPV can inhibit recognition of malignant cellsby the immune system, leading to the development of cancer lesions. When this occurs, radiotherapy and chemotherapy are then used. Unfortunately, about 50% of the HPV-cancer patients still die. In the past decade, a better knowledge of the natural history of the virushost interaction and of the immune response against this viral infection has brought new therapeutic strategies geared to modulate the immune system to generate an efficient virus-specific cytotoxic response. Novel HPV protein-expressing vaccines have shown some significant clinical efficacy and systemic HPV-specific cytotoxic T cell responses. This review will describe the current status of the several therapeutic strategies used to treat HPV-induced lesions, and discuss the various new therapies now being tested. | Ricardo Rosales Carlos Rosales | 2014 | World Journal of Clinical Oncology2014，5，5： | 11 |
| 13 | Immunotherapy for colorectal cancer显示文摘The incidence of colorectal cancer(CRC)is on the rise,and the prognosis for patients with recurrent or metastatic disease is extremely poor.Although chemotherapy and radiation therapy can improve survival rates,it is imperative to integrate alternative strategies such as immunotherapy to improve outcomes for patients with advanced CRC.In this review,we will discuss the effect of immunotherapy for inducing cytotoxic T lymphocytes and the major immunotherapeutic approaches for CRC that are currently in clinical trials,including peptide vaccines,dendritic cell-based cancer vaccines,whole tumor cell vaccines,viral vector-based cancer vaccines,adoptive cell transfer therapy,antibody-based cancer immunotherapy,and cytokine therapy.The possibility of combination therapies will also be discussed along with the challenges presented by tumor escape mechanisms. | Shigeo Koido Toshifumi Ohkusa Sadamu Homma Yoshihisa Namiki Kazuki Takakura Keisuke Saito Zensho Ito Hiroko Kobayashi Mikio Kajihara Kan Uchiyama Seiji Arihiro Hiroshi Arakawa Masato Okamoto Jianlin Gong Hisao Tajiri | 2013 | World Journal of Gastroenterology2013，19，46： | 11 |
| 14 | Effect of combined treatment with cyclophosphamidum and allicin on neuroblastoma-bearing mice显示文摘Objective:To evaluate the efficacy of allicin combined with cyclophosphamide on neuroblastoma(NB)-bearing mice and explore the immunological mechanism in it.Methods:A total of 30NB-bearing mice were equally randomized into model group,cyclophosphamide group and combined therapy group,10 nudemice were set as normal saline(NS) group.Cyclophosphamide group and combined therapy group were weekly injected with 60 mg/kg cyclophosphamide for four weeks;besides,combined therapy group was given with allicin(10 mg/kg/d) by gastric perfusion for 4 weeks;model group and NS group were given with the same volume of NS.Serum VEGF content was detected by ELISA pre-treating(0 d) and on the 3rd d.14 th d and 28 th d;on29th d,all mice were sacrificed and the tumor,liver,spleen and thymic tissues were weighted.Tumors were made into paraffin section for detecting tumor cell apoptosis and proliferation by TUNEI.and BrdU method,respectively.Survival curves were drawn by Kaplan-Meier method.Results:After treatment,both treatment groups relieved on viscera indexes,VEGF level,T cell subsets distribution and tumor growth and each index of combined therapy group was better than cyclophosphamide group(P<0.05 or 0.01);only combined therapy group could significantly increase the lifetime of NB-bearing mice(χ~2=5.667,P=0.017).Conclusions:Allicin can improve T cell subsets distribution and inhibit VEGF expression through its immunomodulatory activity,thereby improve the efficiency on NB in coordination with cyclophosphamide. | Xiang-Yang Gao Xian-Jie Geng Wen-Long Zhai Xian-Wei Zhang Yuan Wei Guang-Jun Hou | 2015 | Asian Pacific Journal of Tropical Medicine2015，8，2： | 11 |
| 15 | Activation of natural killer T cells contributes to triptolide-induced liver injury in mice显示文摘Triptolide (TP) is the main active ingredient of Tripterygium wilfordii Hook.f, which has attracted great interest due to its promising efficacy for autoimmune diseases and tumors. However, severe adverse reactions, especially hepatotoxicity, have restricted its approval in the market. In the present study we explored the role of hepatic natural killer T (NKT) cells in the pathogenesis of TP-induced liver injury in mice. TP (600μg/kg/day, i.g.) was administered to female mice for 1, 3, or 5 days. We found that administration of TP dose-dependently induced hepatotoxicity, evidenced by the body weight reduction, elevated serum ALT and AST levels, as well as significant histopathological changes in the livers. However, the mice were resistant to the development of TP-induced liver injury when their NKT cells were depleted by injection of anti-NK1.1 mAb (200μg, i.p.) on days-2 and-1 before TP administration. We further revealed that TP administration activated NKT cells, dominantly releasing Th1 cytokine IFN-γ, recruiting neutrophils and macrophages, and leading to liver damage. After anti-NK1.1 injection, however, the mice mainly secreted Th2 cytokine IL-4 in the livers and exhibited a significantly lower percentage of hepatic infiltrating neutrophils and macrophages upon TP challenge. The activation of NKT cells was associated with the upregulation of Toll-like receptor (TLR) signaling pathway. Collectively, these results demonstrate a novel role of NKT cells contributing to the mechanisms of TP-induced liver injury. More importantly, the regulation of NKT cells may promote effective measures that control drug-induced liver injury. | Xin-zhi Wang Ru-feng Xue Shen-ye Zhang Ya-ting Zheng Lu-yong Zhang Zhen-zhou Jiang | 2018 | Acta Pharmacologica Sinica2018，39，12： | 9 |
| 16 | Effects of estrogen on CD4^+ CD25^+ regulatory T cell in peripheral blood during pregnancy显示文摘Objective To investigate the effects of estrogen(E_2)level on regulatory T cells(Treg)in peripheral blood during pregnancy.Methods:A total of 30 healthy non-pregnant women were selected as control group,90 pregnant women of early,middle and late pregnancy and 30 postpartum women at 1 month after parturition were selected as experimental groups including early pregnancy group,middle pregnancy group and late pregnancy group;the proportions of CD4^+CD25^+Treg and CD4^+CD25^+CD127^-Treg among CD4 T cells were detected by flow cytometry;the serum estrogen content in peripheral blood was detected by electrochemical immune luminescence method.Results:E_2 level was coincident with the change of Tregs number during pregnancy.The estrogen content in peripheral blood increased gradually from early pregnancy to late pregnancy,then decreased significantly after parturition,and the level at 1 month after parturition down to the level in non-pregnancy group(P>0.05);the level of E_2 in pregnancy groups were significantly higher than those in non-pregnancy group(P<0.01);and there were significant differences among early pregnancy group,middle pregnancy group and late pregnancy group(P<0.05).The proportions of CD4^+CD25^+Treg and CD4^+CD25^+CD127^-Treg in pregnancy groups were significantly higher than those in non-pregnancy group(P<0.05),but decreased significantly after parturition,and there was no significant difference between non-pregnancy group and postpartum women group(P>0.05):the proportions in middle and late pregnancy groups were significantly higher than those in early pregnancy group(P<0.05).but decreased slightly in late pregnancy group,there was no significant difference between late pregnancy group and middle pregnancy group(P>0.05).There was correlation between Tregs number with estrogen level during pregnancy.The proportion of CD4^+CD25^+Treg and CD4^+CD25^+CD 127^-Treg were positively correlated with estrogen level.Conclusions:High proportion of CD4^+CD25^+Trcg and CD4^+CD25^+CD127^-Treg is closely related to the high level of E,during pregnancy.It suggested that high level of estrogen may induce an increase of CD4^+CD25^+Treg in peripheral blood.and then influence the immune function of pregnant women.The results of this experiment might play an important role of estrogen in immune-modulation during pregnancy. | Yuan-Huan Xiong Zhen Yuan Li He | 2013 | Asian Pacific Journal of Tropical Medicine2013，6，9： | 9 |
| 17 | Immunology of tuberculosis显示文摘Various T cells and macrophages as well as cytokines are involved in the immunopathogenesis of tuberculosis(TB). A better understanding of immunology of TB can not only lead to the discovery of new immunodiagnostic tools, accelerate and facilitate the assessment of new therapeutic methods, but also find new treatment regimens. In this highlight topic we cover the latest developments in the role of T cells, macrophages, Natural killer(NK) cells, invariant NK T(iN KT) cells and γδ T cells with TB infection. Histologically, TB displays exudative inflammation, proliferative inflammation and productive inflammation depending on the time course. T cells first recognize antigen within the mycobacterially-infected lung, and then activate, differentiate, but the first T cell activation occurs in the draining lymph nodes of the lung. When protective T cells reach sufficient numbers, they can stop bacterial growth. Except for T cells, neutrophils also participate actively in defense against early-phase TB. NK cells are innate lymphocytes which are a first line of defense against mycobacterial infection. Human NK cells use the NKp46, NCRs and NKG2 D receptors to lyse Mycobacterium TB-infected monocytes and alveolar macrophages. NK cells produce not only interferon-γ, but also interleukin(IL)-22, which is induced by IL-15 and DAP-10. iN KT cells show different phenotypes and functions. Many iN KT cells are CD4+,few iN KT cells are CD8+, while an additional fraction of iN KT cells are negative for both CD4 and CD8. γδ T cells represent an early innate defense in antimycobacterial immunity. Studies done in humans and animal models have demonstrated complex patterns of γδ T cell immune responses during chronic TB. Human alveolar macrophages and monocytes can serve as antigen presentation cells for γδ T cells. Furthermore, the predominance of Vγ9Vδ2 T cells in TB has been confirmed. | Qing Zhang Isamu Sugawara | 2012 | World Journal of Experimental Medicine2012，2，4： | 8 |
| 18 | Engineering T cells for immunotherapy of primary human hepatocellular carcinoma显示文摘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. | Leidy DCaraballo Galva Lun Cai Yanxia Shao Yukai He | 2020 | Journal of Genetics and Genomics2020，47，1： | 8 |
| 19 | Molecular feature and therapeutic perspectives of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome显示文摘Regulatory T(Treg) cells, a subtype of immunosuppressive CD4^+T cells, are vital for maintaining immune homeostasis in healthy people. Forkhead box protein P3(FOXP3), a member of the forkhead-wingedhelix family, is the pivotal transcriptional factor of Treg cells. The expression, post-translational modifications, and protein complex of FOXP3 present a great impact on the functional stability and immune plasticity of Treg cells in vivo. In particular, the mutation of FOXP3 can result in immune dysregulation,polyendocrinopathy, enteropathy, X-linked(IPEX) syndrome, which is a rare genetic disease mostly diagnosed in early childhood and can soon be fatal. IPEX syndrome is related to several manifestations,including dermatitis, enteropathy, type 1 diabetes, thyroiditis, and so on. Here, we summarize some recent findings on FOXP3 regulation and Treg cell function. We also review the current knowledge about the underlying mechanism of FOXP3 mutant-induced IPEX syndrome and some latest clinical prospects.At last, this review offers a novel insight into the role played by the FOXP3 complex in potential therapeutic applications in IPEX syndrome. | Qianru Huang Xu Liu Yujia Zhang Jingyao Huang Dan Li Bin Li | 2020 | Journal of Genetics and Genomics2020，47，1： | 8 |
| 20 | Prognostic value of programmed death.1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1.4N+M0 gastric adenocarcinoma显示文摘Background: Anti-programmed death-1/programmed death-ligand 1(PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses of patients with gastric cancer to anti-PD-1/PD-L1 immunotherapy is controversial. Some studies suggested that intra-and inter-tumoral heterogeneity of PD-L1 expression might explain the controversy.This study aimed to analyze the expression of PD-L1, PD-L2, and PD-1 as well as CD8(+) T-cell density in primary tumors and lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma to explore the heterogeneity of PD-1 signaling pathway molecules.Methods: In primary tumors and metastatic as well as non-metastatic lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma, we detected PD-L1 and PD-L2 expression with immunohistochemistry. CD8(+)T-cell density in primary tumors and PD-1 expression on CD8(+)T cells were detected with immunofluorescence. Univariate analysis was used to determine the prognostic values of them. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival and disease-free survival.Results: Among 119 eligible patients who had undergone surgical resection, the positive rate of PD-L1 was higher in metastatic lymph nodes than in primary tumors(45.4% vs. 38.7%, P = 0.005); the positive rate of PD-1 on CD8(+)T cells was significantly higher in primary tumors and metastatic lymph nodes than in tumor-free lymph nodes(both P < 0.001). The intensity of PD-1 expression on CD8(+) T cells in primary tumors and in metastatic lymph nodes were stronger than that in tumor-free lymph nodes from the same patient. Beside, the positive rate of PD-L2 did not show any differences between primary tumors and metastatic lymph nodes. In multivariate analysis, PD-L1 expression,PD-L2 expression, a low density of CD8(+) T cells in primary tumors, and PD-1 expression on CD8(+) T cells in primary tumors were associated with poor prognosis.Conclusion: The expression of PD-L1 is heterogeneous in primary tumors and in metastatic lymph nodes from patients with stageT1-4 N+M0 gastric adenocarcinoma, which might explain the inconsistent results in assessing the prognostic value of PD-L1 expression in previous studies. | Yuan Gao Su Li Dazhi Xu Shangxiang Chen Yuchen Cai Wenqi Jiang Xinke Zhang Jin Sun Kefeng Wang Boyang Chang Fenghua Wang Minghuang Hong | 2017 | Chinese Journal of Cancer2017，36，11： | 8 |
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