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T cell exhaustion

Junsik Park, Minsuk Kwon, Eui-Cheol Shin
During immune responses antigen-specific T cells are regulated by several mechanisms, including through inhibitory receptors and regulatory T cells, to avoid excessive or persistent immune responses. These regulatory mechanisms, which are called 'immune checkpoints', suppress T cell responses, particularly in patients with chronic viral infections and cancer where viral antigens or tumor antigens persist for a long time and contribute to T cell exhaustion. Among these regulatory mechanisms, cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1) are the most well-known receptors and both have been targeted for drug development...
October 21, 2016: Archives of Pharmacal Research
Vanaja Konduri, Dali Li, Matthew M Halpert, Dan Liang, Zhengdong Liang, Yunyu Chen, William E Fisher, Silke Paust, Jonathan M Levitt, Qizhi Cathy Yao, William K Decker
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States, exhibiting a five-year overall survival (OS) of only 7% despite aggressive standard of care. Recent advances in immunotherapy suggest potential application of immune-based treatment approaches to PDAC. To explore this concept further, we treated orthotopically established K-ras(G12D)/p53(-/-) PDAC tumors with gemcitabine and a cell-based vaccine previously shown to generate durable cell-mediated (TH1) immunity...
2016: Oncoimmunology
Yi Zheng, Yicheng Yang, Shu Wu, Yongqiang Zhu, Xiaolong Tang, Xiaopeng Liu
As the second most common gynecologic malignant tumors with a high mortality rate, cervical cancer jeopardizes women's life worldwide. The low cure rate in cervical cancer patients is mainly attributed to the lack of effective therapies. One feasible novel strategy is to develop immune-based approaches such as adoptive cell immunotherapy of DCCIKs which represents a promising nontoxic antineoplastic immunotherapy preferred in clinic practice. However, the therapeutic effect is not as efficient as anticipated...
October 18, 2016: Bioengineered
Catherine Forconi, Philippe Gatault, Elodie Miquelestorena-Standley, Johan Noble, Sally Al-Hajj, Romain Guillemain, Marc Stern, Thomas Hoffmann, Louis Prat, Caroline Suberbielle, Emeline Masson, Anne Cesbron-Gautier, Catherine Gaudy-Graffin, Alain Goudeau, Gilles Thibault, Fabrice Ivanes, Roseline Guibon, Ihab Kazma, Yvon Lebranchu, Matthias Büchler, Antoine Magnan, Jean-Michel Halimi, Christophe Baron
BACKGROUND: Cytomegalovirus (CMV) has a role in chronic rejection and graft loss in kidney transplant (KTx) and lung transplant (LTx) recipients. In addition, donor CMV seropositivity is an independent risk factor for renal graft loss. The anti-CMV response might modulate this risk. Expression of programmed cell death 1 (PD-1), a receptor involved in viral-specific T-cell exhaustion, is influenced by a single nucleotide polymorphism called PD-1.3 (wild-type allele G, variant allele A)...
August 26, 2016: Journal of Heart and Lung Transplantation
Pravin Kesarwani, Paramita Chakraborty, Radhika Gudi, Shilpak Chatterjee, Gina Scurti, Kyle Toth, Patt Simms, Mahvash Husain, Kent Armeson, Shahid Husain, Elizabeth Garrett-Mayer, Chethamarakshan Vasu, Michael I Nishimura, Shikhar Mehrotra
Advancements in adoptive cell transfer therapy (ACT) has led to the use of T cells engineered with tumor specific T cell receptors, which after rapid expansion can be obtained in sufficient numbers for treating patients. However, due to massive proliferation these cells are close to replicative senescence, exhibit exhausted phenotype, and also display increased susceptibility to activation induced cell death. We have previously shown that tumor reactive T cells undergo caspase-independent cell death upon TCR restimulation with cognate antigen, which involves reactive oxygen species and c-jun N-terminal kinase...
October 14, 2016: Oncotarget
Bert Conings, Aslihan Babayigit, Matthew T Klug, Sai Bai, Nicolas Gauquelin, Nobuya Sakai, Jacob Tse-Wei Wang, Johan Verbeeck, Hans-Gerd Boyen, Henry J Snaith
A robust and expedient gas quenching method is developed for the solution deposition of hybrid perovskite thin films. The method offers a reliable standard practice for the fabrication of a non-exhaustive variety of perovskites exhibiting excellent film morphology and commensurate high performance in both regular and inverted structured solar cell architectures.
October 17, 2016: Advanced Materials
Eoin F McKinney, Kenneth Gc Smith
T cell exhaustion represents a continuous spectrum of cellular dysfunction induced during chronic viral infection, facilitating viral persistence and associating with poor clinical outcome. Modulation of T cell exhaustion can restore function in exhausted CD8 T cells, promoting viral clearance. Exhaustion has also been implicated as playing an important role in anti-tumour responses, whereby exhausted tumour-infiltrating lymphocytes fail to control tumour progression. More recently exhaustion has been linked to long-term clinical outcome in multiple autoimmune diseases but, in contrast to cancer or infection, it is associated with a favourable clinical outcome characterised by fewer relapses...
October 13, 2016: Current Opinion in Immunology
Huaizhou Wang, Beiying Wu, Lei Li, Liang Hu, Jiafei Lin, Cen Jiang, Gang Cai, Qian Shen
Similar to programmed death-1 (PD-1), B and T lymphocyte attenuator (BTLA) is a co-inhibitory molecule of the CD28 family. PD-1 is involved in T cell exhaustion during chronic viral infection. However, the role of BTLA in virus-specific T cells is poorly defined. Here we investigated the expression and function of BTLA in T cells from patients with chronic hepatitis B virus (HBV) infection. The phenotype of peripheral and intrahepatic HBV-specific T cells from 43 patients with chronic HBV infection was assessed by flow cytometry...
October 6, 2016: Cellular Immunology
Rico D Bense, Christos Sotiriou, Martine J Piccart-Gebhart, John B A G Haanen, Marcel A T M van Vugt, Elisabeth G E de Vries, Carolien P Schröder, Rudolf S N Fehrmann
BACKGROUND: Not all breast cancer patients benefit from neoadjuvant or adjuvant therapy, resulting in considerable undertreatment or overtreatment. New insights into the role of tumor-infiltrating immune cells suggest that their composition, as well as their functionality, might serve as a biomarker to enable optimal patient selection for current systemic therapies and upcoming treatment options such as immunotherapy. METHODS: We performed several complementary unbiased in silico analyses on gene expression profiles of 7270 unrelated tumor samples of nonmetastatic breast cancer patients with known clinical follow-up...
January 2017: Journal of the National Cancer Institute
Sana Saif Ur Rehman, Suresh S Ramalingam
Advanced stage nonsmall cell lung cancer had been treated mainly with platinum-based doublet chemotherapy, and other cytotoxic agents that offered significant survival advantage over best supportive care, until recently. Modest improvements were achieved with the addition of antibodies targeting the vascular endothelial growth factor, and the introduction of maintenance chemotherapy. Improvements in our knowledge of lung cancer biology have shifted the current treatment paradigm from being based on histology to one based on molecular biomarkers...
October 2016: Seminars in Respiratory and Critical Care Medicine
Hsi-Hsien Lin, Martin Stacey
As the largest receptor gene family in the human genome, with >800 members, the signal-transducing G protein-coupled receptors (GPCRs) play critical roles in nearly all conceivable physiological processes, ranging from the sensing of photons and odorants to metabolic homeostasis and migration of leukocytes. Unfortunately, an exhaustive review of the several hundred GPCRs expressed by myeloid cells/macrophages (P.J. Groot-Kormelink, L .Fawcett, P.D. Wright, M. Gosling, and T.C. Kent, BMC Immunol 12:57, 2012, doi:10...
August 2016: Microbiology Spectrum
Satoru Konnai, Shiro Murata, Kazuhiko Ohashi
Recently, dysfunction of antigen-specific T cells is well documented as T-cell exhaustion and has been defined by the loss of effector functions during chronic infections and cancer in human. The exhausted T cells are characterized phenotypically by the surface expression of immunoinhibitory receptors, such as programmed death 1 (PD-1), lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and cytotoxic T-lymphocyte antigen 4 (CTLA-4). However, there is still a fundamental lack of knowledge about the immunoinhibitory receptors in the fields of veterinary medicine...
October 8, 2016: Journal of Veterinary Medical Science
M Ali, H Pasic, K Alam, S A N Tiji, N Mannella, T Silva, T Liu
This paper reports development and testing of novel cross-flow wet electrostatic precipitator (WESP), recently patented at Ohio University, which utilizes vertical columns of permeable material in the form of polypropylene ropes placed in a cross flow configuration within a flue gas stream. The cross flow design has large surface area, which provides scrubbing action; therefore it has the potential for removing multiple pollutants including particulates, gases, vapors and mists. In this new method, the ropes are kept wet by the liquid (water) introduced from the top of the cells running downward on the ropes by capillary action, making the permeable materials act as the ground electrode for capturing particles from the flue gas...
October 10, 2016: Journal of the Air & Waste Management Association
Judith Feucht, Simone Kayser, David Gorodezki, Mohamad Hamieh, Michaela Döring, Franziska Blaeschke, Patrick Schlegel, Hans Bösmüller, Leticia Quintanilla-Fend, Martin Ebinger, Peter Lang, Rupert Handgretinger, Tobias Feuchtinger
T-cell immunotherapies are promising options in relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We investigated the effect of co-signaling molecules on T-cell attack against leukemia mediated by CD19/CD3-bispecific T-cell engager. Primary CD19+ ALL blasts (n≥10) and physiologic CD19+CD10+ bone marrow precursors were screened for 20 co-signaling molecules. PD-L1, PD-1, LAG-3, CD40, CD86, CD27, CD70 and HVEM revealed different stimulatory and inhibitory profiles of pediatric ALL compared to physiologic cells, with PD-L1 and CD86 as most prominent inhibitory and stimulatory markers...
September 30, 2016: Oncotarget
Shengbin Li, Joy M Folkvord, Eva G Rakasz, Hadia M Abdelaal, Reece K Wagstaff, Katalin J Kovacs, Hyeon O Kim, Ryoko Sawahata, Samantha MaWhinney, David Masopust, Elizabeth Connick, Pamela J Skinner
: HIV- and simian immunodeficiency virus (SIV)-specific CD8(+) T cells are typically largely excluded from lymphoid B cell follicles where HIV- and SIV-producing cells are most highly concentrated, indicating that B cell follicles are somewhat of an immune privileged site. To gain insights into virus-specific follicular CD8(+) T cells, we determined the location and phenotype of follicular SIV-specific CD8(+) T cells in situ, the local relationship of these cells to Foxp3(+) cells, and effects of CD8 depletion on levels of follicular SIV-producing cells in chronically SIV infected rhesus macaques...
October 5, 2016: Journal of Virology
Cara C Schafer, Yong Wang, Kenneth P Hough, Anandi Sawant, Stefan C Grant, Victor J Thannickal, Jaroslaw Zmijewski, Selvarangan Ponnazhagan, Jessy S Deshane
Indoleamine 2,3-dioxygenase (IDO) has been implicated in immune evasion by tumors. Upregulation of this tryptophan (Trp)-catabolizing enzyme, in tumor cells and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME), leads to Trp depletion that impairs cytotoxic T cell responses and survival; however, exact mechanisms remain incompletely understood. We previously reported that a combination therapy of gemcitabine and a superoxide dismutase mimetic promotes anti-tumor immunity in a mouse model of lung cancer by inhibiting MDSCs, enhancing polyfunctional response of CD8+ memory T cells, and extending survival...
September 26, 2016: Oncotarget
Neel H Shah, Qi Wang, Qingrong Yan, Deepti Karandur, Theresa A Kadlecek, Ian R Fallahee, William P Russ, Rama Ranganathan, Arthur Weiss, John Kuriyan
The sequence of events that initiates T cell signaling is dictated by the specificities and order of activation of the tyrosine kinases that signal downstream of the T cell receptor. Using a platform that combines exhaustive point-mutagenesis of peptide substrates, bacterial surface-display, cell sorting, and deep sequencing, we have defined the specificities of the first two kinases in this pathway, Lck and ZAP-70, for the T cell receptor ζ chain and the scaffold proteins LAT and SLP-76. We find that ZAP-70 selects its substrates by utilizing an electrostatic mechanism that excludes substrates with positively-charged residues and favors LAT and SLP-76 phosphosites that are surrounded by negatively-charged residues...
October 4, 2016: ELife
B Barrou, N Chatauret, T Hauet, R Thuret, F Kleinclauss, M-O Timsit, R Codas, X Matillon, L Badet
AIMS: To describe ischemia-reperfusion mechanisms, the impact on kidney graft and strategies developed to minimize ischemia-reperfusion damages. MATERIAL AND METHODS: An exhaustive systematic review of the scientific literature was performed in the Medline database ( and Embase ( using different associations of the following keywords: ischemia-reperfusion; organ preservation; hypothermic machine perfusion; renal transplantation...
September 29, 2016: Progrès en Urologie
Leah R Miller, Cheryl Marks, Jill B Becker, Patricia D Hurn, Wei-Jung Chen, Teresa Woodruff, Margaret M McCarthy, Farida Sohrabji, Londa Schiebinger, Cora Lee Wetherington, Susan Makris, Arthur P Arnold, Gillian Einstein, Virginia M Miller, Kathryn Sandberg, Susan Maier, Terri L Cornelison, Janine A Clayton
In June 2015, the National Institutes of Health (NIH) released a Guide notice (NOT-OD-15-102) that highlighted the expectation of the NIH that the possible role of sex as a biologic variable be factored into research design, analyses, and reporting of vertebrate animal and human studies. Anticipating these guidelines, the NIH Office of Research on Women's Health, in October 2014, convened key stakeholders to discuss methods and techniques for integrating sex as a biologic variable in preclinical research. The workshop focused on practical methods, experimental design, and approaches to statistical analyses in the use of both male and female animals, cells, and tissues in preclinical research...
September 28, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Christoph Bisig, Michèle Roth, Loretta Müller, Pierre Comte, Norbert Heeb, Andreas Mayer, Jan Czerwinski, Alke Petri-Fink, Barbara Rothen-Rutishauser
Ethanol can be produced from biomass and as such is renewable, unlike petroleum-based fuel. Almost all gasoline cars can drive with fuel containing 10% ethanol (E10), flex-fuel cars can even use 85% ethanol (E85). Brazil and the USA already include 10-27% ethanol in their standard fuel by law. Most health effect studies on car emissions are however performed with diesel exhausts, and only few data exists for other fuels. In this work we investigated possible toxic effects of exhaust aerosols from ethanol-gasoline blends using a multi-cellular model of the human lung...
September 23, 2016: Environmental Research
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