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T cell affinity

T Balber, J Singer, N Berroterán-Infante, M Dumanic, L Fetty, J Fazekas-Singer, C Vraka, L Nics, M Bergmann, K Pallitsch, H Spreitzer, W Wadsak, M Hacker, E Jensen-Jarolim, H Viernstein, M Mitterhauser
Molecular imaging probes such as PET-tracers have the potential to improve the accuracy of tumor characterization by directly visualizing the biochemical situation. Thus, molecular changes can be detected early before morphological manifestation. The A3 adenosine receptor (A3 AR) is described to be highly expressed in colon cancer cell lines and human colorectal cancer (CRC), suggesting this receptor as a tumor marker. The aim of this preclinical study was the evaluation of [18 F]FE@SUPPY as a PET-tracer for CRC using in vitro imaging and in vivo PET imaging...
2018: Contrast Media & Molecular Imaging
Simon J Moore, James T MacDonald, Sarah Wienecke, Alka Ishwarbhai, Argyro Tsipa, Rochelle Aw, Nicolas Kylilis, David J Bell, David W McClymont, Kirsten Jensen, Karen M Polizzi, Rebekka Biedendieck, Paul S Freemont
Native cell-free transcription-translation systems offer a rapid route to characterize the regulatory elements (promoters, transcription factors) for gene expression from nonmodel microbial hosts, which can be difficult to assess through traditional in vivo approaches. One such host, Bacillus megaterium , is a giant Gram-positive bacterium with potential biotechnology applications, although many of its regulatory elements remain uncharacterized. Here, we have developed a rapid automated platform for measuring and modeling in vitro cell-free reactions and have applied this to B...
April 17, 2018: Proceedings of the National Academy of Sciences of the United States of America
Pia Dosenovic, Ervin E Kara, Anna-Klara Pettersson, Andrew T McGuire, Matthew Gray, Harald Hartweger, Eddy S Thientosapol, Leonidas Stamatatos, Michel C Nussenzweig
The discovery that humans can produce potent broadly neutralizing antibodies (bNAbs) to several different epitopes on the HIV-1 spike has reinvigorated efforts to develop an antibody-based HIV-1 vaccine. Antibody cloning from single cells revealed that nearly all bNAbs show unusual features that could help explain why it has not been possible to elicit them by traditional vaccination and instead would require a sequence of different immunogens. This idea is supported by experiments with genetically modified immunoglobulin (Ig) knock-in mice...
April 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
Mario Brameshuber, Florian Kellner, Benedikt K Rossboth, Haisen Ta, Kevin Alge, Eva Sevcsik, Janett Göhring, Markus Axmann, Florian Baumgart, Nicholas R J Gascoigne, Simon J Davis, Hannes Stockinger, Gerhard J Schütz, Johannes B Huppa
T cell antigen recognition requires T cell antigen receptors (TCRs) engaging MHC-embedded antigenic peptides (pMHCs) within the contact region of a T cell with its conjugated antigen-presenting cell. Despite micromolar TCR:pMHC affinities, T cells respond to even a single antigenic pMHC, and higher-order TCRs have been postulated to maintain high antigen sensitivity and trigger signaling. We interrogated the stoichiometry of TCRs and their associated CD3 subunits on the surface of living T cells through single-molecule brightness and single-molecule coincidence analysis, photon-antibunching-based fluorescence correlation spectroscopy and Förster resonance energy transfer measurements...
April 16, 2018: Nature Immunology
Bibiana Bielekova
Daclizumab is a humanized monoclonal antibody that prevents formation of high-affinity interleukin (IL)-2 receptor (IL-2R). Because activated T cells up-regulate high-affinity IL-2R and IL-2 is used to grow activated T cells in vitro, daclizumab was envisioned to selectively inhibit activated T cells. However, the mechanism of action (MOA) of daclizumab is surprisingly broad and it includes many unanticipated effects on innate immunity. Specifically, daclizumab modulates the development of innate lymphoid cells, leading to expansion of immunoregulatory CD56bright natural killer (NK) cells...
April 16, 2018: Cold Spring Harbor Perspectives in Medicine
M A Motaleb, Adli A Selim, M El-Tawoosy, M H Sanad, M A El-Hashash
PURPOSE: dioxime derivative is reported to exhibit high affinity towards tumor cells. The objective of the present study is to synthesis a new dioxime derivative to be labeled with technetium-99m for using as solid tumor marker. MATERIALS AND METHODS: ((2E,2'E,3E,3'E)-3,3'-(cyclohexane-1,2-diylbis (azanylylidene)) bis-(butan-2-one)dioxime was synthesized by condensation of Butan-2,3-dione monooxime and diaminocyclohexane and labeled with 99m Tc, The in-vivo distribution of the agent were studied by carrying out biodistribution in tumor bearing Albino mice...
April 16, 2018: International Journal of Radiation Biology
Gabriel D Vilallonga, Antônio-Carlos G de Almeida, Kelison T Ribeiro, Sergio V A Campos, Antônio M Rodrigues
The sodium-potassium pump (Na+ /K+ pump) is crucial for cell physiology. Despite great advances in the understanding of this ionic pumping system, its mechanism is not completely understood. We propose the use of a statistical model checker to investigate palytoxin (PTX)-induced Na+ /K+ pump channels. We modelled a system of reactions representing transitions between the conformational substates of the channel with parameters, concentrations of the substates and reaction rates extracted from simulations reported in the literature, based on electrophysiological recordings in a whole-cell configuration...
March 2018: Royal Society Open Science
Linjie Zeng, Lu Li, Qiyan Zeng, Yong Deng, Lijun Yin, Liejun Liao
Lectins are a class of carbohydrate-binding proteins or glycoproteins and used in the purification and characterization of glycoproteins according to their specificity to carbohydrates. In the present study, the mitogenic activity of Artocarpus lingnanensis lectin (ALL) and its apoptosis induction in Jurkat T cells were explored. MTT assay revealed strong mitogenic potential of ALL. Meanwhile, the anti-cancer activity of ALL was also explored using the human leukemic Jurkat T cell line. ALL exhibited strong binding affinity (97%) to the cell membrane, which could be effectively inhibited by N-acetyl-D-galactosaminide (NAD)...
April 12, 2018: Journal of Natural Medicines
Nathan Karin
We have previously shown that predominant expression of key inflammatory cytokines and chemokines at autoimmune sites or tumor sites induces loss of B cells tolerance, resulting in autoantibody production against the dominant cytokine/chemokine that is largely expressed at these sites. These autoantibodies are high-affinity neutralizing antibodies. Based on animal models studies, we suggested that they participate in the regulation of cancer and autoimmunity, albeit at the level of their production cannot entirely prevent the development and progression of these diseases...
2018: Frontiers in Immunology
Deborah L Burnett, David B Langley, Peter Schofield, Jana R Hermes, Tyani D Chan, Jennifer Jackson, Katherine Bourne, Joanne H Reed, Kate Patterson, Benjamin T Porebski, Robert Brink, Daniel Christ, Christopher C Goodnow
Antibodies have the specificity to differentiate foreign antigens that mimic self antigens, but it remains unclear how such specificity is acquired. In a mouse model, we generated B cells displaying an antibody that cross-reacts with two related protein antigens expressed on self versus foreign cells. B cell anergy was imposed by self antigen but reversed upon challenge with high-density foreign antigen, leading to germinal center recruitment and antibody gene hypermutation. Single-cell analysis detected rapid selection for mutations that decrease self affinity and slower selection for epistatic mutations that specifically increase foreign affinity...
April 13, 2018: Science
Jonathan Powell, Filipa Mota, David Steadman, Christelle Soudy, Jeremy T Miyauchi, Stuart Crosby, Ashley Jarvis, Tifelle Reisinge, Natalie Winfield, Graham Evans, Aled Finniear, Tamas Yelland, Yi-Tai Chou, A W Edith Chan, Andrew O'Leary, Lili Cheng, Dan Liu, Ntina Fotinou, Carla Milagre, John F Martin, Haiyan Jia, Paul Frankel, Snezana Djordjevic, Stella E Tsirka, Ian C Zachary, David L Selwood
We report the design, synthesis and comprehensive studybiological evaluation of a range ofsome potent small-molecule neuropilin-1 (NRP1) antagonists. NRP1 is implicated in the immune response to tumours, particularly in Treg cell fragility, required for PD1 checkpoint blockade. The design of these compounds was based on a previously identified compound EG00229, EG00229 which was used a starting point for optimisation. Through targeting of specific amino-acid residues additional H-bonding interactions were introduced, which led to increases in binding affinity and potency...
April 12, 2018: Journal of Medicinal Chemistry
David F Wilson, Abigail T J Cember, Franz M Matschinsky
Regulation of insulin release and glucose homeostasis by pancreatic β-cells is dependent on the metabolism of glucose by glucokinase (GK) and the influence of that activity on oxidative phosphorylation. Genetic alterations that result in hyperactivity of mitochondrial glutamate dehydrogenase (GDH-1) can cause hypoglycemia-hyperammonemia following high protein meals, but the role of GDH-1 remains poorly understood. GDH-1 activity is strongly inhibited by GTP, to near zero in the absence of ADP, and cooperatively activated (n=2...
April 12, 2018: Journal of Applied Physiology
Lin Chen, Ye Tian, Kai Zhan, Anan Chen, Zhiming Weng, Jiao Huang, Yanyan Li, Yongjie Sun, Hongjun Zheng, Yi Li
The affinity of T cell receptor (TCR) determines the efficacy of TCR based immunotherapy. By using human leukocyte antigen (HLA)-A*02 transgenic mice, a TCR was generated previously specific for human tumor testis antigen peptide MAGE-A3112-120 (KVAELVHFL) HLA-A*02 complex. We developed an approach to humanize the murine TCR by replacing the mouse framework with sequences of folding optimized human TCR variable domains for retaining binding affinity. The resultant humanized TCR exhibited higher affinity and conferred better anti-tumor activity than its parent murine MAGE-A3 TCR (SRm1)...
April 12, 2018: Immunology
Aarti Asnani
PURPOSE OF REVIEW: This review describes cardiotoxicity associated with adoptive T cell therapy and immune checkpoint blockade. RECENT FINDINGS: Cardiotoxicity is a rare but potentially fatal complication associated with novel immunotherapies. Both affinity-enhanced and chimeric antigen receptor T cells have been reported to cause hypotension, arrhythmia, and left ventricular dysfunction, typically in the setting of cytokine release syndrome. Immune checkpoint inhibitors are generally well-tolerated but have the potential to cause myocarditis, with clinical presentations ranging from asymptomatic cardiac biomarker elevation to heart failure, arrhythmia, and cardiogenic shock...
April 11, 2018: Current Oncology Reports
Neila Chekkat, Caterina M Lombardo, Cendrine Seguin, Marie-Charlotte Lechner, Florent Dufour, Yves Nominé, Marcella De Giorgi, Benoit Frisch, Olivier Micheau, Gilles Guichard, Danièle Altschuh, Sylvie Fournel
Tumor Necrosis Factor Receptor Apoptosis Inducing Ligand (TRAIL) appears as an interesting candidate for targeted cancer therapy as it induces apoptosis in cancer cells without toxicity to normal cells. TRAIL elicits apoptosis through agonist death receptor TRAIL-R1 and TRAIL-R2 engagement. Nevertheless, recombinant soluble TRAIL and monoclonal antibodies against these receptors demonstrated insufficient efficacy in clinical trials. This may be explained by the cell-type dependency of the apoptotic response, itself influenced by the effect on ligand binding mode of factors such as the level of receptor oligomerization or glycosylation...
March 20, 2018: Oncotarget
Sekar Natesampillai, Nathan W Cummins, Zilin Nie, Rahul Sampath, Jason V Baker, Keith Henry, Marilia Pinzone, Una O'Doherty, Eric C Polley, Gary D Bren, David J Katzmann, Andrew D Badley
HIV protease is known to cause cell death which is dependent upon cleavage of procaspase 8. HIV protease cleavage of procaspase 8 generates Casp8p41 which directly binds Bak with nanomolar affinity causing Bak activation and consequent cell death. Casp8p41 can also bind Bcl2 with nanomolar affinity in which case cell death is averted. Central memory CD4 T cells express high levels of Bcl2 possibly explaining why these cells do not die when they reactivate HIV. Here we determine that the Casp8p41:Bcl2 complex is polyubiquitinated and degraded by the proteasome...
April 11, 2018: Journal of Virology
Soon Ok Cho, Min-Hyun Kim, Hyeyoung Kim
Background: Oxidative stress occurs in white adipose tissue and dysregulates the expression of adipokines secreted from adipocytes. Since adipokines influence inflammation, supplementation with antioxidants might be beneficial for preventing oxidative stress-mediated inflammation in adipocytes and inflammation-associated complications. β-Carotene is the most prominent antioxidant carotenoid and scavenges reactive oxygen species in various tissues. The purpose of this study was to determine whether β-carotene regulates the expression of adipokines, such as adiponectin, monocyte chemoattractant protein-1 (MCP-1), and regulated on activation, normal T cell expressed and secreted (RANTES) in 3T3-L1 adipocytes treated with glucose/glucose oxidase (G/GO)...
March 2018: Journal of Cancer Prevention
Ben S Wendel, Daniel Del Alcazar, Chenfeng He, Perla M Del Río-Estrada, Benjamas Aiamkitsumrit, Yuria Ablanedo-Terrazas, Stefany M Hernandez, Ke-Yue Ma, Michael R Betts, Laura Pulido, Jun Huang, Phyllis A Gimotty, Gustavo Reyes-Terán, Ning Jiang, Laura F Su
Follicular helper CD4+ T cells (TFH ) play an integral role in promoting B cell differentiation and affinity maturation. Whereas TFH cell frequencies are increased in lymph nodes (LNs) from individuals infected with HIV, humoral immunity remains impaired during chronic HIV infection. Whether HIV inhibits TFH responses in LNs remains unclear. Advances in this area have been limited by the difficulty of accessing human lymphoid tissues. Here, we combined high-dimensional mass cytometry with T cell receptor repertoire sequencing to interrogate the composition of TFH cells in primary human LNs...
April 6, 2018: Science Immunology
Andrea J Sant, Katherine A Richards, Jennifer Nayak
CD4 T cells play a multiplicity of roles in protective immunity to influenza. Included in these functions are help for high affinity antibody production, enhancement of CD8 T cell expansion, function and memory, acceleration of the early innate response to infection and direct cytotoxicity. The influenza-specific CD4 T cell repertoire in humans established through exposures to infection and vaccination has been found to be highly variable in abundance, specificity and functionality. Deficits in particular subsets of CD4 T cells recruited into the response result in diminished antibody responses and protection from infection...
April 2, 2018: Current Opinion in Immunology
Monica Casucci, Laura Falcone, Barbara Camisa, Margherita Norelli, Simona Porcellini, Anna Stornaiuolo, Fabio Ciceri, Catia Traversari, Claudio Bordignon, Chiara Bonini, Attilio Bondanza
Chimeric antigen receptor (CAR)-T cell immunotherapy is at the forefront of innovative cancer therapeutics. However, lack of standardization of cellular products within the same clinical trial and lack of harmonization between different trials have hindered the clear identification of efficacy and safety determinants that should be unveiled in order to advance the field. With the aim of facilitating the isolation and in vivo tracking of CAR-T cells, we here propose the inclusion within the CAR molecule of a novel extracellular spacer based on the low-affinity nerve-growth-factor receptor (NGFR)...
2018: Frontiers in Immunology
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