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CD40L

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https://www.readbyqxmd.com/read/29155846/soluble-cd40-ligand-directly-alters-glomerular-permeability-and-may-act-as-a-circulating-permeability-factor-in-fsgs
#1
Sophie Doublier, Cristina Zennaro, Luca Musante, Tiziana Spatola, Giovanni Candiano, Maurizio Bruschi, Luca Besso, Massimo Cedrino, Michele Carraro, Gian Marco Ghiggeri, Giovanni Camussi, Enrico Lupia
CD40/CD40 ligand (CD40L) dyad, a co-stimulatory bi-molecular complex involved in the adaptive immune response, has also potent pro-inflammatory actions in haematopoietic and non-haematopoietic cells. We describe here a novel role for soluble CD40L (sCD40L) as modifier of glomerular permselectivity directly acting on glomerular epithelial cells (GECs). We found that stimulation of CD40, constitutively expressed on GEC cell membrane, by the sCD40L rapidly induced redistribution and loss of nephrin in GECs, and increased albumin permeability in isolated rat glomeruli...
2017: PloS One
https://www.readbyqxmd.com/read/29155517/expression-of-cd40-cd40l-in-colon-cancer-and-its-effect-on-proliferation-and-apoptosis-of-sw48-colon-cancer-cells
#2
Xueqin Pang, Lifeng Zhang, Jiaming Wu, Chen Ma, Chuanyong Mu, Guangbo Zhang, Weichang Chen
PURPOSE: To study was to study the expression of CD40/CD40L in colon cancer and investigate the effects of CD40/CD40L overexpression on the proliferation and apoptosis of SW48 colon cancer cell line. METHODS: Immunohistochemistry was used to detect the expression of CD40 protein in colon cancer tissue samples from 70 patients, and 10 adjacent normal tissue samples. A CD40L gene-containing plasmid was transfected into SW48 colon cancer cells using lipofectamine 2000...
July 2017: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
https://www.readbyqxmd.com/read/29154745/differential-gene-expression-in-chicken-primary-b-cells-infected-ex-vivo-with-attenuated-and-very-virulent-strains-of-infectious-bursal-disease-virus-ibdv
#3
Katherine L Dulwich, Efstathios S Giotis, Alice Gray, Venugopal Nair, Michael A Skinner, Andrew J Broadbent
Infectious bursal disease virus (IBDV) belongs to the family Birnaviridae and is economically important to the poultry industry worldwide. IBDV infects B cells in the bursa of Fabricius (BF), causing immunosuppression and morbidity in young chickens. In addition to strains that cause classical Gumboro disease, the so-called 'very virulent' (vv) strain, also in circulation, causes more severe disease and increased mortality. IBDV has traditionally been controlled through the use of live attenuated vaccines, with attenuation resulting from serial passage in non-lymphoid cells...
November 20, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/29133396/repression-of-mir-31-by-bcl6-stabilizes-the-helper-function-of-human-follicular-helper-t-cells
#4
A Ripamonti, E Provasi, M Lorenzo, M De Simone, V Ranzani, S Vangelisti, S Curti, R J P Bonnal, L Pignataro, S Torretta, J Geginat, G Rossetti, M Pagani, S Abrignani
Follicular helper T cells (TFHs) are a key component of adaptive immune responses as they help antibody production by B cells. Differentiation and function of TFH cells are controlled by the master gene BCL6, but it is largely unclear how this transcription repressor specifies the TFH program. Here we asked whether BCL6 controlled helper function through down-regulation of specific microRNAs (miRNAs). We first assessed miRNA expression in TFH cells and defined a TFH-specific miRNA signature. We report that hsa-miR-31-5p (miR-31) is down-regulated in TFH; we showed that BCL6 suppresses miR-31 expression by binding to its promoter; and we demonstrated that miR-31 inhibits the expression of molecules that control T-helper function, such as CD40L and SAP...
November 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29132233/prospects-for-modulating-the-cd40-cd40l-pathway-in-the-therapy-of-the-hyper-igm-syndrome
#5
Xiangxue Meng, Bin Yang, Wen-Chen Suen
The critical role of the CD40/CD40L pathway in B-cell proliferation, immunoglobulin (Ig) isotype switching and germinal center formation has been studied and described extensively in previous literature. Interruption of the CD40/CD40L signal causes hyper-IgM (HIGM) syndrome, which has been classified and recognized as a group of rare inherited immune deficiency disorders. Defects in CD40 and CD40L interactions or in downstream signaling molecules, including activation-induced cytidine deaminase, uracyl-DNA-glycosylase, NF-κB and DNA repair enzymes, result in an increased level of serum IgM and a significantly decreased or absent level of IgA, IgG and IgE that is accompanied by severe recurrent infections and autoimmune diseases...
January 1, 2017: Innate Immunity
https://www.readbyqxmd.com/read/29127458/safety-pharmacokinetics-and-pharmacodynamics-of-single-rising-doses-of-bi-655064-an-antagonistic-anti-cd40-antibody-in-healthy-subjects-a-potential-novel-treatment-for-autoimmune-diseases
#6
Fredrik N Albach, Frank Wagner, Andreas Hüser, Julia Igel, David Joseph, James Hilbert, Corinna Schoelch, Steven J Padula, Jürgen Steffgen
PURPOSE: The CD40-CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and lupus nephritis. The safety, pharmacokinetics and pharmacodynamics of BI 655064, a novel humanised antagonistic anti-CD40 monoclonal antibody, were investigated in this first-in-human trial. METHODS: Healthy male subjects (n = 72) were randomised 3:1, within each BI 655064 dose group, to single intravenous (IV; 0...
November 10, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29127283/environmental-sensing-by-mature-b-cells-is-controlled-by-the-transcription-factors-pu-1-and-spib
#7
Simon N Willis, Julie Tellier, Yang Liao, Stephanie Trezise, Amanda Light, Kristy O'Donnell, Lee Ann Garrett-Sinha, Wei Shi, David M Tarlinton, Stephen L Nutt
Humoral immunity requires B cells to respond to multiple stimuli, including antigen, membrane and soluble ligands, and microbial products. Ets family transcription factors regulate many aspects of haematopoiesis, although their functions in humoral immunity are difficult to decipher as a result of redundancy between the family members. Here we show that mice lacking both PU.1 and SpiB in mature B cells do not generate germinal centers and high-affinity antibody after protein immunization. PU.1 and SpiB double-deficient B cells have a survival defect after engagement of CD40 or Toll-like receptors (TLR), despite paradoxically enhanced plasma cell differentiation...
November 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/29111976/cd40-is-a-major-regulator-of-dendrite-growth-from-developing-excitatory-and-inhibitory-neurons
#8
Paulina Carriba, Alun M Davies
Dendrite size and morphology are key determinants of the functional properties of neurons and neural circuits. Here we show that CD40, a member of the TNF receptor superfamily, is a major regulator of dendrite growth and elaboration in the developing brain. The dendrites of hippocampal excitatory neurons were markedly stunted in Cd40(-/-) mice, whereas those of striatal inhibitory neurons were much more exuberant. These striking and opposite phenotypic changes were also observed in excitatory and inhibitory neurons cultured from Cd40(-/-) mice and were rescued by soluble CD40...
November 7, 2017: ELife
https://www.readbyqxmd.com/read/29108250/local-irradiation-does-not-enhance-the-effect-of-immunostimulatory-adcd40l-gene-therapy-combined-with-low-dose-cyclophosphamide-in-melanoma-patients
#9
Sandra Irenaeus, Aglaia Schiza, Sara M Mangsbo, Jessica Wenthe, Emma Eriksson, Johan Krause, Anders Sundin, Håkan Ahlström, Thomas H Tötterman, Angelica Loskog, Gustav J Ullenhag
Background: AdCD40L is an immunostimulatory gene therapy under evaluation for advanced melanoma, including ocular melanoma. Herein, we present the final data of a Phase I/IIa trial using AdCD40L alone or in combination with low dose cyclophosphamide +/- radiation therapy. Methods: AdCD40L is a replication-deficient adenovirus carrying the gene for CD40 ligand (CD40L). Twenty-four patients with advanced melanoma were enrolled and treated with AdCD40L monotherapy, or combined with cyclophosphamide +/- single fraction radiotherapy...
October 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29089645/identification-and-characterization-of-hla-a24-specific-xbp1-cd138-syndecan-1-and-cs1-slamf7-peptides-inducing-antigens-specific-memory-cytotoxic-t-lymphocytes-targeting-multiple-myeloma
#10
J Bae, T Hideshima, G L Zhang, J Zhou, D B Keskin, N C Munshi, K C Anderson
XBP1 (X-box binding protein 1), CD138 (Syndecan-1), and CS1 (SLAMF7) are highly expressed antigens in cancers including multiple myeloma (MM). Here we identify and characterize immunogenic HLA-A24 peptides derived from these antigens for potential vaccination therapy of HLA-A24+ patients with MM. The identified immunogenic HLA-A24-specific XBP1 unspliced (UN)185-193 (I S P W I L A V L), XBP1 spliced (SP)223-231 (V Y P E G P S S L), CD138265-273 (I F A V C L V G F) and CS1240-248 (L F V L G L F L W) peptides induced antigen-specific CTL with anti-MM activity in an HLA-A24 restricted manner...
November 1, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29065175/comparative-analysis-of-activation-induced-marker-aim-assays-for-sensitive-identification-of-antigen-specific-cd4-t-cells
#11
COMPARATIVE STUDY
Samantha Reiss, Amy E Baxter, Kimberly M Cirelli, Jennifer M Dan, Antigoni Morou, Audrey Daigneault, Nathalie Brassard, Guido Silvestri, Jean-Pierre Routy, Colin Havenar-Daughton, Shane Crotty, Daniel E Kaufmann
The identification and study of antigen-specific CD4 T cells, both in peripheral blood and in tissues, is key for a broad range of immunological research, including vaccine responses and infectious diseases. Detection of these cells is hampered by both their rarity and their heterogeneity, in particular with regards to cytokine secretion profiles. These factors prevent the identification of the total pool of antigen-specific CD4 T cells by classical methods. We have developed assays for the highly sensitive detection of such cells by measuring the upregulation of surface activation induced markers (AIM)...
2017: PloS One
https://www.readbyqxmd.com/read/29052524/soluble-cd40l-is-associated-with-increased-oxidative-burst-and-neutrophil-extracellular-trap-release-in-beh%C3%A3-et-s-disease
#12
Sandro Félix Perazzio, Paulo Vitor Soeiro-Pereira, Viviane Cardoso Dos Santos, Marlon Vilela de Brito, Bruno Salu, Maria Luiza Vilela Oliva, Anne Margherite Stevens, Alexandre Wagner Silva de Souza, Hans D Ochs, Troy R Torgerson, Antonio Condino-Neto, Luis Eduardo Coelho Andrade
BACKGROUND: Studies have suggested that soluble factors in plasma from patients with active (aBD) and inactive (iBD) Behçet's disease (BD) stimulate neutrophil function. Soluble CD40 ligand (sCD40L) is an important mediator of inflammation in BD. Its expression and effect on neutrophil oxidative burst and neutrophil extracellular trap (NET) release have not been characterized. In this study, we sought to investigate the role of plasma and the CD40L pathway on NET release and the oxidative burst profile in patients with aBD and iBD...
October 19, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/29050818/decreased-serum-levels-of-scd40l-and-il-31-correlate-in-treated-patients-with-relapsing-remitting-multiple-sclerosis
#13
José de J Guerrero-García, Argelia E Rojas-Mayorquín, Yeminia Valle, Jorge R Padilla-Gutiérrez, Víctor A Castañeda-Moreno, Mario A Mireles-Ramírez, José F Muñoz-Valle, Daniel Ortuño-Sahagún
The CD40/CD40L system is a binding key for co-stimulation of immune cells. Soluble form of CD40L has been widely studied as marker of inflammatory and autoimmune diseases. Here we analyze serum concentrations of sCD40L, as well as 14 cytokines, in patients with Multiple Sclerosis (MS) treated with Glatiramer acetate or Interferon beta. In the healthy control group, we found in serum a highly positive correlation between sCD40L and Interleukin (IL)-31, an anti-inflammatory Th2 cytokine. Additionally, an important reduction in IL-31 and sCD40L serum levels, as well as a significant reduction in CD40 mRNA expression and complete depletion of CD40L mRNA, detected from peripheral blood cells, was found in treated patients with MS...
October 5, 2017: Immunobiology
https://www.readbyqxmd.com/read/29040209/inherited-and-acquired-clinical-phenotypes-associated-with-neuroendocrine-tumors
#14
Rory E Nicholaides, M Teresa de la Morena
PURPOSE OF REVIEW: Overview of neuroendocrine neoplasms in the context of their associations with primary and secondary immunodeficiency states. RECENT FINDINGS: Malignancies of neuroendocrine origin are well known to be associated with hereditary syndromes, including multiple endocrine neoplasia type 1, von Hippel-Lindau syndrome, neurofibromatosis type 1, and tuberous sclerosis. This review includes the X-linked form of hyper-IgM syndrome (XHIGM), due to mutations in the CD40Ligand gene (CD40LG), as an additional inherited disorder with susceptibility to such malignancies, and discusses neuroendocrine tumors (NETs) arising in other immunocompromised states...
December 2017: Current Opinion in Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29038485/a-versatile-pretargeting-approach-for-tumour-selective-delivery-and-activation-of-tnf-superfamily-members
#15
Yuan He, Peter E van Bommel, Douwe F Samplonius, Edwin Bremer, Wijnand Helfrich
TNFR superfamily (TNFRSF) members have important immunoregulatory functions and are of clear interest for cancer immunotherapy. Various TNFRSF agonists have been clinically evaluated, but have met with limited efficacy and/or toxicity. Recent insights indicate that 'first-generation' TNFRSF agonists lack efficacy as they do not effectively cross-link their corresponding receptor. Reversely, ubiquitous TNFRSF receptor(s) cross-linking by CD40 and Fas agonistic antibodies resulted in dose-limiting liver toxicity...
October 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29037856/platelet-cd40-mediates-leukocyte-recruitment-and-neointima-formation-after-arterial-denudation-injury-in-atherosclerosis-prone-mice
#16
Rong Jin, Adam Y Xiao, Zifang Song, Shiyong Yu, Jarvis Li, Mei-Zhen Cui, Guohong Li
The role of platelets in the development of thrombosis and abrupt closure after angioplasty is well recognized. However, the direct impact of platelets on neointima formation after arterial injury remains undetermined. Herein, we show that neointima formation after carotid artery wire injury reduces markedly in CD40(-/-) apolipoprotein E-deficient (apoE(-/-)) mice but only slightly in CD40 ligand(-/-)apoE(-/-) mice, compared with apoE(-/-) mice. Wild-type and CD40-deficient platelets were isolated from blood of apoE(-/-) and CD40(-/-)apoE(-/-) mice, respectively...
October 14, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/29036612/cd40l-controls-obesity-associated-vascular-inflammation-oxidative-stress-and-endothelial-dysfunction-in-mice-translational-aspects-for-man
#17
Sebastian Steven, Mobin Dib, Michael Hausding, Fatemeh Kashani, Matthias Oelze, Swenja Kröller-Schön, Alina Hanf, Steffen Daub, Siyer Roohani, Yves Gramlich, Esther Lutgens, Eberhard Schulz, Christian Becker, Karl J Lackner, Hartmut Kleinert, Christoph Knosalla, Beate Niesler, Philipp S Wild, Thomas Münzel, Andreas Daiber
Aims: CD40 ligand (CD40L) signaling controls vascular oxidative stress and related dysfunction in angiotensin-II-induced arterial hypertension by regulating vascular immune cell recruitment and platelet activation. Here we investigated the role of CD40L in experimental hyperlipidemia. Methods and Results: Male wild type and CD40L-/- mice (C57BL/6 background) were subjected to high fat diet for sixteen weeks. Weight, cholesterol, HDL and LDL levels, endothelial function (isometric tension recording), oxidative stress (NADPH oxidase expression, dihydroethidium fluorescence) and inflammatory parameters (inducible nitric oxide synthase, interleukin-6 expression) were assessed...
September 26, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/29034364/microenvironmental-agonists-generate-de-novo-phenotypic-resistance-to-combined-ibrutinib-plus-venetoclax-in-cll-and-mcl
#18
Kallesh D Jayappa, Craig A Portell, Vicki L Gordon, Brian J Capaldo, Stefan Bekiranov, Mark J Axelrod, L Kyle Brett, Julia D Wulfkuhle, Rosa I Gallagher, Emanuel F Petricoin, Timothy P Bender, Michael E Williams, Michael J Weber
De novo resistance and rapid recurrence often characterize responses of B-cell malignancies to ibrutinib (IBR), indicating a need to develop drug combinations that block compensatory survival signaling and give deeper, more durable responses. To identify such combinations, we previously performed a combinatorial drug screen and identified the Bcl-2 inhibitor venetoclax (VEN) as a promising partner for combination with IBR in Mantle Cell Lymphoma (MCL). We have opened a multi-institutional clinical trial to test this combination...
June 13, 2017: Blood Advances
https://www.readbyqxmd.com/read/29024591/small-molecule-inhibitors-of-the-cd40-cd40l-costimulatory-protein-protein-interaction
#19
Jinshui Chen, Yun Song, Damir Bojadzic, Alejandro Tamayo-Garcia, Ana Marie Landin, Bonnie B Blomberg, Peter Buchwald
Costimulatory interactions are required for T cell activation and development of an effective immune response; hence, they are valuable therapeutic targets for immunomodulation. However, they, as all other protein-protein interactions, are difficult to target by small molecules. Here, we report the identification of novel small-molecule inhibitors of the CD40-CD40L interaction designed starting from the chemical space of organic dyes. For the most promising compounds such as DRI-C21045, activity (IC50) in the low micromolar range has been confirmed in cell assays including inhibition of CD40L-induced activation in NF-κB sensor cells, THP-1 myeloid cells, and primary human B cells as well as in murine allogeneic skin transplant and alloantigen-induced T cell expansion in draining lymph node experiments...
October 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29023539/despite-disorganized-synapse-structure-th2-cells-maintain-directional-delivery-of-cd40l-to-antigen-presenting-b-cells
#20
Jennifer L Gardell, David C Parker
Upon recognition of peptide displayed on MHC molecules, Th1 and Th2 cells form distinct immunological synapse structures. Th1 cells have a bull's eye synapse structure with TCR/ MHC-peptide interactions occurring central to a ring of adhesion molecules, while Th2 cells have a multifocal synapse with small clusters of TCR/MHC interactions throughout the area of T cell/antigen-presenting cell interaction. In this study, we investigated whether this structural difference in the immunological synapse affects delivery of T cell help...
2017: PloS One
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