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https://www.readbyqxmd.com/read/28388955/blocking-the-pd-1-pd-l1-pathway-in-glioma-a-potential-new-treatment-strategy
#1
REVIEW
Song Xue, Man Hu, Veena Iyer, Jinming Yu
Gliomas are the most common type of primary brain tumor in adults. High-grade neoplasms are associated with poor prognoses, whereas low-grade neoplasms are associated with 5-year overall survival rates of approximately 85%. Despite considerable progress in treatment modalities, the outcomes remain dismal. As is the case with many other tumors, gliomas express or secrete several immunosuppressive molecules that regulate immune cell function. Programmed death-ligand 1 (PD-L1) is a coinhibitory ligand that is predominantly expressed by tumor cells...
April 7, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28360089/atvb-distinguished-scientist-award-how-costimulatory-and-coinhibitory-pathways-shape-atherosclerosis
#2
REVIEW
Klaus Ley, Norbert Gerdes, Holger Winkels
OBJECTIVE: Immune cells play a critical role in atherosclerosis. Costimulatory and coinhibitory molecules of the tumor necrosis factor receptor and CD28 immunoglobulin superfamilies not only shape T-cell and B-cell responses but also have a major effect on antigen-presenting cells and nonimmune cells. APPROACH AND RESULTS: Pharmacological inhibition or activation of costimulatory and coinhibitory molecules and genetic deletion demonstrated their involvement in atherosclerosis...
March 30, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28351852/leukocyte-immunoglobulin-like-receptors-in-human-diseases-an-overview-of-their-distribution-function-and-potential-application-for-immunotherapies
#3
REVIEW
Jilu Zhang, Sunny Mai, Hui-Ming Chen, Kyeongah Kang, Xian Chang Li, Shu-Hsia Chen, Ping-Ying Pan
Myeloid-derived suppressor cells (MDSCs), a population of immature myeloid cells expanded and accumulated in tumor-bearing mice and in patients with cancer, have been shown to mediate immune suppression and to promote tumor progression, thereby, posing a major hurdle to the success of immune-activating cancer therapies. MDSCs, like their healthy counterparts, such as monocytes/macrophages and granulocytes, express an array of costimulatory and coinhibitory molecules as well as myeloid activators and inhibitory receptors, such as leukocyte immunoglobulin-like receptors (LILR) A and B...
March 28, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28321218/the-induction-and-maintenance-of-transplant-tolerance-engages-both-regulatory-and-anergic-cd4-t-cells
#4
Alix Besançon, Marije Baas, Tania Goncalves, Fabrice Valette, Herman Waldmann, Lucienne Chatenoud, Sylvaine You
Therapeutic tolerance to self-antigens or foreign antigens is thought to depend on constant vigilance by Foxp3(+) regulatory T cells (Tregs). Previous work using a pancreatic islet allograft model and a short pulse of CD3 antibody therapy has shown that CD8(+) T cells become anergic and use TGFβ and coinhibitory signaling as their contribution to the tolerance process. Here, we examine the role of CD4(+) T cells in tolerization by CD3 antibodies. We show that both Foxp3(+) Tregs and CD4(+) T cell anergy play a role in the induction of tolerance and its maintenance...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28320914/two-strikes-and-you-re-out-the-pathogenic-interplay-of-coinhibitor-deficiency-and-lymphopenia-induced-proliferation
#5
REVIEW
Kristofor K Ellestad, Colin C Anderson
Lymphopenia-induced proliferation (LIP) occurs when resources for T cell survival in a host are in excess. LIP has been associated with the development of inflammatory disease in situations where an additional disease-predisposing cofactor is present during LIP. This has led to the view of LIP-driven autoimmunity as a two hit model; however, not all cofactors have equal ability to precipitate autoimmunity and we have recently shown that in some circumstances, such as the absence of the coinhibitory molecule PD-1, additional hits are required...
April 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28258702/advances-in-targeting-co-inhibitory-and-co-stimulatory-pathways-in-transplantation-settings-the-yin-to-the-yang-of%C3%A2-cancer-immunotherapy
#6
REVIEW
Leslie S Kean, Laurence A Turka, Bruce R Blazar
In the past decade, the power of harnessing T-cell co-signaling pathways has become increasingly understood to have significant clinical importance. In cancer immunotherapy, the field has concentrated on two related modalities: First, targeting cancer antigens through highly activated chimeric antigen T cells (CAR-Ts) and second, re-animating endogenous quiescent T cells through checkpoint blockade. In each of these strategies, the therapeutic goal is to re-ignite T-cell immunity, in order to eradicate tumors...
March 2017: Immunological Reviews
https://www.readbyqxmd.com/read/28115719/immunoinhibitory-checkpoint-deficiency-in-medium-and-large-vessel-vasculitis
#7
Hui Zhang, Ryu Watanabe, Gerald J Berry, Augusto Vaglio, Yaping Joyce Liao, Kenneth J Warrington, Jörg J Goronzy, Cornelia M Weyand
Giant cell arteritis (GCA) causes autoimmune inflammation of the aorta and its large branches, resulting in aortic arch syndrome, blindness, and stroke. CD4(+) T cells and macrophages form organized granulomatous lesions in the walls of affected arteries, destroy the tunica media, and induce ischemic organ damage through rapid intimal hyperplasia and luminal occlusion. Pathogenic mechanisms remain insufficiently understood; specifically, it is unknown whether the unopposed activation of the immune system is because of deficiency of immunoinhibitory checkpoints...
February 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28114251/novel-checkpoints-and-cosignaling-molecules-in-cancer-immunotherapy
#8
Iulia Giuroiu, Jeffrey Weber
The recent demonstration of the antitumor efficacy of checkpoint protein inhibition has resulted in the approval of blocking antibodies against the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway in multiple different histologic findings. Therapeutic successes with PD-1/PD-L1 antibodies in melanoma and lung cancer have been followed by approvals in bladder, renal, and head and neck cancers and Hodgkin lymphoma, with others undoubtedly to come. However, PD-1 is only one of many checkpoints and agonistic regulatory molecules expressed on T cells by which maintenance of the balance between costimulatory and coinhibitory signaling pathways is perturbed in cancer...
January 2017: Cancer Journal
https://www.readbyqxmd.com/read/28012568/improved-survival-after-induction-of-sepsis-by-cecal-slurry-in-pd-1-knockout-murine-neonates
#9
Whitney A Young, Eleanor A Fallon, Daithi S Heffernan, Philip A Efron, William G Cioffi, Alfred Ayala
BACKGROUND: Sepsis and the ensuing immune dysfunction continue to be major contributors to neonatal morbidity and mortality. Neonatal sepsis also is associated with profound immune dysfunction. We have recently identified a role for a family of coinhibitory molecules that are altered in murine sepsis and in critically ill adult patients, which may be a target for development of novel therapies. There is, however, a paucity of data pertaining to the role of coinhibitory checkpoint proteins in the control and modulation of neonatal sepsis...
May 2017: Surgery
https://www.readbyqxmd.com/read/27993215/anti-pd-l1-peptide-improves-survival-in-sepsis
#10
Yuichiro Shindo, Jacquelyn S McDonough, Katherine C Chang, Murali Ramachandra, Pottayil G Sasikumar, Richard S Hotchkiss
BACKGROUND: Sepsis remains a leading cause of death in most intensive care units. Many deaths in sepsis are due to nosocomial infections in patients who have entered the immunosuppressive phase of the disorder. One cause of immunosuppression in sepsis is T-cell exhaustion mediated by programmed cell death-1 (PD-1) interaction with its ligand (PD-L1). Studies demonstrated that blocking the interaction of PD-1 with PD-L1 with knockout mice or inhibitory antibodies reversed T-cell dysfunction and improved sepsis survival...
February 2017: Journal of Surgical Research
https://www.readbyqxmd.com/read/27956634/brief-treatment-with-a-highly-selective-immunoproteasome-inhibitor-promotes-long-term-cardiac-allograft-acceptance-in-mice
#11
Esilida Sula Karreci, Hao Fan, Mayuko Uehara, Albana B Mihali, Pradeep K Singh, Ahmed T Kurdi, Zhabiz Solhjou, Leonardo V Riella, Irene Ghobrial, Teresina Laragione, Sujit Routray, Jean Pierre Assaker, Rong Wang, George Sukenick, Lei Shi, Franck J Barrat, Carl F Nathan, Gang Lin, Jamil Azzi
Constitutive proteasomes (c-20S) are ubiquitously expressed cellular proteases that degrade polyubiquitinated proteins and regulate cell functions. An isoform of proteasome, the immunoproteasome (i-20S), is highly expressed in human T cells, dendritic cells (DCs), and B cells, suggesting that it could be a potential target for inflammatory diseases, including those involving autoimmunity and alloimmunity. Here, we describe DPLG3, a rationally designed, noncovalent inhibitor of the immunoproteasome chymotryptic subunit β5i that has thousands-fold selectivity over constitutive β5c...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27941003/efficacy-of-pd-1-blockade-is-potentiated-by-metformin-induced-reduction-of-tumor-hypoxia
#12
Nicole E Scharping, Ashley V Menk, Ryan D Whetstone, Xue Zeng, Greg M Delgoffe
Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers, resulting in remarkable responses. However, despite successes in the clinic, most patients do not respond to PD-1 blockade. Metabolic dysregulation is a common phenotype in cancer, but both patients and tumors are metabolically heterogeneous. We hypothesized that the deregulated oxidative energetics of tumor cells present a metabolic barrier to antitumor immunity through the generation of a hypoxic microenvironment and that normalization of tumor hypoxia might improve response to immunotherapy...
January 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/27898465/the-intragraft-microenvironment-as-a-central-determinant-of-chronic-rejection-or-local-immunoregulation-tolerance
#13
Johannes Wedel, Hironao Nakayama, Nora M Kochupurakkal, Josephine Koch, Michael Klagsbrun, Diane R Bielenberg, David M Briscoe
PURPOSE OF REVIEW: Chronic rejection is associated with persistent mononuclear cell recruitment, endothelial activation and proliferation, local tissue hypoxia and related biology that enhance effector immune responses. In contrast, the tumor microenvironment elicits signals/factors that inhibit effector T cell responses and rather promote immunoregulation locally within the tissue itself. The identification of immunoregulatory check points and/or secreted factors that are deficient within allografts is of great importance in the understanding and prevention of chronic rejection...
February 2017: Current Opinion in Organ Transplantation
https://www.readbyqxmd.com/read/27849166/first-in-human-study-in-healthy-subjects-with-fr104-a-pegylated-monoclonal-antibody-fragment-antagonist-of-cd28
#14
Nicolas Poirier, Gilles Blancho, Maryvonne Hiance, Caroline Mary, Tim Van Assche, Jos Lempoels, Steven Ramael, Weirong Wang, Virginie Thepenier, Cecile Braudeau, Nina Salabert, Regis Josien, Ian Anderson, Ian Gourley, Jean-Paul Soulillou, Didier Coquoz, Bernard Vanhove
FR104 is a monovalent pegylated Fab' Ab, antagonist of CD28, under development for treatment of transplant rejection and autoimmune diseases. In contrast to CD80/86 antagonists (CTLA4-Ig), FR104 selectively blunts CD28 costimulation while sparing CTLA-4 and PD-L1 coinhibitory signals. In the present work, FR104 has been evaluated in a first-in-human study to evaluate the safety, pharmacokinetics, pharmacodynamics, and potency of i.v. administrations in healthy subjects. Sixty-four subjects were randomly assigned to four single ascending dose groups, two double dose groups and four single ascending dose groups challenged with keyhole limpet hemocyanin...
December 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27829150/programmed-death-1-culls-peripheral-accumulation-of-high-affinity-autoreactive-cd4%C3%A2-t-cells-to-protect-against-autoimmunity
#15
Tony T Jiang, Tijana Martinov, Lijun Xin, Jeremy M Kinder, Justin A Spanier, Brian T Fife, Sing Sing Way
Self-reactive CD4 T cells are incompletely deleted during thymic development, and their peripheral seeding highlights the need for additional safeguards to avert autoimmunity. Here, we show an essential role for the coinhibitory molecule programmed death-1 (PD-1) in silencing the activation of high-affinity autoreactive CD4 T cells. Each wave of self-reactive CD4 T cells that escapes thymic deletion autonomously upregulates PD-1 to maintain self-tolerance. By tracking the progeny derived from individual autoreactive CD4 T cell clones, we demonstrate that self-reactive cells with the greatest autoimmune threat and highest self-antigen affinity express the most PD-1...
November 8, 2016: Cell Reports
https://www.readbyqxmd.com/read/27803740/antagonizing-programmed-death-1-and-programmed-death-ligand-1-as-a-therapeutic-approach-for-gastric-cancer
#16
REVIEW
Xiaojun Liu, Zhongxia Yang, Olivier Latchoumanin, Liang Qiao
Malignant tumor cells are equipped with mechanisms that can help them escape the surveillance by host immune system. Immune checkpoint molecules can transduce coinhibitory signals to immunocompetent cells and exert immunosuppressive roles in antitumor immunity. Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) are the two important checkpoint molecules with great potential in targeted cancer therapy. Several antibodies targeting PD-1 and PD-L1 have been approved for clinical use. In this review, we focus on the recent development of targeting PD-1 and PD-L1 in gastric cancer (GC) therapy...
November 2016: Therapeutic Advances in Gastroenterology
https://www.readbyqxmd.com/read/27802341/acute-malaria-induces-pd1-ctla4-effector-t-cells-with-cell-extrinsic-suppressor-function
#17
Maria Sophia Mackroth, Annemieke Abel, Christiane Steeg, Julian Schulze Zur Wiesch, Thomas Jacobs
In acute Plasmodium falciparum (P. falciparum) malaria, the pro- and anti-inflammatory immune pathways must be delicately balanced so that the parasitemia is controlled without inducing immunopathology. An important mechanism to fine-tune T cell responses in the periphery is the induction of coinhibitory receptors such as CTLA4 and PD1. However, their role in acute infections such as P. falciparum malaria remains poorly understood. To test whether coinhibitory receptors modulate CD4+ T cell functions in malaria, blood samples were obtained from patients with acute P...
November 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27731324/unique-b7-h1-expression-on-masticatory-mucosae-in-the-oral-cavity-and-trans-coinhibition-by-b7-h1-expressing-keratinocytes-regulating-cd4-t-cell-mediated-mucosal-tissue-inflammation
#18
S Kang, C Zhang, T Ohno, M Azuma
The PD-1/B7-H1 pathway regulates immune responses and maintains homeostasis. Here, we identified a unique expression of B7 homolog 1 (B7-H1) on masticatory mucosae in the oral cavity. B7-H1 was physiologically expressed on the dorsal surface of the tongue, gingiva, and hard palate. Other squamous epithelia and other structures of the epithelia did not express B7-H1 in the steady state. Physiological B7-H1 expression on masticatory mucosae was limited on prickle cells, and its expression on basal keratinocytes (KCs) was strictly regulated...
May 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/27617403/hepatitis-b-core-antigen-upregulates-b7-h1-on-dendritic-cells-by-activating-the-akt-erk-p38-pathway-a-possible-mechanism-of-hepatitis-b-virus-persistence
#19
Man Li, Zhen-Hua Zhou, Xue-Hua Sun, Xin Zhang, Xiao-Jun Zhu, Shu-Gen Jin, Ya-Ting Gao, Yun Jiang, Yue-Qiu Gao
B7-H1 binding to programmed death-1 may deliver a coinhibitory signal to T cells that is involved in the regulation of T-cell activation and tolerance. B7-H1 plays a key role in dysfunction of dendritic cells (DCs) during chronic HBV infection, but the expression mechanism of B7-H1 remains unclear. One hundred and twenty-nine patients with chronic HBV infection were categorized into either the immune tolerance phase (HBV-IT), the immune clearance phase (HBV-IC), or the inactive carrier phase (HBV-IA). Twenty healthy volunteers were enrolled as controls...
September 12, 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/27591335/costimulation-blockade-in-autoimmunity-and-transplantation-the-cd28-pathway
#20
Andrew B Adams, Mandy L Ford, Christian P Larsen
T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. TCR signaling in the absence of costimulatory signals can lead to an abortive attempt at activation and subsequent anergy. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86. The development of the fusion protein CTLA-4-Ig as an experimental and subsequent therapeutic tool is one of the major success stories in modern immunology...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
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