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https://www.readbyqxmd.com/read/30546955/inhibition-of-mek-with-trametinib-enhances-the-efficacy-of-anti-pd-l1-inhibitor-by-regulating-anti-tumor-immunity-in-head-and-neck-squamous-cell-carcinoma
#1
Seong-Ho Kang, Bhumsuk Keam, Yong-Oon Ahn, Ha-Ram Park, Miso Kim, Tae Min Kim, Dong-Wan Kim, Dae Seog Heo
Major histocompatibility complex (MHC) class I downregulation is the primary immune evasion mechanism associated with failure in anti-PD-1/PD-L1 blockade therapies for cancer. Here, we examined the role of MEK signaling pathway inhibition in head and neck squamous cell carcinoma (HNSCC) both in vitro and in vivo . We found that trametinib, a small molecule inhibitor of MEK, significantly enhanced MHC class I and PD-L1 expression in human HNSCC cell lines, and this occurred via STAT3 activation. Trametinib also further upregulated the increase in CXCL9 and CXCL10 expression caused by IFN-γ in HNSCC cells, which is associated with T cell infiltration in tumor tissues...
2019: Oncoimmunology
https://www.readbyqxmd.com/read/30546945/dnax-activating-protein-10-co-stimulation-enhances-the-anti-tumor-efficacy-of-chimeric-antigen-receptor-t-cells
#2
Ruocong Zhao, Lin Cheng, Zhiwu Jiang, Xinru Wei, Baiheng Li, Qiting Wu, Suna Wang, Simiao Lin, Youguo Long, Xuchao Zhang, Yilong Wu, Xin Du, Duanqing Pei, Pentao Liu, Yangqiu Li, Shuzhong Cui, Yao Yao, Peng Li
Chimeric antigen receptor (CAR) T cell immunotherapies have shown remarkable efficacy in treating multiple types of hematological malignancies but are not sufficiently effective at treating solid tumors. NKG2D is a strong activating receptor for NK cells and a co-stimulatory receptor for T cells. NKG2D signal transduction depends on DNAX-activating protein 10 (DAP10). Here, we introduced the cytoplasmic domain of DAP10 into the second-generation CARs M28z and G28z to generate M28z10 and G28z10, which target mesothelin (MSLN) and glypican 3 (GPC3), respectively...
2019: Oncoimmunology
https://www.readbyqxmd.com/read/30544712/topical-application-of-jak1-jak2-inhibitor-momelotinib-exhibits-significant-anti-inflammatory-responses-in-dncb-induced-atopic-dermatitis-model-mice
#3
Wenyu Jin, Wei Huang, Liqing Chen, Mingji Jin, Qiming Wang, Zhonggao Gao, Zhehu Jin
Atopic dermatitis (AD) is a chronic recurrent skin disease dominated by T-helper 2 inflammation. Momelotinib (MMB) is a novel JAK1/JAK2 inhibitor suppressing the signal transduction of multiple pro-inflammatory cytokines. Recent studies indicated that JAK inhibitor could play a therapeutic role in AD disease. In this study, we evaluated the efficacy of MMB as a novel JAK1/JAK2 inhibitor in DNCB-induced AD mice and TSLP-activated dendritic cells. Our data showed that topical application of MMB reduced the skin severity scores and total serum IgE levels, and alleviated the histological indexes including epidermal thickness measurement and mast cell number...
December 10, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/30544288/efficient-interleukin-21-production-by-optimization-of-codon-and-signal-peptide-in-chinese-hamster-ovarian-cells
#4
Hee Jun Cho, Byung Moo Oh, Jong-Tae Kim, Jeewon Lim, Sang Yoon Park, Yo Sep Hwang, Kyoung Eun Baek, Bo-Yeon Kim, Inpyo Choi, Hee Gu Lee
Interleukin-21 is a common γ-chain cytokine that controls the immune responses of B cells, T cells, and natural killer cells. Targeting IL-21 to strengthen the immune system is promising for the development of vaccines as well as anti-infection and anti-tumor therapies. However, the practical application of IL-21 is limited by the high production cost. In this study, we improved IL-21 production by codon optimization and selection of appropriate signal peptide in CHO-K1 cells. Codon-optimized or non-optimized human IL-21 was stably transfected into CHO-K1 cells...
December 7, 2018: Journal of Microbiology and Biotechnology
https://www.readbyqxmd.com/read/30543054/hematopoietic-stem-cell-transplantation-in-patients-with-heterozygous-stat1-gain-of-function-mutation
#5
Ayca Kiykim, Louis Marie Charbonnier, Arzu Akcay, Elif Karakoc-Aydiner, Ahmet Ozen, Gulyuz Ozturk, Talal A Chatila, Safa Baris
PURPOSE: Human signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations present with a broad range of manifestations ranging from chronic mucocutaneous candidiasis and autoimmunity to combined immunodeficiency (CID). So far, there is very limited experience with hematopoietic stem cell transplantation (HSCT) as a therapeutic modality in this disorder. Here, we describe two patients with heterozygous STAT1 GOF mutations mimicking CID who were treated with HSCT...
December 13, 2018: Journal of Clinical Immunology
https://www.readbyqxmd.com/read/30539423/regulatory-t-cells-regulate-the-distribution-of-natural-killer-t-cells-through-cd39-signal-transduction-in-asthma
#6
Yanming Lu, Yaqin Li, Wenjing Zhou, Bo Ding, Qing Yu
Natural killer T cells (NKT cells) and regulatory T cells (Treg cells) are two important immune regulatory cells which both play critical roles in asthma. Our previous experiments revealed that activation of Treg cells suppressed NKT cells in asthma. However, the possible regulatory effects and the mechanisms linking Treg cells and NKT cells remain poorly understood. The current study was designed to further investigate the regulatory effect and its possible mechanisms of Treg cells on NKT cells function, especially the distribution of NKT cells...
December 11, 2018: Human Cell
https://www.readbyqxmd.com/read/30537988/hdac-is-indispensable-for-ifn-%C3%AE-induced-b7-h1-expression-in-gastric-cancer
#7
Rui Deng, Peng Zhang, Weizhen Liu, Xiangyu Zeng, Xianxiong Ma, Liang Shi, Tao Wang, Yuping Yin, Weilong Chang, Pei Zhang, Guobin Wang, Kaixiong Tao
BACKGROUND: B7 homolog 1 (B7-H1) overexpression on tumor cells is an important mechanism of immune evasion in gastric cancer (GC). Elucidation of the regulation of B7-H1 expression is urgently required to guide B7-H1-targeted cancer therapy. Interferon gamma (IFN-γ) is thought to be the main driving force behind B7-H1 expression, and epigenetic factors including histone acetylation are recently linked to the process. Here, we investigated the potential role of histone deacetylase (HDAC) in IFN-γ-induced B7-H1 expression in GC...
December 11, 2018: Clinical Epigenetics
https://www.readbyqxmd.com/read/30536991/ccr5-deficiency-enhances-hepatic-innate-immune-cell-recruitment-inflammation-in-a-murine-model-of-acute-hepatitis-b-infection
#8
Kathleen E Stevens, Chloe L Thio, William O Osburn
Human genetic studies demonstrate a link between the 32-bp deletion that produces a nonfunctional CCR5 receptor (CCR5∆32) and enhanced recovery from acute hepatitis B virus (HBV) infection. To investigate the role of CCR5 in immune responses to acute HBV, we intravenously infected Ccr5+/+ (WT) and Ccr5-/- (KO) mice with a replication-incompetent adenovirus containing the overlapping HBV1.3 construct (AdHBV), or vector control. At day 3 following AdHBV infection, analysis of intrahepatic leukocytes (IHL) showed KO mice had increased CD11b+ NK cells compared to WT (18...
December 8, 2018: Immunology and Cell Biology
https://www.readbyqxmd.com/read/30536524/the-role-of-eomes-in-human-cd4-t-cell-differentiation-a-question-of-context
#9
Anne S Dejean, Emeline Joulia, Thierry Walzer
Eomesodermin (Eomes) is a transcription factor (TF) of the T-box family closely related to T-bet known for its role in CD8 T cell and natural killer cell differentiation. However, the role of Eomes in CD4 T-cell differentiation is less well appreciated. In this issue of the European Journal of Immunology [Eur. J. Immunol. 2019. 49: XXXX-XXXX] Mazzoni et al. and Gruarin et al. studied the role of Eomes in human CD4 T-cell differentiation. Mazzoni et al. showed that Eomes plays a key role in helper T cell (Th) plasticity by favoring the phenotype shift of Th17 cells towards non-classic Th1 cells; while Gruarin et al...
December 7, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30536476/neonatal-influenza-specific-effector-ctls-retain-elevated-cd31-levels-at-the-site-of-infection-and-have-decreased-ifn-%C3%AE-production
#10
Adam J Fike, Ogan K Kumova, Virginie J Tardif, Alison J Carey
The underlying mechanisms that regulate neonatal immune suppression are poorly characterized. CD31 (PECAM1) is highly expressed on neonatal lymphocytes and is a known modulator of TCR signaling. To further characterize the role of CD31 in the neonatal CTL response, 3-d and 7-d-old murine neonates were infected with influenza virus and compared to adults. The majority of the pulmonary viral-specific CTLs in the 3-d-old murine neonate retain CD31 expression, whereas adult CTLs have decreased CD31 expression. In addition, CD31+ neonatal viral-specific CTLs demonstrate decreased IFN-γ production, decreased proliferative capacity, and increased likelihood of death...
December 11, 2018: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/30536048/jak-inhibitors-for-atopic-dermatitis-an-update
#11
Helen He, Emma Guttman-Yassky
Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. AD is driven by barrier dysfunction and abnormal immune activation of T helper (Th) 2, Th22, and varying degrees of Th1 and Th17 among various subtypes. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and spleen tyrosine kinase (SYK) pathways are involved in signaling of several AD-related cytokines, such as IFN-γ, IL-4, IL-13, IL-31, IL-33, IL-23, IL-22, and IL-17, mediating downstream inflammation and barrier alterations...
December 7, 2018: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/30533413/thy-1-cd90-signaling-preferentially-promotes-ror%C3%AE-t-expression-and-a-th17-response
#12
Suzanne Furlong, Melanie R Power Coombs, Javad Ghassemi-Rad, David W Hoskin
Thy-1 (CD90) is a glycosylphosphatidylinositol-anchored protein (GPI-AP) with signaling properties that is abundant on mouse T cells. Upon antibody-mediated crosslinking, Thy-1 provides a T cell receptor (TcR)-like signal that is sufficient to drive CD4+ T cell proliferation and differentiation into effector cells when costimulatory signals are provided by syngeneic lipopolysaccharide-matured bone marrow-derived dendritic cells. In this study, we investigated the impact of Thy-1 signaling on the production of the T helper (Th) cell subset-associated cytokines, interferon (IFN) γ, interleukin (IL)-4 and IL-17A, as well as the in vitro polarization of highly purified resting CD4+ T cells into Th1, Th2, and Th17 cells...
2018: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/30528734/eosinophils-attenuate-arthritis-by-inducing-m2-macrophage-polarization-via-inhibiting-the-i%C3%AE%C2%BAb-p38-mapk-signaling-pathway
#13
Liu Liu, Yuanyuan Zhang, Xu Zheng, Li Jin, Nan Xiang, Min Zhang, Zhu Chen
Rheumatoid arthritis (RA) represents a type of autoimmune disease that mainly affect the joints due to persistent synovitis. Eosinophils were Th2 effector cells that have been shown to have anti-inflammatory role recently. In this study, we aimed to investigate the effects of eosinophils transfer on arthritis and underlying mechanisms. DBA/1 mice were induced with collagen-induced arthritis (CIA) and treated with purified eosinophils at different time points. We showed that eosinophils transfer attenuated arthritis in CIA mice...
December 8, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/30522623/metformin-associated-inflammation-levels-regulation-in-type-2-diabetes-mellitus-tuberculosis-coinfection-patients-a-case-report
#14
Bernadette Dian Novita, Endang Isbandiati Soediono, Jusak Nugraha
IFN-γ elevation is one of the indicators of successful treatment in active tuberculosis (TB) infection due to macrophage and Th-1 activation in inducing autophagy process. However, IL-10 also inhibits interferon-mediated mycobactericid activities by blocking IFN-γ; signaling pathways in autophagy. Therefore, ratio IFN-γ/IL-10 has to be greater than 1 (>1) then IFN-γ remains has anti-mycobacterium. Metformin (MET) is a potent combination drug to elevate anti-TB efficacy and able to regulate inflammation...
October 2018: Indian Journal of Tuberculosis
https://www.readbyqxmd.com/read/30522193/-signaling-pathway-of-m2-type-polarization-induced-by-mycobacterium-tuberculosis-specific-peptide-e7-in-monocyte-macrophages
#15
H J Meng, J Wang, Y M Fang, D M Shen, L Mao, H B Kuang, H J Qin, X M Lai, S Y Tan
Objective: To explore the signal pathway of M2-type polarization induced by Mycobacterium tuberculosis (MTB)-specific peptide E7. Methods: Monocyte-macrophages were divided into blank control group, M1 positive stimulus group [co-stimulated with lipopolysaccharide and gamma interferon (IFN-γ)], M2 positive group(co-stimulated with IL-4 and IL-13), and E7 experimental group (with MTB-specificity polypeptide E7 stimulated). The expression of M1 type markers CD(16), IL-6, TNF-α and M2 type markers CD(163), CD(206), IL-10 were detected at 12, 18, 24 and 36 h...
December 12, 2018: Chinese Journal of Tuberculosis and Respiratory Diseases
https://www.readbyqxmd.com/read/30517881/clethodim-exposure-induces-developmental-immunotoxicity-and-neurobehavioral-dysfunction-in-zebrafish-embryos
#16
Guanghua Xiong, Lufang Zou, Yunyun Deng, Yunlong Meng, Xinjun Liao, Huiqiang Lu
Clethodim is one of the most widely used herbicides in agriculture, but its potential negative effects on aquatic organisms are still poorly understood. This study examined the effects of clethodim on zebrafish at aspects of early stage embryonic development, immune toxicity, cell apoptosis and locomotor behavior. Firstly, clethodim exposure markedly decreased the survival rate, body length, and heart rate and resulted in a series of morphological abnormalities, primarily spinal deformities (SD) and yolk sac edema, in zebrafish larvae...
December 2, 2018: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/30517642/insights-into-local-orbital-immunity-evidence-for-the-involvement-of-the-th17-cell-pathway-in-thyroid-associated-ophthalmopathy
#17
Sijie Fang, Yazhuo Huang, Ningjian Wang, Shuo Zhang, Sisi Zhong, Yinwei Li, Jing Sun, Xingtong Liu, Yang Wang, Ping Gu, Bin Li, Huifang Zhou, Xianqun Fan
Context: Unique features of local immunity in thyroid-associated ophthalmopathy (TAO) may affect disease progression. Objective: To investigate the association between the orbital immune microenvironment and TAO development. Design/Setting/Participants: TAO and control orbital connective tissues were collected. Main Outcome Measures: Single-cell sequencing examined orbital lymphocytic infiltrates. Multi-color flow cytometry explored the phenotypes of different cell subsets and in vitro models for cell functional studies...
December 3, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/30515321/immunosenescence-of-natural-killer-cells-inflammation-and-alzheimer-s-disease
#18
REVIEW
Corona Solana, Raquel Tarazona, Rafael Solana
Alzheimer's disease (AD) represents the most common cause of dementia in the elderly. AD is a neurodegenerative disorder characterized by progressive memory loss and cognitive decline. Although the aetiology of AD is not clear, both environmental factors and heritable predisposition may contribute to disease occurrence. In addition, inflammation and immune system alterations have been linked to AD. The prevailing hypothesis as cause of AD is the deposition in the brain of amyloid beta peptides (A β ). Although A β have a role in defending the brain against infections, their accumulation promotes an inflammatory response mediated by microglia and astrocytes...
2018: International Journal of Alzheimer's Disease
https://www.readbyqxmd.com/read/30515168/delivery-of-il-35-by-lactococcus-lactis-ameliorates-collagen-induced-arthritis-in-mice
#19
Massimo Maddaloni, Irina Kochetkova, Carol Hoffman, David W Pascual
IL-35, a relatively newly discovered cytokine belonging to the larger IL-12 family, shows unique anti-inflammatory properties, believed to be associated with dedicated receptors and signaling pathways. IL-35 plays a pivotal role in the development and the function of both regulatory B (Bregs) and T cells (Tregs). In order to further its therapeutic potential, a dairy Lactococcus lactis strain was engineered to express murine IL-35 (LL-IL35), and this recombinant strain was applied to suppress collagen-induced arthritis (CIA)...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/30514403/purinergic-targeting-enhances-immunotherapy-of-cd73-solid-tumors-with-piggybac-engineered-chimeric-antigen-receptor-natural-killer-cells
#20
Jiao Wang, Kyle B Lupo, Andrea M Chambers, Sandro Matosevic
BACKGROUND: The anti-tumor immunity of natural killer (NK) cells can be paralyzed by the CD73-induced generation of immunosuppressive adenosine from precursor ATP within the hypoxic microenvironment of solid tumors. In an effort to redirect purinergic immunosuppression of NK cell anti-tumor function, we showed, for the first time, that immunometabolic combination treatment with NKG2D-engineered CAR-NK cells alongside blockade of CD73 ectonucleotidase activity can result in significant anti-tumor responses in vivo...
December 4, 2018: Journal for Immunotherapy of Cancer
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