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https://www.readbyqxmd.com/read/29578532/critical-role-of-ox40-signaling-in-the-tcr-independent-phase-of-human-and-murine-thymic-treg-generation
#1
Prabhakaran Kumar, Alejandra Marinelarena, Divya Raghunathan, Vandhana K Ragothaman, Shikha Saini, Palash Bhattacharya, Jilao Fan, Alan L Epstein, Ajay V Maker, Bellur S Prabhakar
Regulatory T cells (Tregs) play a pivotal role in immune-tolerance, and loss of Treg function can lead to the development of autoimmunity. Natural Tregs generated in the thymus substantially contribute to the Treg pool in the periphery, where they suppress self-reactive effector T cells (Teff) responses. Recently, we showed that OX40L (TNFSF4) is able to drive selective proliferation of peripheral Tregs independent of canonical antigen presentation (CAP-independent) in the presence of low-dose IL-2. Therefore, we hypothesized that OX40 signaling might be integral to the TCR-independent phase of murine and human thymic Treg (tTreg) development...
March 26, 2018: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/29563320/an-ox40-ox40l-interaction-directs-successful-immunity-to-hepatitis-b-virus
#2
Jean Publicover, Anuj Gaggar, Jillian M Jespersen, Ugur Halac, Audra J Johnson, Amanda Goodsell, Lia Avanesyan, Stephen L Nishimura, Meghan Holdorf, Keith G Mansfield, Joyce Bousquet Judge, Arya Koshti, Michael Croft, Adil E Wakil, Philip Rosenthal, Eric Pai, Stewart Cooper, Jody L Baron
Depending on age of acquisition, hepatitis B virus (HBV) can induce a cell-mediated immune response that results in either cure or progressive liver injury. In adult-acquired infection, HBV antigens are usually cleared, whereas in infancy-acquired infection, they persist. Individuals infected during infancy therefore represent the majority of patients chronically infected with HBV (CHB). A therapy that can promote viral antigen clearance in most CHB patients has not been developed and would represent a major health care advance and cost mitigator...
March 21, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29554934/ox40l-induces-helper-t-cell-differentiation-during-cell-immunity-of-asthma-through-pi3k-akt-and-p38-mapk-signaling-pathway
#3
Li Huang, Meijuan Wang, Yongdong Yan, Wenjing Gu, Xinxing Zhang, Jiahong Tan, Huiming Sun, Wei Ji, Zhengrong Chen
BACKGROUND: The aim of this study was to investigate the mechanisms of OX40L in regulating helper T (Th) cells differentiation through phosphoinositide 3-kinase (PI3K)/AKT and p38 mitogen-activated protein kinase signaling pathway in vitro and in vivo experiments. METHODS: Serum samples of patients with asthma and healthy controls were used to explore the association between OX40L and Th cells. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum concentrations of OX40L, IL-4, IFN-γ, IL-17 and TGF-β...
March 20, 2018: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29545330/potent-immune-modulation-by-medi6383-an-engineered-human-ox40-ligand-igg4p-fc-fusion-protein
#4
Michael D Oberst, Catherine Auge, Chad Morris, Stacy Kentner, Kathy Mulgrew, Kelly McGlinchey, James Hair, Shino Hanabuchi, Qun Du, Melissa Damschroder, Hui Feng, Steven Eck, Nicholas Buss, Lolke de Haan, Andrew J Pierce, Haesun Park, Andrew Sylwester, Michael K Axthelm, Louis Picker, Nicholas P Morris, Andrew Weinberg, Scott A Hammond
Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells...
March 15, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29455927/fibroblast-heterogeneity-and-immunosuppressive-environment-in-human-breast-cancer
#5
Ana Costa, Yann Kieffer, Alix Scholer-Dahirel, Floriane Pelon, Brigitte Bourachot, Melissa Cardon, Philemon Sirven, Ilaria Magagna, Laetitia Fuhrmann, Charles Bernard, Claire Bonneau, Maria Kondratova, Inna Kuperstein, Andrei Zinovyev, Anne-Marie Givel, Maria-Carla Parrini, Vassili Soumelis, Anne Vincent-Salomon, Fatima Mechta-Grigoriou
Carcinoma-associated fibroblasts (CAF) are key players in the tumor microenvironment. Here, we characterize four CAF subsets in breast cancer with distinct properties and levels of activation. Two myofibroblastic subsets (CAF-S1, CAF-S4) accumulate differentially in triple-negative breast cancers (TNBC). CAF-S1 fibroblasts promote an immunosuppressive environment through a multi-step mechanism. By secreting CXCL12, CAF-S1 attracts CD4+ CD25+ T lymphocytes and retains them by OX40L, PD-L2, and JAM2. Moreover, CAF-S1 increases T lymphocyte survival and promotes their differentiation into CD25High FOXP3High , through B7H3, CD73, and DPP4...
February 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29431869/separation-of-plasma-derived-exosomes-into-cd3-and-cd3-fractions-allows-for-association-of-immune-cell-and-tumor-cell-markers-with-disease-activity-in-hnscc-patients
#6
Marie-Nicole Theodoraki, Thomas K Hoffmann, Theresa L Whiteside
Head and neck squamous cell carcinoma (HNSCC) is a highly immunosuppressive malignancy. Exosomes in HNSCC patients' plasma are enriched in inhibitory cargo and mediate immunosuppression. As these exosomes are products of various cells, the cellular origin of immunoregulatory proteins they carry is unknown. To test whether tumor- or T cell-derived exosomes in patient's plasma are immunosuppressive and impact on disease activity, we separated CD3(-) from CD3(+) exosomes by immunocapture using anti-CD3 Abs. The exosome protein cargo was evaluated for immunoregulatory proteins using on-bead flow cytometry...
February 12, 2018: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/29424313/mesenchymal-stem-cells-inhibited-dendritic-cells-via-the-regulation-of-stat1-and-stat6-phosphorylation-in-experimental-autoimmune-uveitis
#7
L Dong, X Chen, H Shao, L Bai, X Li, X Zhang
PURPOSE: We have previously reported that MSCs inhibited experimental autoimmune uveitis (EAU) in rodent models induced by either uveitogenic antigens or antigen-specific T cells. In this study, we explored the inhibitory mechanisms of MSCs on dendritic cells (DCs) in EAU. METHODS: We collected the DCs from the lymph nodes of MSC treated or untreated EAU rats, as well as bone marrow derived DCs cultured in vitro with or without MSC treatment. The levels of costimulatory molecules of CD80, CD86, CD40, OX40L and suppressors of cytokine signaling (SOCS1, SOCS2, and SOCS3) on these DCs were analyzed by flow Cytometry...
February 7, 2018: Current Molecular Medicine
https://www.readbyqxmd.com/read/29407480/characterisation-of-chicken-ox40-and-ox40l
#8
Stephanie Scherer, Thomas W Göbel
The Tumour Necrosis Factor superfamilies of receptors and ligands play a crucial role in the regulation of effective immune responses against pathogens and malignant cells. In chickens, only few members have been identified. Here, we characterise the chicken homologues for mammalian costimulatory molecules OX40 and OX40L, which are involved in sustaining T cell responses. Both genes were identified by virtue of their genomic localisation close to highly conserved genes and their structural relationship to their mammalian homologues...
January 27, 2018: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/29344664/crucial-role-of-ox40-ox40l-signaling-in-a-murine-model-of-asthma
#9
Wei Lei, Daxiong Zeng, Gaoqin Liu, Yehan Zhu, Jiajia Wang, Hongya Wu, Junhong Jiang, Jianan Huang
The aim of the present study was to explore the roles of OX40/OX40 ligand (OX40L) signaling and OX40+ T cells in ovalbumin (OVA)‑induced mouse asthma model. Asthma was induced by OVA exposure and subsequent co‑treatment with OX40L protein, neutralizing anti‑OX40L blocking antibody, OX40+ T cells or PBS. The protein expression levels of interleukin (IL)‑4, IL‑6, IL‑13, IL‑17, tumor necrosis factor (TNF)‑α and interferon (IFN)‑γ in bronchoalveolar lavage fluid (BALF) were examined using murine cytokine‑specific ELISA...
January 18, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29330050/production-and-characterization-of-a-novel-site-specific-modifiable-anti-ox40-receptor-single-chain-variable-fragment-for-targeted-drug-delivery
#10
Aki Tanabe, Kazumi Nakano, Makoto Nakakido, Satoru Nagatoishi, Yuetsu Tanaka, Kouhei Tsumoto, Kaoru Uchimaru, Toshiki Watanabe
OX40 receptor (tumor necrosis factor receptor superfamily, member 4; CD134) is a T-cell co-stimulatory molecule that plays an important role in T-cell activation and survival. OX40 receptor is activated by its ligand, OX40L; and modulation of the OX40-OX40L interaction is a promising target for the treatment of autoimmune diseases and cancers. Here, we generated a high-affinity anti-OX40 single-chain variable fragment carrying a C-terminal cysteine residue (scFvC). Physicochemical and functional analyses revealed that the scFvC bound to OX40-expressing cells and was internalized via OX40-mediated endocytosis without inducing phosphorylation of IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha), an important complex in the classical NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathway...
February 5, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29321210/the-immune-checkpoint-modulator-ox40-and-its-ligand-ox40l-in-nk-cell-immunosurveillance-and-acute-myeloid-leukemia
#11
Tina Nuebling, Carla Emilia Schumacher, Martin Hofmann, Ilona Hagelstein, Benjamin Joachim Schmiedel, Stefanie Maurer, Birgit Federmann, Kathrin Rothfelder, Malte Roerden, Daniela Dörfel, Pascal Schneider, Gundram Jung, Helmut Rainer Salih
The TNF receptor family member OX40 promotes activation and proliferation of T cells, which fuels efforts to modulate this immune checkpoint to reinforce antitumor immunity. Besides T cells, NK cells are a second cytotoxic lymphocyte subset that contributes to antitumor immunity, particularly in leukemia. Accordingly, these cells are being clinically evaluated for cancer treatment through multiple approaches, such as adoptive transfer of ex vivo expanded polyclonal NK cells (pNKC). Here, we analyzed whether and how OX40 and its ligand (OX40L) influence NK-cell function and antileukemia reactivity...
February 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29209565/tumor-targeted-costimulation-with-antibody-fusion-proteins-improves-bispecific-antibody-mediated-immune-response-in-presence-of-immunosuppressive-factors
#12
Sabrina Sapski, Nadine Beha, Roland Kontermann, Dafne Müller
Therapeutic strategies aiming for the induction of an effective immune response at the tumor site can be severely hampered by the encounter of an immunosuppressive microenvironment. We investigated here the potential of concerted costimulation by tumor-directed antibody-fusion proteins with B7.1, 4-1BBL and OX40L to enforce bispecific antibody-induced T cell stimulation in presence of recognized immunosuppressive factors including IL-10, TGF-β, indoleamine 2,3-dioxygenase (IDO), PD-L1 and regulatory T cells...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29207606/combination-therapy-with-an-ox40l-fusion-protein-and-a-vaccine-targeting-the-transcription-factor-twist-inhibits-metastasis-in-a-murine-model-of-breast-cancer
#13
Anthony S Malamas, Scott A Hammond, Jeffrey Schlom, James W Hodge
OX40 is a costimulatory receptor that potentiates proliferation, survival, memory formation, and effector function of CD4+ and CD8+ T-cells, while overcoming the suppressive activity of regulatory T-cells (Tregs). Here, we explored the combination of an OX40L fusion protein (OX40L-FP) with a poxvirus-based cancer vaccine (MVA-Twist-TRICOM) to inhibit tumor metastasis in the 4T1 murine breast cancer model. Contrary to the single agent treatments, the combination therapy significantly decreased the number of metastatic colonies per lung and prolonged survival...
October 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/29150240/dichotomous-expression-of-tnf-superfamily-ligands-on-antigen-presenting-cells-controls-post-priming-anti-viral-cd4-t-cell-immunity
#14
Yu-Han Chang, Kuan Chung Wang, Kuan-Lun Chu, Derek L Clouthier, Anh T Tran, Miguel S Torres Perez, Angela C Zhou, Ali A Abdul-Sater, Tania H Watts
T cell antigen-presenting cell (APC) interactions early during chronic viral infection are crucial for determining viral set point and disease outcome, but how and when different APC subtypes contribute to these outcomes is unclear. The TNF receptor superfamily (TNFRSF) member GITR is important for CD4+ T cell accumulation and control of chronic lymphocytic choriomeningitis virus (LCMV). We found that type I interferon (IFN-I) induced TNFSF ligands GITRL, 4-1BBL, OX40L, and CD70 predominantly on monocyte-derived APCs and CD80 and CD86 predominantly on classical dendritic cells (cDCs)...
November 21, 2017: Immunity
https://www.readbyqxmd.com/read/29147616/mrna-expression-levels-of-genes-involved-in-antitumor-immunity-identification-of-a-3-gene-signature-associated-with-prognosis-of-muscle-invasive-bladder-cancer
#15
Constance Le Goux, Sophie Vacher, Géraldine Pignot, Mathilde Sibony, Nicolas Barry Delongchamps, Benoit Terris, Eliane Piaggio, Marc Zerbib, Diane Damotte, Ivan Bieche
Immunotherapy for bladder cancer has given promising results. Here we aimed to evaluate the possible involvement and prognostic value of 33 genes involved in the immune response during bladder carcinogenesis. Expression levels were assessed by quantitative real-time RT-PCR in normal and tumor human bladder samples. Immunohistochemistry was performed to evaluate the protein expression of 2 genes and relation of the mRNA and protein levels was analyzed. Tumors were obtained from 154 patients (83 with muscle-invasive bladder cancer [MIBC] and 71 non-MIBC [NMIBC]) who underwent transurethral bladder resection or radical cystectomy between 2002 and 2006...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29124973/divergent-hypersensitivity-responses-following-topical-application-of-the-quaternary-ammonium-compound-didecyldimethylammonium-bromide
#16
Hillary L Shane, Ewa Lukomska, Aleksandr B Stefaniak, Stacey E Anderson
Didecyldimethylammonium bromide (DDAB) is a fourth generation dialkyl-quaternary ammonium compound (QAC) that is used in numerous products for its antimicrobial properties. While many QACs have been associated with allergic disease, the toxicity and sensitization of DDAB have not been thoroughly investigated. The purpose of these studies was to evaluate the irritancy and sensitization potential of DDAB following dermal application in a murine model. DDAB induced significant irritancy (0.0625-2%), evaluated by ear swelling in female BALB/c mice...
December 2017: Journal of Immunotoxicology
https://www.readbyqxmd.com/read/29118006/the-immunobiology-of-cd27-and-ox40-and-their-potential-as-targets-for-cancer-immunotherapy
#17
REVIEW
Sarah L Buchan, Anne Rogel, Aymen Al-Shamkhani
In recent years, monoclonal antibodies (mAbs) able to reinvigorate antitumor T-cell immunity have heralded a paradigm shift in cancer treatment. The most high profile of these mAbs block the inhibitory checkpoint receptors PD-1 and CTLA-4 and have improved life expectancy for patients across a range of tumor types. However, it is becoming increasingly clear that failure of some patients to respond to checkpoint inhibition is attributable to inadequate T-cell priming. For full T-cell activation, 2 signals must be received, and ligands providing the second of these signals, termed costimulation, are often lacking in tumors...
January 4, 2018: Blood
https://www.readbyqxmd.com/read/29100993/hepatitis-c-virus-induced-natural-killer-cell-proliferation-involves-monocyte-derived-cells-and-the-ox40-ox40l-axis
#18
Julia Pollmann, Jana-Julia Götz, Daniel Rupp, Otto Strauss, Markus Granzin, Oliver Grünvogel, Pascal Mutz, Catharina Kramer, Felix Lasitschka, Volker Lohmann, Niklas K Björkström, Robert Thimme, Ralf Bartenschlager, Adelheid Cerwenka
BACKGROUND & AIMS: Natural killer (NK) cells are found at increased frequencies in patients with hepatitis C virus (HCV). NK cell activation has been shown to correlate with HCV clearance and to predict a favourable treatment response. The aim of our study was to dissect mechanisms leading to NK cell activation and proliferation in response to HCV. METHODS: NK cell phenotype, proliferation, and function were assessed after the 6-day co-culture of human peripheral blood mononuclear cells with either HCV replicon-containing HuH6 hepatoblastoma cells or HCV-infected HuH7...
March 2018: Journal of Hepatology
https://www.readbyqxmd.com/read/29081529/transplantation-combining-ox40l-and-mtor-blockade
#19
Sarah Crunkhorn
No abstract text is available yet for this article.
October 30, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/29024606/role-of-the-tslp-dc-ox40l-pathway-in-asthma-pathogenesis-and-airway-inflammation-in-mice
#20
Shuang Feng, Li Zhang, Xu-Hua Bian, Ying Luo, Guang-Hui Qin, Rui-Ming Shi
This study aims to explore the effect of the TSLP/DC/OX40L pathway in asthma pathogenesis and airway inflammation in mice. Sixty-five male BALF/c mice were divided into the control, asthma, IgG + asthma (IgG, 500 g/500 l, intratracheal injection of 50 l each time), LY294002 (OX40L inhibitor) + asthma (intratracheal injection of 2 mg/kg LY294002), and anti-TSLP + asthma (intratracheal injection of 500 ug/500 l TSLP antibody, 50 l each time) groups. ELISA was applied to measure the serum levels of IgE, ovalbumin (OVA)-sIgE, interleukin-4 (IL-4), IL-5, IL-13 and interferon-γ (IFN-γ), flow cytometry was employed to detect Treg cells and dendritic cell (DC) and lymphopoiesis...
October 12, 2017: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
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