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T cell affinity

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https://www.readbyqxmd.com/read/29453292/clonal-selection-drives-protective-memory-b-cell-responses-in-controlled-human-malaria-infection
#1
Rajagopal Murugan, Lisa Buchauer, Gianna Triller, Cornelia Kreschel, Giulia Costa, Gemma Pidelaserra Martí, Katharina Imkeller, Christian E Busse, Sumana Chakravarty, B Kim Lee Sim, Stephen L Hoffman, Elena A Levashina, Peter G Kremsner, Benjamin Mordmüller, Thomas Höfer, Hedda Wardemann
Affinity maturation, the clonal selection and expansion of antigen-activated B cells expressing somatically mutated antibody variants that develop during T cell-dependent germinal center reactions, is considered pivotal for efficient development of protective B cell memory responses to infection and vaccination. Repeated antigen exposure promotes affinity maturation but each time also recruits antigen-reactive naïve B cells into the response. Here, we determined the relative impact of affinity maturation versus antigen-mediated clonal selection of naïve B cells to mount potent B cell memory responses in humans after repeated exposure to a complex pathogen, the malaria parasite Plasmodium falciparum (Pf)...
February 16, 2018: Science Immunology
https://www.readbyqxmd.com/read/29452367/variant-in-human-pofut1-reduces-enzymatic-activity-and-likely-causes-a-recessive-microcephaly-global-developmental-delay-with-cardiac-and-vascular-features
#2
Hideyuki Takeuchi, Derek Wong, Michael Schneider, Hudson H Freeze, Megumi Takeuchi, Steven J Berardinelli, Atsuko Ito, Hane Lee, Stanley F Nelson, Robert S Haltiwanger
Protein O-fucosyltransferase-1 (POFUT1) adds O-fucose monosaccharides to epidermal growth factor-like (EGF) repeats found on approximately 100 mammalian proteins, including Notch receptors. Haploinsufficiency of POFUT1 has been linked to adult-onset Dowling Degos Disease (DDD) with hyperpigmentation defects. Homozygous deletion of mouse Pofut1 results in embryonic lethality with severe Notch-like phenotypes including defects in somitogenesis, cardiogenesis, vasculogenesis, and neurogenesis, but the extent to which POFUT1 is required for normal human development is not yet understood...
February 14, 2018: Glycobiology
https://www.readbyqxmd.com/read/29450576/immunopet-imaging-of-cd38-in-murine-lymphoma-models-using-89-zr-labeled-daratumumab
#3
Lei Kang, Dawei Jiang, Christopher G England, Todd E Barnhart, Bo Yu, Zachary T Rosenkrans, Rongfu Wang, Jonathan W Engle, Xiaojie Xu, Peng Huang, Weibo Cai
PURPOSE: CD38 is considered a potential biomarker for multiple myeloma (MM) and has shown a strong link with chronic lymphocytic leukemia due to high and uniform expression on plasma cells. In vivo evaluation of CD38 expression may provide useful information about lesion detection and prognosis of treatment in MM. In this study, immunoPET imaging with 89 Zr-labeled daratumumab was used for differentiation of CD38 expression in murine lymphoma models to provide a potential non-invasive method for monitoring CD38 in the clinic...
February 15, 2018: European Journal of Nuclear Medicine and Molecular Imaging
https://www.readbyqxmd.com/read/29449847/potential-epigenetic-regulation-in-the-germinal-center-reaction-of-lymphoid-tissues-in-hiv-siv-infection
#4
REVIEW
Xiaolei Wang, Huanbin Xu
The production of high-affinity and broadly neutralizing antibodies plays a key role in the defense against pathogens. These antibody responses require effective germinal center (GC) reaction within anatomical niches of GCs, where follicular helper T (Tfh) cells provide cognate help to B cells for T cell-dependent antibody responses. Emerging evidences indicate that GC reaction in normal state and perhaps establishment of latent Tfh cell reservoir in HIV/SIV infection are tightly regulated by epigenetic histone modifications, which are responsible for activating or silencing chromatin...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29448960/double-negative-cd27-igd-b-cells-are-expanded-in-nsclc-and-inversely-correlate-with-affinity-matured-b-cell-populations
#5
Sara M Centuori, Cecil J Gomes, Samuel S Kim, Charles W Putnam, Brandon T Larsen, Linda L Garland, David W Mount, Jesse D Martinez
BACKGROUND: The presence of B cells in early stage non-small cell lung cancer (NSCLC) is associated with longer survival, however, the role these cells play in the generation and maintenance of anti-tumor immunity is unclear. B cells differentiate into a variety of subsets with differing characteristics and functions. To date, there is limited information on the specific B cell subsets found within NSCLC. To better understand the composition of the B cell populations found in NSCLC we have begun characterizing B cells in lung tumors and have detected a population of B cells that are CD79A + CD27 - IgD - ...
February 15, 2018: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29447930/linked-help-from-bacterial-proteins-drives-autoantibody-production-in-small-vessel-vasculitis
#6
David B G Oliveira
The small vessel vasculitides granulomatosis with polyangiitis (GPA) and microscopic polyangiitis are associated with autoantibodies to neutrophil cytoplasm antigens (ANCA), principally proteinase-3 (PR3) and myeloperoxidase (MPO). There is an association between GPA and nasal carriage of Staphylococcus aureus. The recent finding that S. aureus produces proteins that bind tightly to and block the function of both PR3 and MPO suggests a mechanism for ANCA formation. The bacterial protein-autoantigen conjugate is recognised by B cells with ANCA specificity, internalised, and the bacterial protein processed and presented to T cells with specificity for bacterial peptides...
March 2018: Medical Hypotheses
https://www.readbyqxmd.com/read/29446085/dr4-mediates-the-progression-invasion-metastasis-and-survival-of-colorectal-cancer-through-the-sp1-nf1-switch-axis-on-genomic-locus
#7
Shenshen Wu, Qingtao Meng, Chengcheng Zhang, Hao Sun, Runze Lu, Na Gao, Hongbao Yang, Xiaobo Li, Michael Aschner, Rui Chen
The single nucleotide polymorphism (SNP), -397G>T (rs13278062) polymorphism, in the promoter of Death Receptor 4 (DR4) had been reported to be associated with a significantly increased risk for bladder cancer. However, the association of this SNP with the risk of colorectal cancer has not been reported. In this study, we performed a case-control study in 1,078 colorectal cancer patients and 1,175 matched healthy controls to evaluate the association of the potential functional genetic variants in DR4 with risk and survival of colorectal cancer...
February 15, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29444872/fviii-proteins-with-a-modified-immunodominant-t-cell-epitope-exhibit-reduced-immunogenicity-and-normal-fviii-activity
#8
Ruth A Ettinger, Joseph A Liberman, Devi Gunasekera, Komal Puranik, Eddie A James, Arthur R Thompson, Kathleen P Pratt
Factor VIII (FVIII)-neutralizing antibodies (inhibitors) are a serious complication in hemophilia A (HA). The peptide FVIII 2194-2213 contains an immunodominant HLA-DRA*01-DRB1*01:01 (DRB1*01:01)-restricted epitope recognized by CD4 + T-effector cells from HA subjects. The aim of this study was to identify amino acid substitutions to deimmunize this epitope while retaining procoagulant function and expression levels comparable to those of wild-type (WT) FVIII proteins. The shortest DRB1*01:01-binding peptide was FVIII 2194-2205 , and residues important for affinity were identified as F2196, M2199, A2201, and S2204...
February 27, 2018: Blood Advances
https://www.readbyqxmd.com/read/29440380/comparative-transcriptome-analysis-reveals-distinct-genetic-modules-associated-with-helios-expression-in-intratumoral-regulatory-t-cells
#9
Kathleen Yates, Kevin Bi, W Nicholas Haining, Harvey Cantor, Hye-Jung Kim
Regulatory T cells (Tregs) are key modulators of immune tolerance, capable of suppressing inflammatory immune responses and promoting nonlymphoid tissue homeostasis. Helios, a transcription factor (TF) that is selectively expressed by Tregs, has been shown to be essential for the maintenance of Treg lineage stability in the face of inflammatory conditions that include autoimmune disease and cancer. Helios-deficient Tregs within tumors acquire effector T cell function and contribute to immune responses against cancer...
February 9, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29438723/discovery-and-development-of-odm-204-a-novel-nonsteroidal-compound-for-the-treatment-of-castration-resistant-prostate-cancer-by-blocking-the-androgen-receptor-and-inhibiting-cyp17a1
#10
REVIEW
Riikka Oksala, Anu Moilanen, Reetta Riikonen, Petteri Rummakko, Arja Karjalainen, Mikko Passiniemi, Gerd Wohlfahrt, Päivi Taavitsainen, Chira Malmström, Meri Ramela, Hanna-Maija Metsänkylä, Riikka Huhtaniemi, Pekka J Kallio, Mika Vj Mustonen
We report the discovery of a novel nonsteroidal dual-action compound, ODM-204, that holds promise for treating patients with castration-resistant prostate cancer (CRPC), an advanced form of prostate cancer characterised by high androgen receptor (AR) expression and persistent activation of the AR signaling axis by residual tissue androgens. For ODM-204, has a dual mechanism of action. The compound is anticipated to efficiently dampen androgenic stimuli in the body by inhibiting CYP17A1, the prerequisite enzyme for the formation of dihydrotestosterone (DHT) and testosterone (T), and by blocking AR with high affinity and specificity...
February 10, 2018: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29434597/92r-monoclonal-antibody-inhibits-human-ccr9-leukemia-cells-growth-in-nsg-mice-xenografts
#11
Beatriz Somovilla-Crespo, Maria Teresa Martín Monzón, Maria Vela, Isabel Corraliza-Gorjón, Silvia Santamaria, Jose A Garcia-Sanz, Leonor Kremer
CCR9 is as an interesting target for the treatment of human CCR9+-T cell acute lymphoblastic leukemia, since its expression is limited to immature cells in the thymus, infiltrating leukocytes in the small intestine and a small fraction of mature circulating T lymphocytes. 92R, a new mouse mAb (IgG2a isotype), was raised using the A-isoform of hCCR9 as immunogen. Its initial characterization demonstrates that binds with high affinity to the CCR9 N-terminal domain, competing with the previously described 91R mAb for receptor binding...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29433938/b-cell-lymphoma-immunotherapy-using-tlr9-targeted-oligonucleotide-stat3-inhibitors
#12
Xingli Zhao, Zhuoran Zhang, Dayson Moreira, Yu-Lin Su, Haejung Won, Tomasz Adamus, Zhenyuan Dong, Yong Liang, Hongwei H Yin, Piotr Swiderski, Raju K Pillai, Larry Kwak, Stephen Forman, Marcin Kortylewski
Growing evidence links the aggressiveness of non-Hodgkin's lymphoma, especially the activated B cell-like type diffuse large B cell lymphomas (ABC-DLBCLs) to Toll-like receptor 9 (TLR9)/MyD88 and STAT3 transcription factor signaling. Here, we describe a dual-function molecule consisting of a clinically relevant TLR9 agonist (CpG7909) and a STAT3 inhibitor in the form of a high-affinity decoy oligodeoxynucleotide (dODN). The CpG-STAT3dODN blocked STAT3 DNA binding and activity, thus reducing expression of downstream target genes, such as MYC and BCL2L1, in human and mouse lymphoma cells...
January 17, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29432828/identification-of-two-novel-foot-and-mouth-disease-virus-cytotoxic-t-lymphocyte-epitopes-that-can-bind-six-sla-i-proteins
#13
Feng-Shan Gao, Xiao-Xin Zhai, Ping Jiang, Qiang Zhang, Hua Gao, Zi-Bin Li, Yong Han, Jie Yang, Zong-Hui Zhang
Currently available vaccines from inactivated Foot-and-mouth disease virus (FMDV) only protect animals by inducing neutralizing antibodies. A vaccine that contains cytotoxic T lymphocytes (CTL) epitopes to induce strong CTL responses might protect animals more effectively. Herein, we used swine leukocyte antigen class I (SLAI) proteins derived from six different strains of domestic pigs to screen and identify shared FMDV CTL epitopes. Four potential FMDV CTL epitopes (Q01, Q02, AS3, and QA4) were confirmed by mass spectrometry...
February 9, 2018: Gene
https://www.readbyqxmd.com/read/29432739/kshv-vpk-inhibits-wnt-signaling-via-preventing-interactions-between-%C3%AE-catenin-and-tcf4
#14
Seho Cha, Myung-Suk Kang, Taegun Seo
Viral factors interact with host cellular proteins, leading to dysregulation of signaling pathways. The Wnt pathway is known to participate in embryonic development and oncogenesis under dysregulation conditions. A downstream factor of the Wnt signaling pathway, β-catenin, activates T-cell factor (TCF)-dependent transcription, which contributes to cell proliferation and tumorigenesis. In this study, we demonstrated that viral protein kinase (vPK) encoded by Kaposi's sarcoma-associated herpesvirus inhibits the Wnt signaling pathway without affecting nuclear localization and expression of β-catenin...
February 9, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29430345/design-of-peptide-based-epitope-vaccine-and-further-binding-site-scrutiny-led-to-groundswell-in-drug-discovery-against-lassa-virus
#15
Mohammad Uzzal Hossain, Taimur Md Omar, Arafat Rahman Oany, K M Kaderi Kibria, Abu Zaffar Shibly, Md Moniruzzaman, Syed Raju Ali, Md Monirul Islam
Lassa virus (LASV) is responsible for an acute viral hemorrhagic fever known as Lassa fever. Sequence analyses of LASV proteome identified the most immunogenic protein that led to predict both T-cell and B-cell epitopes and further target and binding site depiction could allow novel drug findings for drug discovery field against this virus. To induce both humoral and cell-mediated immunity peptide sequence SSNLYKGVY, conserved region 41-49 amino acids were found as the most potential B-cell and T-cell epitopes, respectively...
February 2018: 3 Biotech
https://www.readbyqxmd.com/read/29426822/chemical-array-system-a-platform-to-identify-novel-hepatitis-b-virus-entry-inhibitors-targeting-sodium-taurocholate-cotransporting-polypeptide
#16
Manabu Kaneko, Yushi Futamura, Senko Tsukuda, Yasumitsu Kondoh, Tomomi Sekine, Hiroyuki Hirano, Kento Fukano, Hirofumi Ohashi, Wakana Saso, Ryo Morishita, Satoko Matsunaga, Fumihiro Kawai, Akihide Ryo, Sam-Yong Park, Ryosuke Suzuki, Hideki Aizaki, Naoko Ohtani, Camille Sureau, Takaji Wakita, Hiroyuki Osada, Koichi Watashi
Current anti-hepatitis B virus (HBV) agents including interferons and nucleos(t)ide analogs efficiently suppress HBV infection. However, as it is difficult to eliminate HBV from chronically infected liver, alternative anti-HBV agents targeting a new molecule are urgently needed. In this study, we applied a chemical array to high throughput screening of small molecules that interacted with sodium taurocholate cotransporting polypeptide (NTCP), an entry receptor for HBV. From approximately 30,000 compounds, we identified 74 candidates for NTCP interactants, and five out of these were shown to inhibit HBV infection in cell culture...
February 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29424002/perpetual-complexity-predicting-human-cd8-t-cell-responses-to-pathogenic-peptides
#17
REVIEW
Anthony R Di Carluccio, Cristina F Triffon, Weisan Chen
The accurate prediction of human CD8+ T cell epitopes has great potential clinical and translational implications in the context of infection, cancer and autoimmunity. Prediction algorithms have traditionally focused on calculated peptide affinity for the binding groove of MHC-I. However, over the years it has become increasingly clear that the ultimate T cell recognition of MHC-I-bound peptides is governed by many contributing factors within the complex antigen presentation pathway. Recent advances in next-generation sequencing and immunnopeptidomics have increased the precision of HLA-I sub-allele classification, and have led to the discovery of peptide processing events and individual allele-specific binding preferences...
February 9, 2018: Immunology and Cell Biology
https://www.readbyqxmd.com/read/29422332/heterobicyclic-inhibitors-of-transforming-growth-factor-beta-receptor-i-tgf%C3%AE-ri
#18
Lalgudi S Harikrishnan, Jayakumar Warrier, Andrew J Tebben, Gopikishan Tonukunuru, Sudhakara R Madduri, Vishweshwaraiah Baligar, Raju Mannoori, Balaji Seshadri, Hasibur Rahaman, P N Arunachalam, Amol G Dikundwar, Brian E Fink, Joseph Fargnoli, Mark Fereshteh, Yi Fan, Jonathan Lippy, Ching-Ping Ho, Barri Wautlet, Steven Sheriff, Max Ruzanov, Robert M Borzilleri
The TGFβ-TGFβR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFβR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFβRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0...
January 31, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29416316/durvalumab-an-investigational-anti-pd-l1-monoclonal-antibody-for-the-treatment-of-urothelial-carcinoma
#19
REVIEW
Izak Faiena, Amy L Cummings, Anna M Crosetti, Allan J Pantuck, Karim Chamie, Alexandra Drakaki
Our expanding knowledge of immunotherapy for solid tumors has led to an explosion of clinical trials aimed at urothelial carcinoma. The primary strategy is centered on unleashing the immune system by releasing the inhibitory signals propagated by programmed cell death-1 (PD-1) and its ligand programmed cell death ligand-1 (PD-L1). Many antibody constructs have been developed to block these interactions and are used in clinical trials. The Food and Drug Administration has already approved a number of checkpoint inhibitors such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibodies including ipilimumab; anti-PD-1 monoclonal antibodies including nivolumab and pembrolizumab; anti-PD-L1 antibodies including atezolizumab, avelumab, and durvalumab...
2018: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29415028/polymicrobial-sepsis-and-non-specific-immunization-induce-adaptive-immunosuppression-to-a-similar-degree
#20
Katrin Schmoeckel, Daniel M Mrochen, Jochen Hühn, Christian Pötschke, Barbara M Bröker
Sepsis is frequently complicated by a state of profound immunosuppression, in its extreme form known as immunoparalysis. We have studied the role of the adaptive immune system in the murine acute peritonitis model. To read out adaptive immunosuppression, we primed post-septic and control animals by immunization with the model antigen TNP-ovalbumin in alum, and measured the specific antibody-responses via ELISA and ELISpot assay as well as T-cell responses in a proliferation assay after restimulation. Specific antibody titers, antibody affinity and plasma cell counts in the bone marrow were reduced in post-septic animals...
2018: PloS One
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