Trispecific killer engager 161519 enhances natural killer cell function and provides anti-tumor activity against CD19-positive cancers

Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.Methods:We constructed a trispecific killer engager(TriKE)consisting of anti-CD16,IL-15,and anti-CD19.This TriKE was designed to attract CD19^(+)tumor cells to CD16^(+)NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK cells.Results:Treatment with 161519 TriKE in the presence of CD19^(+)targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK cells.NK cells"armed"with 161519 TriKE showed stronger cytolysis against CD19+targets compared with that of"unarmed"NK cells.A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 BiKE.Combined use of IL-2 was a more effective treatment with 1619 BiKE,when compared with that using 161519 TriKE.Conclusions:The newly generated 161519 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19+tumor cells.The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.

Effect of Metformin on Lactate Metabolism in Normal Hepatocytes under High Glucose Stress in Vitro

Objective To study the effect of metformin on lactate metabolism in hepatocytes in vitro under high glucose stress.In vitro LO2 cells,liver cells were randomly divided into blank control group,25 tendency/L glucose solution,27 tendency/L glucose solution,29 tendency/L glucose solution,31 tendency/L glucose solution,33 tendency/L glucose solution,35 tendency/L glucose solution treatment group,the optimal concentation of 31 tendency after L,use 30 tendency for L metformin solution,and then divided into blank control group,the optimal concentration of glucose solution,normal liver cells+metformin solution normal liver cells.The optimal concentration of glucose solution normal liver cells+metformin solution respectively in the 12h,24 h,48 h on cell count plate to calculate the mumber of liver cells,and using lactic acid determination kit the optimal concentration of glucose solution+normal liver cells and normal liver cells+the optimal concentration of glucose solution+metformin solution respectively in the 12 h,24 h,48 h of cell cultures of lactic acid value.There was no significant change in the lactic acid concentration but significant increase in the number of suviving hepatocytes in the high-glycemic control group compared with that in the high-glycemic control group without metformin.Metformin has no significant effect on lactic acid metabolism of hepatocytes under high glucose stess in vito,and has a protective effect on hepatocytes under high glucose stress.Based on this,it is preliminanily believed that metformin is not the direct factor leading to diabetic lactic acidosis.

Hepatitis B Virus Down-Regulates Expressions of MHC Class I Molecules on Hepatoplastoma Cell Line

Chronic HBV infection is associated with a 100-fold high risk of developing hepatocellular carcinoma. Tumor recognition is of the most importance during the immune surveillance process that prevents cancer development in humans. In the present study, the expressions of MHC class Ⅰ molecules on hepatoplastoma cell line HepG2.2.15 were investigated to indicate the possible effects of HBV on the immune recognition during HBV-associated hepatocellular carcinoma. It was found that the expressions of MHC class Ⅰ molecules HLA-ABC, HLA-E and MICA were much lower in HepG2.2.15 cells compared with HepG2 cells. The expressing HBV in human hepatoplastoma cell line significantly down-regulated the expressions of MHC class Ⅰ molecules. Additionally, it was observed that in murine chronic HBsAg carriers the expression of classical MHC-I molecule on hepatocytes was down-regulated. These results demonstrated that HBV might affect the immune recognition during HBV- associated hepatocellular carcinoma such as the recognition of CD8^＋ T, NK-CTL and NK cells and prevent the immune surveillance against tumors. However, the effects of HBV down-regulation of MHC class I molecules on the target cells in vivo should be further studied. Cellular ＆ Molecular Immunology.

Innate lymphocytes:pathogenesis and therapeutic targets of liver diseases and cancer

The liver is a lymphoid organ with unique immunological properties,particularly,its predominant innate immune system.The balance between immune tolerance and immune activity is critical to liver physiological functions and is responsible for the sensitivity of this organ to numerous diseases,including hepatotropic virus infection,alcoholic liver disease,nonalcoholic fatty liver disease,autoimmune liver disease,and liver cancer,which are major health problems globally.In the past decade,with the discovery of liver-resident natural killer cells,the importance of innate lymphocytes with tissue residency has gradually become the focus of research.In this review,we address the current knowledge regarding hepatic innate lymphocytes with unique characteristics,including NK cells,ILC1/2/3s,NKT cells,γδ T cells,and MAIT cells,and their potential roles in liver homeostasis maintenance and the progression of liver diseases and cancer.A better understanding of the immunopathogenesis of hepatic innate lymphocytes will be helpful for proposing effective treatments for liver diseases and cancer.

Norlichexanthone purified from plant endophyte prevents postmenopausal osteoporosis by targeting ERa to inhibit RANKL signaling

Although different types of drugs are available for postmenopausal osteoporosis,the limitations of the current therapies including drug resistances and adverse effects require identification of novel anti-osteoporosis agents.Here,we defined that norlichexanthone(NOR),a natural product,is a ligand of estrogen receptor-alpha(ERα)and revealed its therapeutic potential for postmenopausal osteoporosis.We used mammalian-one hybrid assay to screen for ERαmodulators from crude extracts of several plant endophytes.As a result,NOR purified from the extract of endophyte ARL-13 was identified as a selective ERαmodulator.NOR directly bound to ERαwith an affinity in nanomolar range,revealing that it is a natural ligand of ERα.NOR induced osteoblast formation in MC3T3-E1 precursor cells.Conversely,NOR inhibited receptor activator of nuclear factor-kappa B ligand(RANKL)-induced osteoclast formation in both RAW264.7 macrophages and mouse primary monocytes.Mechanistically,NOR inhibited RANKL-induced association of ERαand TRAF6 to prevent ERα-mediated TRAF6 activation via Lys63-linked ubiquitination.Importantly,NOR exhibited potent anti-osteoporosis efficacy in an ovariectomized mouse model.Comparing to estrogen,NOR was of much less capability in stimulating endometrial hyperplasia and promoting mammalian cancer cell proliferation.Taken together,our study identified NOR as a natural and high affinity ligand of ERαwith substantial anti-osteoporosis but less estrogenic activity.

Soluble CD163 and CD163 Expression on Monocytes Associated with Chronic Hepatitis B Inflammation and HBsAg Loss

Background and Aims:Monocyte/macrophage-associat-ed CD163 is an indicator of the severity of liver inflam-mation and cirrhosis,but the difference of soluble CD163(sCD163)levels in chronic hepatitis B(CHB)patients and hepatitis B surface antigen(HBsAg)-loss patients is un-clear.Herein,we aimed to compare the sCD163 levels in CHB patients and HBsAg-loss patients with or without an-tiviral treatment.Methods:sCD163 and CD163 expres-sion on monocytes were compared among four groups,healthy subjects,treatment-naïve CHB patients,sponta-neous HBsAg-loss patients,and treatment-related HBsAg-loss patients.The correlation between sCD163 levels and clinical parameters in CHB patients was analyzed.A group of 80 patients with hepatitis B virus(HBV)infection and liver biopsy were recruited.Results:sCD163 levels were higher in the CHB group than in the other three groups.sCD163 levels were higher in treatment-related HBsAg-loss patients than in spontaneous HBsAg-loss patients.sCD163 levels were negatively correlated with hepatitis B e-antigen(HBeAg)and HBsAg levels in HBeAg-positive patients.Liv-er biopsy results further demonstrated that sCD163 levels were elevated in CHB patients with substantial inflamma-tion(A≥2)or fibrosis(F≥2).The sCD163 model was more sensitive in predicting inflammation than other noninvasive models.Its levels were higher in patients with normal ala-nine aminotransferase levels and significant inflammation(A≥2)than in patients with no or mild inflammation.Con-clusions:sCD163 and CD163 expression on monocytes were associated with CHB inflammation and HBsAg loss,and may be used as markers to predict HBV-specific im-mune activation.

HBsAg-specific CD8^(+)T cells as an indispensable trigger to induce murine hepatocellular carcinoma

Hepatitis B virus(HBV)-associated hepatocellular carcinoma(HCC)is mediated by an inappropriate attack by HBV-specific T cells in patients.However,this immunopathogenic process has not been clarified because of the lack of a suitable animal model.Here,we used immunocompetent Fah^(-/-)mice as the recipients in the adoptive transfer of HBsAg^(+)hepatocytes from HBs-Tg mice to replace the recipient hepatocytes(HBs-HepR).HBs-HepR mice exhitited persistent HBsAg expression with chronic hepatitis and eventually developed HCC with a prevalence of 100%.HBsAg-specific CD8^(+)T cells were generated and specifically and continuously induced hepatocyte apoptosis with progressive chronic inflammation,and the depletion of CD8^(+)T cells or their deficiency prevented HCC,which could then be reproduced by the transfer of HBsAg-specific CD8^(+)T cells.In summary,our results demonstrated that CD8^(+)T cells plays a critical role in HBsAg-driven inflammtion and HCC tumorigenesis.

Regional immunity in tissue homeostasis and diseases

The immune system functions in the organ/tissue of the body.The immune cell differentiation and function are influenced by the organ/tissue microenvironments in which they reside,and the interaction of immune cells with the organ/tissue microenvironments may affect and even determine the outcome of the immune responses(Hu and Pasare,2013;Zajac and Harrington,2014).It has been

Antibiotics in Drinking Water and Health Risks — China, 2017

Summary What is already known about this topic?Antibiotic contaminations in the environment are understood to pose human health risks including disturbing the microbiome in the human body and producing antibiotic-resistant bacteria,which pose serious public health risks.Antibiotics have been detected in aquatic environments and drinking water worldwide.

Natural killer cell lines in tumor immunotherapy

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.