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https://www.readbyqxmd.com/read/28431892/a-humanized-hla-dr4-mouse-model-for-autoimmune-myocarditis
#1
M Emrah Şelli, Anita C Thomas, David C Wraith, Andrew C Newby
Myocarditis, the principal cause of dilated cardiomyopathy and heart failure in young adults, is associated with autoimmunity to human cardiac α-myosin (hCAM) and the DR4 allele of human major histocompatibility II (MHCII). We developed an hCAM-induced myocarditis model in human HLA-DR4 transgenic mice that lack all mouse MHCII genes, demonstrating that immunization for 3weeks significantly increased splenic T-cell proliferative responses and titres of IgG1 and IgG2c antibodies, abolished weight gain, provoked cardiac inflammation and significantly impaired cardiac output and fractional shortening, by echocardiography, compared to adjuvant-injected mice...
April 18, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28428041/structure-of-a-myeloid-cell-leukemia-1-mcl-1-inhibitor-bound-to-drug-site-3-of-human-serum-albumin
#2
Bin Zhao, John Sensintaffar, Zhiguo Bian, Johannes Belmar, Taekyu Lee, Edward T Olejniczak, Stephen W Fesik
Amplification of the gene encoding Myeloid cell leukemia-1 (Mcl-1) is one of the most common genetic aberrations in human cancer and is associated with high tumor grade and poor survival. Recently, we reported on the discovery of high affinity Mcl-1 inhibitors that elicit mechanism-based cell activity. These inhibitors are lipophilic and contain an acidic functionality which is a common chemical profile for compounds that bind to albumin in plasma. Indeed, these Mcl-1 inhibitors exhibited reduced in vitro cell activity in the presence of serum...
March 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28422751/twelve-year-survival-and-immune-correlates-in-dendritic-cell-vaccinated-melanoma-patients
#3
Stefanie Gross, Michael Erdmann, Ina Haendle, Steve Voland, Thomas Berger, Erwin Schultz, Erwin Strasser, Peter Dankerl, Rolf Janka, Stefan Schliep, Lucie Heinzerling, Karl Sotlar, Pierre Coulie, Gerold Schuler, Beatrice Schuler-Thurner
BACKGROUND: Reports on long-term (≥10 years) effects of cancer vaccines are missing. Therefore, in 2002, we initiated a phase I/II trial in cutaneous melanoma patients to further explore the immunogenicity of our DC vaccine and to establish its long-term toxicity and clinical benefit after a planned 10-year followup. METHODS: Monocyte-derived DCs matured by TNFα, IL-1β, IL-6, and PGE2 and then loaded with 4 HLA class I and 6 class II-restricted tumor peptides were injected intradermally in high doses over 2 years...
April 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28421694/molecular-engineering-and-plant-expression-of-an-immunoglobulin-heavy-chain-scaffold-for-delivery-of-a-dengue-vaccine-candidate
#4
Mi-Young Kim, Craig Van Dolleweerd, Alastair Copland, Matthew John Paul, Sven Hofmann, Gina R Webster, Emily Julik, Ivonne Ceballos-Olvera, Jorge Reyes-Del Valle, Moon-Sik Yang, Yong-Suk Jang, Rajko Reljic, Julian K Ma
In order to enhance vaccine uptake by the immune cells in vivo, molecular engineering approach was employed to construct a Polymeric Immunoglobulin G Scaffold (PIGS) that incorporates multiple copies of an antigen and targets the Fc gamma receptors on antigen-presenting cells. These self-adjuvanting immunogens were tested in the context of dengue infection, for which there is currently no globally licensed vaccine yet. Thus, the consensus domain III sequence (cEDIII) of dengue glycoprotein E was incorporated into PIGS and expressed in both tobacco plants and Chinese Ovary Hamster cells...
April 19, 2017: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/28421069/engineering-chimeric-antigen-receptor-t-cells-for-racing-in-solid-tumors-don-t-forget-the-fuel
#5
REVIEW
Melita Irving, Romain Vuillefroy de Silly, Kirsten Scholten, Nahzli Dilek, George Coukos
T-cells play a critical role in tumor immunity. Indeed, the presence of tumor-infiltrating lymphocytes is a predictor of favorable patient prognosis for many indications and is a requirement for responsiveness to immune checkpoint blockade therapy targeting programmed cell death 1. For tumors lacking immune infiltrate, or for which antigen processing and/or presentation has been downregulated, a promising immunotherapeutic approach is chimeric antigen receptor (CAR) T-cell therapy. CARs are hybrid receptors that link the tumor antigen specificity and affinity of an antibody-derived single-chain variable fragment with signaling endodomains associated with T-cell activation...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28418077/therapeutic-protein-deimmunization-by-t-cell-epitope-removal-antigen-specific-immune-responses-in-vitro-and-in-vivo
#6
Saeme Asgari, Azadeh Ebrahim-Habibi, Mehdi Mahdavi, Mohammad Choopani, Hasan Mirzahoseini
Hirudin III is an effective anti-coagulant; however, in 40% of treated patients, a high-titer of anti-Hirudin III IgG antibodies is observed. Development of antibody responses requires the activation of helper T lymphocyte (HTL), which is dependent on peptide epitopes binding to HLA class II molecules. Based on computational prediction softwares, four new mutants of Hirudin III, T4K, S9G, V21G, and V21K, had been designed with the aim of reducing the binding affinity of these HTL epitopes. The constructed mutants have been purified and assayed for bioactivity...
April 18, 2017: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
https://www.readbyqxmd.com/read/28416666/drebrin-restricts-rotavirus-entry-by-inhibiting-dynamin-mediated-endocytosis
#7
Bin Li, Siyuan Ding, Ningguo Feng, Nancie Mooney, Yaw Shin Ooi, Lili Ren, Jonathan Diep, Marcus R Kelly, Linda L Yasukawa, John T Patton, Hiroyuki Yamazaki, Tomoaki Shirao, Peter K Jackson, Harry B Greenberg
Despite the wide administration of several effective vaccines, rotavirus (RV) remains the single most important etiological agent of severe diarrhea in infants and young children worldwide, with an annual mortality of over 200,000 people. RV attachment and internalization into target cells is mediated by its outer capsid protein VP4. To better understand the molecular details of RV entry, we performed tandem affinity purification coupled with high-resolution mass spectrometry to map the host proteins that interact with VP4...
April 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28416578/quantitative-mass-spectrometry-analysis-of-pd-l1-protein-expression-n-glycosylation-and-expression-stoichiometry-with-pd-1-and-pd-l2-in-human-melanoma
#8
Carlos A Morales-Betanzos, Hyoungjoo Lee, Paula I Gonzalez-Ericsson, Justin M Balko, Douglas B Johnson, Lisa J Zimmerman, Daniel C Liebler
Quantitative assessment of key proteins that control the tumor-immune interface is one of the most formidable analytical challenges in immunotherapeutics. We developed a targeted mass spectrometry (MS) platform to quantify programmed cell death-1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2) at fmol/microgram protein levels in formalin fixed, paraffin-embedded sections from 22 human melanomas. PD-L1 abundance ranged 50-fold, from approximately 0.03 to 1.5 fmol/microgram protein and the PRM data were largely concordant with total PD-L1-positive cell content, as analyzed by immunohistochemistry (IHC) with the E1L3N antibody...
April 17, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28411378/immune-responses-and-long-term-disease-recurrence-status-after-telomerase-based-dendritic-cell-immunotherapy-in-patients-with-acute-myeloid-leukemia
#9
Hanna J Khoury, Robert H Collins, William Blum, Patrick S Stiff, Laurence Elias, Jane S Lebkowski, Anita Reddy, Kevin P Nishimoto, Debasish Sen, Edward D Wirth, Casey C Case, John F DiPersio
BACKGROUND: Telomerase activity in leukemic blasts frequently is increased among patients with high-risk acute myeloid leukemia (AML). In the current study, the authors evaluated the feasibility, safety, immunogenicity, and therapeutic potential of human telomerase reverse transcriptase (hTERT)-expressing autologous dendritic cells (hTERT-DCs) in adult patients with AML. METHODS: hTERT-DCs were produced from patient-specific leukapheresis, electroporated with an mRNA-encoding hTERT and a lysosomal-targeting sequence, and cryopreserved...
April 14, 2017: Cancer
https://www.readbyqxmd.com/read/28410427/tcr-stimulation-strength-is-inversely-associated-with-establishment-of-functional-brain-resident-memory-cd8-t-cells-during-persistent-viral-infection
#10
Saumya Maru, Ge Jin, Todd D Schell, Aron E Lukacher
Establishing functional tissue-resident memory (TRM) cells at sites of infection is a newfound objective of T cell vaccine design. To directly assess the impact of antigen stimulation strength on memory CD8 T cell formation and function during a persistent viral infection, we created a library of mouse polyomavirus (MuPyV) variants with substitutions in a subdominant CD8 T cell epitope that exhibit a broad range of efficiency in stimulating TCR transgenic CD8 T cells. By altering a subdominant epitope in a nonstructural viral protein and monitoring memory differentiation of donor monoclonal CD8 T cells in immunocompetent mice, we circumvented potentially confounding changes in viral infection levels, virus-associated inflammation, size of the immunodominant virus-specific CD8 T cell response, and shifts in TCR affinity that may accompany temporal recruitment of endogenous polyclonal cells...
April 14, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28410296/neoantigen-discovery-in-human-cancers
#11
Elaine R Mardis
Cancer is caused by alterations to DNA that ultimately are translated into altered proteins with unique amino acid sequences when compared with their counterparts in normal cells. By inference, these altered proteins have the potential to elicit immune responses such as T-cell recognition, if properly presented by the immune system following protein degradation and major histocompatibility complex binding. Historically, identifying tumor-specific mutant antigens was painstaking work that involved molecular cloning and immune screening...
March 2017: Cancer Journal
https://www.readbyqxmd.com/read/28408532/-68-ga-thp-psma-a-pet-imaging-agent-for-prostate-cancer-offering-rapid-room-temperature-one-step-kit-based-radiolabeling
#12
Jennifer D Young, Vincenzo Abbate, Cinzia Imberti, Levente K Meszaros, Michelle T Ma, Samantha Y A Terry, Robert C Hider, Greg E Mullen, Philip J Blower
The clinical impact and accessibility of (68)Ga tracers for the prostate-specific membrane antigen (PSMA) and other targets would be greatly enhanced by the availability of a simple, one-step kit-based labeling process. Radiopharmacy staff are accustomed to such procedures in the daily preparation of (99m)Tc radiopharmaceuticals. Currently, chelating agents used in (68)Ga radiopharmaceuticals do not meet this ideal. AIM: To develop and evaluate preclinically a (68)Ga radiotracer for imaging PSMA expression that could be radiolabeled simply by addition of (68)Ga generator eluate to a cold kit...
April 13, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28405498/cergutuzumab-amunaleukin-cea-il2v-a-cea-targeted-il-2-variant-based-immunocytokine-for-combination-cancer-immunotherapy-overcoming-limitations-of-aldesleukin-and-conventional-il-2-based-immunocytokines
#13
Christian Klein, Inja Waldhauer, Valeria G Nicolini, Anne Freimoser-Grundschober, Tapan Nayak, Danielle J Vugts, Claire Dunn, Marije Bolijn, Jörg Benz, Martine Stihle, Sabine Lang, Michaele Roemmele, Thomas Hofer, Erwin van Puijenbroek, David Wittig, Samuel Moser, Oliver Ast, Peter Brünker, Ingo H Gorr, Sebastian Neumann, Maria Cristina de Vera Mudry, Heather Hinton, Flavio Crameri, Jose Saro, Stefan Evers, Christian Gerdes, Marina Bacac, Guus van Dongen, Ekkehard Moessner, Pablo Umaña
We developed cergutuzumab amunaleukin (CEA-IL2v, RG7813), a novel monomeric CEA-targeted immunocytokine, that comprises a single IL-2 variant (IL2v) moiety with abolished CD25 binding, fused to the C-terminus of a high affinity, bivalent carcinoembryonic antigen (CEA)-specific antibody devoid of Fc-mediated effector functions. Its molecular design aims to (i) avoid preferential activation of regulatory T-cells vs. immune effector cells by removing CD25 binding; (ii) increase the therapeutic index of IL-2 therapy by (a) preferential retention at the tumor by having a lower dissociation rate from CEA-expressing cancer cells vs...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28404966/a-novel-bispecific-c-met-pd-1-antibody-with-therapeutic-potential-in-solid-cancer
#14
Zu-Jun Sun, Yi Wu, Wei-Hua Hou, Yu-Xiong Wang, Qing-Yun Yuan, Hui-Jie Wang, Min Yu
The bispecific antibody is a novel antibody, which can target two different antigens and mediate specific killing effects by selectively redirecting effector cells to the target cells. Here, we designed and synthesized a bispecific antibody (BsAb) that can bind cellular-mesenchymal to epithelial transition factor (c-MET, overexpressed in several human solid tumor), and programmed death-1 (PD-1, involved in cancer cell immune evasion) with high affinity and specificity. We found that BsAb can induce the degradation of c-MET protein in cancer cells, including MKN45, a gastric cancer cell line, and A549, a lung cancer cell line...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28400484/amino-acid-polymorphisms-in-the-fibronectin-binding-repeats-of-fibronectin-binding-protein-a-affect-bond-strength-and-fibronectin-conformation
#15
Nadia N Casillas-Ituarte, Carlos H B Cruz, Roberto D Lins, Alex C DiBartola, Jessica Howard, Xiaowen Liang, Magnus Höök, Isabelle F T Viana, M Roxana Sierra-Hernández, Steven K Lower
The Staphylococcus aureus cell surface contains cell wall-anchored proteins such as fibronectin-binding protein A (FnBPA) that bind to host ligands (e.g. fibronectin; Fn) present in the extracellular matrix of tissue or coatings on cardiac implants. Recent clinical studies have found a correlation between cardiovascular infections caused by S. aureus and nonsynonymous single nucleotide polymorphisms (SNPs) in FnBPA. Atomic force microscopy (AFM), surface plasmon resonance (SPR), and molecular simulations were used to investigate interactions between Fn and each of eight, 20-mer peptide variants containing amino acids A, H, I, K, N, and Q at positions equivalent to 782 and/or 786 in Fn-binding repeat-9 (FnBR-9) of FnBPA...
April 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28400258/gating-modifier-toxin-interactions-with-ion-channels-and-lipid-bilayers-is-the-trimolecular-complex-real
#16
REVIEW
Akello J Agwa, Sónia T Henriques, Christina I Schroeder
Spider peptide toxins have attracted attention because of their ability to target voltage-gated ion channels, which are involved in several pathologies including chronic pain and some cardiovascular conditions. A class of these peptides acts by modulating the gating mechanism of voltage-gated ion channels and are thus called gating modifier toxins (GMTs). In addition to their interactions with voltage-gated ion channels, some GMTs have affinity for lipid bilayers. This review discusses the potential importance of the cell membrane on the mode of action of GMTs...
April 8, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28393923/altered-b-cell-signalling-in-autoimmunity
#17
REVIEW
David J Rawlings, Genita Metzler, Michelle Wray-Dutra, Shaun W Jackson
Recent work has provided new insights into how altered B cell-intrinsic signals - through the B cell receptor (BCR) and key co-receptors - function together to promote the pathogenesis of autoimmunity. These combined signals affect B cells at two distinct stages: first, in the selection of the naive repertoire; and second, during extrafollicular or germinal centre activation responses. Thus, dysregulated signalling can lead to both an altered naive BCR repertoire and the generation of autoantibody-producing B cells...
April 10, 2017: Nature Reviews. Immunology
https://www.readbyqxmd.com/read/28393919/association-of-c-type-lectin-mincle-with-fc%C3%AE%C2%B5ri%C3%AE-%C3%AE-subunits-leads-to-functional-activation-of-rbl-2h3-cells-through-syk
#18
Chisato Honjoh, Kazuyasu Chihara, Hatsumi Yoshiki, Shota Yamauchi, Kenji Takeuchi, Yuji Kato, Yukio Hida, Tamotsu Ishizuka, Kiyonao Sada
Macrophage-inducible C-type lectin (Mincle) interacts with the γ-subunit of high-affinity IgE receptor (FcεRIγ) and activates Syk by recognizing its specific ligand, trehalose-6,6'-dimycolate, a glycolipid produced by Mycobacterium tuberculosis. It has been suggested that mast cells participate in the immune defense against pathogenic microbes including M. tuberculosis, although the functions are still uncertain. In this study, we examined the Mincle-mediated signaling pathway and cellular responses using RBL-2H3 cells...
April 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28393253/recombinant-adenovirus-of-sea-and-cd80-genes-driven-by-mmre-and-mouse-tert-promoter-induce-effective-antitumor-immune-responses-against-different-types-of-tumor-cells-in%C3%A2-vitro-and-in%C3%A2-vivo
#19
Shao-Yan Si, Jun-Li Liu, Jun-Lian Liu, Bing-Xin Xu, Jian-Zhong Li, Ya-Ya Qin, Shu-Jun Song
Staphylococcus enterotoxin A (SEA) is a powerful immunostimulant and can stimulate T cells bearing certain T-cell receptor β-chain variable regions when bound to major histocompatibility complex II molecules. SEA is widely used in research of antitumor therapy. The low affinity T-cell receptor (TCR) interaction with SEA in the absence of MHC class II antigens is sufficient for the induction of cytotoxicity but requires additional CD28/B7 signaling to result in proliferation of resting T cells. In this study, we constructed recombinant adenovirus (named as Ad-MMRE-mTERT-BIS) carrying membrane-expressing SEA (named as SEAtm) and CD80 driven by Myc-Max response elements (MMRE) and mouse telomerase reverse transcriptase (mTERT) promoter to reduce toxicity and to improve safety and efficiency...
April 6, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28389388/prolonged-immunomodulation-in-inflammatory-arthritis-using-the-selective-kv1-3-channel-blocker-hstx1-r14a-and-its-pegylated-analog
#20
Mark R Tanner, Rajeev B Tajhya, Redwan Huq, Elizabeth J Gehrmann, Kathia E Rodarte, Mustafa A Atik, Raymond S Norton, Michael W Pennington, Christine Beeton
Effector memory T lymphocytes (TEM cells) that lack expression of CCR7 are major drivers of inflammation in a number of autoimmune diseases, including multiple sclerosis and rheumatoid arthritis. The Kv1.3 potassium channel is a key regulator of CCR7(-) TEM cell activation. Blocking Kv1.3 inhibits TEM cell activation and attenuates inflammation in autoimmunity, and as such, Kv1.3 has emerged as a promising target for the treatment of TEM cell-mediated autoimmune diseases. The scorpion venom-derived peptide HsTX1 and its analog HsTX1[R14A] are potent Kv1...
April 4, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
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