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T cell exhaustion

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https://www.readbyqxmd.com/read/28431010/clinical-trial-of-the-anti-pd-l1-antibody-bms-936559-in-hiv-1-infected-participants-on-suppressive-antiretroviral-therapy
#1
Cynthia L Gay, Ronald J Bosch, Justin Ritz, Jason M Hataye, Evgenia Aga, Randall L Tressler, Stephen W Mason, Carey K Hwang, Dennis M Grasela, Neelanjana Ray, Josh C Cyktor, John M Coffin, Edward P Acosta, Richard A Koup, John W Mellors, Joseph J Eron
Background.: Reversing immune exhaustion with an anti-PD-L1 antibody may improve HIV-1-specific immunity and increase clearance of HIV-1 expressing cells. Methods.: Phase I, randomized, double-blind, placebo-controlled dose-escalating study of BMS-936559including HIV-1-infected adults ≥18 to ≤70 years on suppressive antiretroviral therapy with CD4+ counts ≥350 cells/μL and detectable plasma HIV-1 RNA by single copy assay. Data on single infusions of BMS-936559 (0...
April 18, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28428786/challenge-of-humans-with-wild-type-salmonella-enterica-serovar-typhi-elicits-changes-in-the-activation-and-homing-characteristics-of-mucosal-associated-invariant-t-cells
#2
Rosângela Salerno-Goncalves, David Luo, Stephanie Fresnay, Laurence Magder, Thomas C Darton, Claire Jones, Claire S Waddington, Christoph J Blohmke, Brian Angus, Myron M Levine, Andrew J Pollard, Marcelo B Sztein
Gastrointestinal infections by Salmonella enterica serovar Typhi (S. Typhi) are rare in industrialized countries. However, they remain a major public health problem in the developing world with an estimated 26.9 million new cases annually and significant mortality when untreated. Recently, we provided the first direct evidence that CD8(+) MAIT cells are activated and have the potential to kill cells exposed to S. Typhi, and that these responses are dependent on bacterial load. However, MAIT cell kinetics and function during bacterial infections in humans remain largely unknown...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28428275/epithelial-to-mesenchymal-transition-contributes-to-immunosuppression-in-breast-carcinomas
#3
Anushka Dongre, Mohammad Rashidian, Ferenc Reinhardt, Aaron Bagnato, Zuzana Keckesova, Hidde L Ploegh, Robert A Weinberg
The Epithelial-to-mesenchymal transition (EMT) is a cell-biological program that confers mesenchymal traits on carcinoma cells and drives their metastatic dissemination. It is, unclear, however, whether activation of EMT in carcinoma cells can change their susceptibility to immune attack. We demonstrate here that mammary tumor cells arising from more epithelial carcinoma cell lines expressed high levels of MHC-I, low levels of PD-L1 and contained within their stroma CD8+ T cells and M1 (anti-tumor) macrophages...
April 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28426535/frailty-in-hiv-infected-people-a-new-risk-factor-for-bone-mineral-density-loss
#4
Sylvie Bregigeon, Anne Galinier, Olivia Zaegel-Faucher, Carla E Cano, Véronique Obry, Hélène Laroche, Sophie Trijau, Armelle Saout, Isabelle Poizot-Martin
OBJECTIVE: This study aims to assess the association between bone mineral density (BMD) and frailty in a cohort of HIV-infected patients. DESIGN: A cross-sectional study in an HIV outpatient unit where nearly 1,000 patients are monitored. METHODS: Subjects undergoing bone densitometry were proposed an evaluation of frailty using criteria of the Cardiovascular Health Study (CHS) and the Study of Osteoporotic Fractures (SOF). Frailty markers (FM) were weight-loss, self-reported exhaustion, physical activity, grip strength, chair stands, and slow gait...
April 19, 2017: AIDS
https://www.readbyqxmd.com/read/28423678/influence-of-ipilimumab-on-expanded-tumour-derived-t-cells-from-patients-with-metastatic-melanoma
#5
Jon Bjoern, Rikke Lyngaa, Rikke Andersen, Lisbet Hölmich Rosenkrantz, Sine Reker Hadrup, Marco Donia, Inge Marie Svane
INTRODUCTION: Tumour infiltrating lymphocyte (TIL) based adoptive cell therapy (ACT) is a promising treatment for patients with advanced melanoma. Retrospective studies suggested an association between previous treatment with anti-CTLA-4 antibodies and long term survival after subsequent ACT. Thus, we hypothesized that treatment with anti-CTLA-4 antibodies can induce favourable changes to be detected in TILs. RESULTS: Expanded T cells from Ipilimumab treated patients had a higher proportion of cells expressing CD27, intracellular CTLA-4, TIM-3 and LAG-3...
March 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28421069/engineering-chimeric-antigen-receptor-t-cells-for-racing-in-solid-tumors-don-t-forget-the-fuel
#6
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/28419653/hcv-viremia-associates-with-nk-cell-activation-and-dysfunction-in-anti-retroviral-hiv-hcv-co-infected-subjects
#7
E Papasavvas, L Azzoni, X Yin, Q Liu, J Joseph, A Mackiewicz, B Ross, K M Lynn, J M Jacobson, K Mounzer, J R Kostman, L J Montaner
The impact of Hepatitis C virus (HCV) RNA levels on immune status in chronically HCV mono-infected when compared to HIV/HCV co-infected on antiretroviral therapy (ART) remains poorly understood. A total of 78 African American subjects HCV viremic/naïve to HCV treatment (33 HCV genotype 1 mono-infected, 45 HCV genotype 1/HIV co-infected on ART) were studied. Clinical and liver enzymes measurements were performed. Whole blood was analyzed for immune subset changes by flow-cytometry. Peripheral blood mononuclear cells (PBMC) were used for same-day constitutive and in vitro Interferon (IFN)-α-induced Signal Transducer and Activator of Transcription (STAT) phosphorylation, K562 target cell lysis and K562 target cell recognition-mediated IFN-γ production...
April 17, 2017: Journal of Viral Hepatitis
https://www.readbyqxmd.com/read/28414300/pd-l1-serves-as-a-double-agent-in-separating-gvl-from-gvhd
#8
Todd V Brennan, Yiping Yang
Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative treatment for a variety of hematologic malignancies due to the well-recognized graft-versus-leukemia/lymphoma (GVL) effect that is mediated by donor-derived alloreactive T cells. However, graft-versus-host disease (GVHD) is mediated by the same T cells and remains a significant clinical problem associated with substantial morbidity and mortality. In this issue of the JCI, Ni and colleagues used several murine models of GVHD to evaluate the effect of CD4+ T cell depletion on GVL versus GVHD and revealed that depletion of CD4+ T cells leads to the upregulation of PD-L1 by recipient tissues and donor CD8+ T cells...
April 17, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28414296/pd-l1-interacts-with-cd80-to-regulate-graft-versus-leukemia-activity-of-donor-cd8-t-cells
#9
Xiong Ni, Qingxiao Song, Kaniel Cassady, Ruishu Deng, Hua Jin, Mingfeng Zhang, Haidong Dong, Stephen Forman, Paul J Martin, Yuan-Zhong Chen, Jianmin Wang, Defu Zeng
Programmed death ligand-1 (PD-L1) interacts with programmed death-1 (PD-1) and the immunostimulatory molecule CD80 and functions as a checkpoint to regulate immune responses. The interaction of PD-L1 with CD80 alone has been shown to exacerbate the severity of graft-versus-host disease (GVHD), whereas costimulation of CD80 and PD-1 ameliorates GVHD. Here we have demonstrated that temporary depletion of donor CD4+ T cells early after hematopoietic cell transplantation effectively prevents GVHD while preserving strong graft-versus-leukemia (GVL) effects in allogeneic and xenogeneic murine GVHD models...
April 17, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28408783/prokaryotic-expression-of-the-extracellular-domain-of-porcine-programmed-death-1-pd-1-and-its-ligand-pd-l1-and-identification-of-the-binding-with-peripheral-blood-mononuclear-cells-in-vitro
#10
Yan-Ping Zhu, Feng Yue, Yong He, Peng Li, Yuan Yang, Yu-Ting Han, Yan-Fang Zhang, Guo-Peng Sun, Dong-Guang Guo, Mei Yin, Xuan-Nian Wang
Programmed cell death protein 1 (PD-1), a costimulatory molecule of the CD28 family, has 2 ligands, PD-L1 and PD-L2. Our previous studies showed that the expression of PD-1 and PD-L1 is up-regulated during viral infection in pigs. Extensive studies have shown that blockade of the PD-1/PD-L1 pathways by anti-PD-L1 antibody or soluble PD-1 restores exhausted T-cells in humans and mice. In the present study the extracellular domains of PD-1 and PD-L1 were used to evaluate the binding of PD-1 and PD-L1 with peripheral blood mononuclear cells (PBMCs)...
April 2017: Canadian Journal of Veterinary Research, Revue Canadienne de Recherche Vétérinaire
https://www.readbyqxmd.com/read/28408179/5-year-expression-and-neutrophil-defect-repair-after-gene-therapy-in-alpha-1-antitrypsin-deficiency
#11
Christian Mueller, Gwladys Gernoux, Alisha M Gruntman, Florie Borel, Emer P Reeves, Roberto Calcedo, Farshid N Rouhani, Anthony Yachnis, Margaret Humphries, Martha Campbell-Thompson, Louis Messina, Jeffrey D Chulay, Bruce Trapnell, James M Wilson, Noel G McElvaney, Terence R Flotte
Alpha-1 antitrypsin deficiency is a monogenic disorder resulting in emphysema due principally to the unopposed effects of neutrophil elastase. We previously reported achieving plasma wild-type alpha-1 antitrypsin concentrations at 2.5%-3.8% of the purported therapeutic level at 1 year after a single intramuscular administration of recombinant adeno-associated virus serotype 1 alpha-1 antitrypsin vector in alpha-1 antitrypsin deficient patients. We analyzed blood and muscle for alpha-1 antitrypsin expression and immune cell response...
April 10, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28405520/the-immune-molecular-landscape-of-the-b7-and-tnfr-immunoregulatory-ligand-receptor-families-in-head-and-neck-cancer-a-comprehensive-overview-and-the-immunotherapeutic-implications
#12
Yu-Pei Chen, Jian Zhang, Ya-Qin Wang, Na Liu, Qing-Mei He, Xiao-Jing Yang, Ying Sun, Jun Ma
The B7 family and tumor necrosis factor receptor (TNFR) superfamily play a vital role in the T-cell co-stimulatory and co-inhibitory pathways, regulating T-cell activation, tolerance, and exhaustion; therapeutic modulation of these pathways is translated into effective new cancer treatments. Better understanding of the immune molecular landscapes of the B7 and TNFR families would guide head and neck immuno-oncology clinical research. We performed comprehensive molecular profiling of 10 B7 and 6 TNFR family members in head and neck cancer...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28405501/pdl1-expression-is-a-poor-prognosis-factor-in-soft-tissue-sarcomas
#13
François Bertucci, Pascal Finetti, Delphine Perrot, Agnès Leroux, Françoise Collin, Axel Le Cesne, Jean-Michel Coindre, Jean-Yves Blay, Daniel Birnbaum, Emilie Mamessier
Soft-tissue sarcomas (STS) are a group of rare, heterogeneous, and aggressive tumors, with high metastatic risk and relatively few efficient systemic therapies. In the quest for new treatments, the immune system represents an attractive therapeutic target. Recently, PD1/PDL1 inhibitors showed very promising results in patients with solid tumors. PDL1 expression has been rarely studied in STS, in small series only, by using immunohistochemistry (IHC), and with non-concordant prognostic implications. Here, we have analyzed PDL1 mRNA expression in 758 clinical STS samples retrospectively profiled using DNA microarrays and RNAseq, and searched for correlations with clinicopathological variables including metastasis-free survival (MFS) after surgery...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28401068/modulation-of-tim-3-expression-by-antigen-dependent-and-independent-factors-on-t-cells-from-patients-with-chronic-hepatitis-b-virus-infection
#14
Jie Dong, Xiao-Fei Yang, Lin-Xu Wang, Xin Wei, An-Hui Wang, Chun-Qiu Hao, Huan-Jun Shen, Chang-Xing Huang, Ye Zhang, Jian-Qi Lian
T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) was up-regulated on viral specific T cells and contributed to T cells exhaustion during chronic hepatitis B virus (HBV) infection. However, modulation of Tim-3 expression was still not fully elucidated. To evaluate the potential viral and inflammatory factors involved in the inductor of Tim-3 expression on T cells, 76 patients with chronic HBV infection (including 40 chronic hepatitis B [CHB] and 36 asymptomatic HBV carriers [AsC]) and 40 of normal controls (NCs) were enrolled in this study...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28397821/t-cell-invigoration-to-tumour-burden-ratio-associated-with-anti-pd-1-response
#15
Alexander C Huang, Michael A Postow, Robert J Orlowski, Rosemarie Mick, Bertram Bengsch, Sasikanth Manne, Wei Xu, Shannon Harmon, Josephine R Giles, Brandon Wenz, Matthew Adamow, Deborah Kuk, Katherine S Panageas, Cristina Carrera, Phillip Wong, Felix Quagliarello, Bradley Wubbenhorst, Kurt D'Andrea, Kristen E Pauken, Ramin S Herati, Ryan P Staupe, Jason M Schenkel, Suzanne McGettigan, Shawn Kothari, Sangeeth M George, Robert H Vonderheide, Ravi K Amaravadi, Giorgos C Karakousis, Lynn M Schuchter, Xiaowei Xu, Katherine L Nathanson, Jedd D Wolchok, Tara C Gangadhar, E John Wherry
Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells)...
April 10, 2017: Nature
https://www.readbyqxmd.com/read/28397730/programmed-cell-death-1-programmed-death-ligand-1-pathway-a-new-target-for-sepsis
#16
REVIEW
Qiang Liu, Chun-Sheng Li
OBJECTIVE: Sepsis remains a leading cause of death in many Intensive Care Units worldwide. Immunosuppression has been a primary focus of sepsis research as a key pathophysiological mechanism. Given the important role of the negative costimulatory molecules programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in the occurrence of immunosuppression during sepsis, we reviewed literatures related to the PD-1/PD-L1 pathway to examine its potential as a new target for sepsis treatment...
April 20, 2017: Chinese Medical Journal
https://www.readbyqxmd.com/read/28393361/immune-checkpoints-and-their-inhibition-in-cancer-and-infectious-diseases
#17
REVIEW
Lydia Dyck, Kingston H G Mills
The development of chronic infections and cancer is facilitated by a variety of immune subversion mechanisms, such as the production of anti-inflammatory cytokines, induction of regulatory T (Treg) cells and expression of immune checkpoint molecules, including CTLA-4 and PD-1. CTLA-4, expressed on T cells, interacts with CD80/CD86, thereby limiting T-cell activation and leading to anergy. PD-1 is predominantly expressed on T cells and its interaction with PD-L1 and PD-L2 expressed on antigen presenting cells (APCs) and tumours sends a negative signal to T cells, which can lead to T-cell exhaustion...
April 9, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28393295/elevated-galectin-9-suppresses-th1-effector-function-and-induces-apoptosis-of-activated-cd4-t-cells-in-osteoarthritis
#18
Shufeng Yang, Jin Wang, Fengrong Chen, Guoyin Liu, Zhiqiang Weng, Jianmin Chen
T cell immunoglobulin and mucin domain 3 (Tim-3) is a critical regulatory molecule found on activated Th1 cells, exhausted CD8(+) T cells, and resting monocytes/macrophages. Galectin-9 (Gal-9) is an identified ligand for Tim-3. Interaction between Tim-3 and Gal-9 is thought to inhibit Th1 responses. The regulation and function of Tim-3 and Gal-9 in osteoarthritis (OA) have not been intensively investigated. We found that in peripheral blood, CD4(+) T cells, but not CD8(+) T cells or CD14(+) monocytes, from OA patients presented significantly elevated Tim-3 and Gal-9 expression compared to those from healthy controls (HC)...
April 10, 2017: Inflammation
https://www.readbyqxmd.com/read/28391394/lifelong-training-improves-anti-inflammatory-environment-and-maintains-the-number-of-regulatory-t-cells-in-masters-athletes
#19
Luciele G Minuzzi, Luis Rama, Nicolette C Bishop, Fátima Rosado, António Martinho, Artur Paiva, Ana M Teixeira
PURPOSE: The purpose of this study was to quantify and characterize peripheral blood regulatory T cells (Tregs), as well as the IL-10 plasma concentration, in Masters athletes at rest and after an acute exhaustive exercise test. METHODS: Eighteen Masters athletes (self-reported training: 24.6 ± 1.83 years; 10.27 ± 0.24 months and 5.45 ± 0.42 h/week per each month trained) and an age-matched control group of ten subjects (that never took part in regular physical training) volunteered for this study...
April 8, 2017: European Journal of Applied Physiology
https://www.readbyqxmd.com/read/28388539/preferential-accumulation-of-regulatory-t-cells-with-highly-immunosuppressive-characteristics-in-breast-tumor-microenvironment
#20
Azharuddin Sajid Syed Khaja, Salman M Toor, Haytham El Salhat, Issam Faour, Navid Ul Haq, Bassam R Ali, Eyad Elkord
Immunosuppressive cells such as regulatory T cells (Tregs) have an ambiguous role in breast cancer prognosis, with studies reporting both positive and negative correlations between Treg infiltration and prognosis. This discrepancy could be due to the different immunosuppressive molecules present in these cells. In the present study, we phenotypically characterize different Treg subsets infiltrating the tumor microenvironment (TME), compared to adjacent normal tissue and peripheral blood of primary breast cancer (PBC) patients...
March 25, 2017: Oncotarget
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