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https://www.readbyqxmd.com/read/29437767/t-cell-exhaustion-signatures-vary-with-tumor-type-and-are-severe-in-glioblastoma
#1
Karolina Woroniecka, Pakawat Chongsathidkiet, Kristen E Rhodin, Hanna R Kemeny, Cosette A Dechant, Samuel H Farber, Aladine A Elsamadicy, Xiuyu Cui, Shohei Koyama, Christina C Jackson, Landon J Hansen, Tanner M Johanns, Luis Sanchez-Perez, Vidyalakshmi Chandramohan, Yen-Rei A Yu, Darell D Bigner, Amber J Giles, Patrick Healy, Glenn Dranoff, Kent J Weinhold, Gavin P Dunn, Peter E Fecci
PURPOSE: T cell dysfunction is a hallmark of GBM. While anergy and tolerance have been well characterized, T cell exhaustion remains relatively unexplored. Exhaustion, characterized in part by the upregulation of multiple immune checkpoints, is a known contributor to failures amidst immune checkpoint blockade, a strategy that has lacked success thus far in GBM. This study is among the first to examine, and credential as bona fide, exhaustion among T cells infiltrating human and murine GBM...
February 7, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29427438/nanoparticle-based-approaches-to-immune-tolerance-for-the-treatment-of-autoimmune-diseases
#2
REVIEW
Pau Serra, Pere Santamaria
Autoimmune diseases are caused by antigenically complex immune responses of the adaptive and innate immune system against specific cells, tissues or organs. Antigen-specific approaches for induction of immune tolerance in autoimmunity, based on the use of antigenic peptides or proteins, have failed to deliver the desired therapeutic results in clinical trials. These approaches, which are largely relying on triggering clonal anergy and/or deletion of defined autoreactive specificities, do not address the overwhelming antigenic, molecular and cellular complexity of most autoimmune diseases, which involve various immune cells and ever-growing repertoires of antigenic epitopes on numerous self-antigens...
February 10, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/29415126/central-nervous-system-germinomas-express-programmed-death-ligand-1
#3
Miriam E Wildeman, Matthew J Shepard, Edward H Oldfield, M Beatriz S Lopes
Immunomodulation and tumor-induced tolerance is one of the central mechanisms in the oncogenesis of malignant and benign neoplasms. While numerous pathways have been described, signaling through the programmed death receptor 1 (PD-1) on T lymphocytes, via activation through its ligand, programmed death ligand 1 (PD-L1) expressed on tumor cells is one of the central pathways involved in tumor-induced tolerance. While the neoplastic component of germinomas of the CNS is the germ cell, these tumors also exhibit an abundance of quiescent tumor-infiltrating lymphocytes...
February 5, 2018: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/29408931/inhibition-of-experimental-autoimmune-encephalomyelitis-by-tolerance-promoting-dna-vaccination-focused-to-dendritic-cells
#4
Timo Castor, Nir Yogev, Thomas Blank, Christina Barwig, Marco Prinz, Ari Waisman, Matthias Bros, Angelika B Reske-Kunz
In this study we analysed the effects of prophylactic biolistic DNA vaccination with plasmids encoding the encephalitogenic protein myelin oligodendrocyte glycoprotein (MOG) on the severity of a subsequently MOGp35-55-induced EAE and on the underlying immune response. We compared the outcome of vaccination with MOG-encoding plasmids alone or in combination with vectors encoding the regulatory cytokines IL-10 and TGF-ß1, respectively. MOG expression was restricted to skin dendritic cells (DCs) by the use of the DC-specific promoter of the fascin1 gene (pFscn-MOG)...
2018: PloS One
https://www.readbyqxmd.com/read/29403498/two-distinct-pathways-in-mice-generate-antinuclear-antigen-reactive-b-cell-repertoires
#5
Martin Faderl, Fabian Klein, Oliver F Wirz, Stefan Heiler, Llucia Albertí-Servera, Corinne Engdahl, Jan Andersson, Antonius Rolink
The escape of anti-self B cells from tolerance mechanisms like clonal deletion, receptor editing, and anergy results in the production of autoantibodies, which is a hallmark of many autoimmune disorders. In this study, we demonstrate that both germline sequences and somatic mutations contribute to autospecificity of B cell clones. For this issue, we investigated the development of antinuclear autoantibodies (ANAs) and their repertoire in two different mouse models. First, in aging mice that were shown to gain several autoimmune features over time including ANAs...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29395522/reduced-pathogenicity-of-fructose-1-6-bisphosphatase-deficient-leishmania-donovani-and-its-use-as-an-attenuated-strain-to-induce-protective-immunogenicity
#6
Savita Saini, Ayan Kumar Ghosh, Sushmita Das, Ruby Singh, Kumar Abhishek, Sudha Verma, Ajay Kumar, Abhishek Mandal, Bidyut Purkait, Kislay Kumar Sinha, Pradeep Das
Currently, there is no approved vaccine for visceral leishmaniasis (VL) caused by L. donovani. The ability to manipulate Leishmania genome by eliminating or introducing genes necessary for parasites' survival considered as the powerful strategy to generate the live attenuated vaccine. In the present study fructose-1,6-bisphosphatase (LdFBPase) gene deleted L. donovani (Δfbpase) was generated using homologous gene replacement strategy. Though LdFBPase gene deletion (Δfbpase) does not affect the growth of parasite in the promastigote form but axenic amastigotes display a marked reduction in their capacity to multiply in vitro inside macrophages and in vivo in Balb/c mice...
February 21, 2018: Vaccine
https://www.readbyqxmd.com/read/29393500/indoleamine-2-3-dioxygenase-regulation-of-immune-response-review
#7
Hao Wu, Jianping Gong, Yong Liu
Indoleamine 2, 3-dioxygenase (IDO) catalyzes the initial and rate‑limiting step in the degradation pathway of the essential amino acid tryptophan and is expressed by professional antigen presenting cells (APCs), epithelial cells, vascular endothelium and tumor cells. IDO‑mediated catabolic products, which are additionally termed 'kynurenines', exerts important immunosuppressive functions primarily via regulating T effector cell anergy and inducing the proliferation of T regulatory cells. This endogenous tolerogenic pathway has a critical effect on mediating the magnitude of immune responses under various stress conditions, including tumor, infection and transplantation...
February 1, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29379043/early-immune-anergy-towards-recall-antigens-and-mitogens-in-patients-at-onset-of-septic-shock
#8
M Feuerecker, L Sudhoff, B Crucian, J-I Pagel, C Sams, C Strewe, A Guo, G Schelling, J Briegel, I Kaufmann, A Choukèr
The pathology of sepsis is typically characterized by an infection and excessive initial inflammation including a cytokine storm, followed by a state of immune suppression or paralysis. This classical view of a two peak kinetic immune response is currently controversially discussed. This study was a sub-study of the randomized clinical Trial SISPCT registered with www.clinicaltrials.gov (NCT00832039, Registration date: 29/01/2009). Blood samples from 76 patients with severe sepsis and septic shock were incubated for 48 h at 37 °C in vitro with bacterial or fungal recall-antigens or specific mitogen antigens within 24 hours of sepsis onset...
January 29, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29374560/cellular-and-functional-biomarkers-of-clinical-transplant-tolerance
#9
REVIEW
James M Mathew, Mohammed Javeed Ansari, Lorenzo Gallon, Joseph R Leventhal
Development of tolerance protocols requires assays or biomarkers that distinguish tolerant recipients from non-tolerant ones to be established. In addition, a thorough understanding of the plausible mechanisms associated with clinical transplant tolerance is necessary to take the field forward. Unlike the majority of molecular signature analyses utilized by others, the emphasis of this article is on the cellular and functional biomarkers of induced transplant tolerance. Immunity to an organ transplant is very complex, comprised of two broad categories - innate and acquired or adaptive immune responses...
January 25, 2018: Human Immunology
https://www.readbyqxmd.com/read/29367423/chemotherapy-induces-enrichment-of-cd47-cd73-pdl1-immune-evasive-triple-negative-breast-cancer-cells
#10
Debangshu Samanta, Youngrok Park, Xuhao Ni, Huili Li, Cynthia A Zahnow, Edward Gabrielson, Fan Pan, Gregg L Semenza
Triple-negative breast cancer (TNBC) is treated with cytotoxic chemotherapy and is often characterized by early relapse and metastasis. To form a secondary (recurrent and/or metastatic) tumor, a breast cancer cell must evade the innate and adaptive immune systems. CD47 enables cancer cells to evade killing by macrophages, whereas CD73 and PDL1 mediate independent mechanisms of evasion of cytotoxic T lymphocytes. Here, we report that treatment of human or murine TNBC cells with carboplatin, doxorubicin, gemcitabine, or paclitaxel induces the coordinate transcriptional induction of CD47, CD73, and PDL1 mRNA and protein expression, leading to a marked increase in the percentage of CD47+CD73+PDL1+ breast cancer cells...
January 24, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29343548/loss-of-b-cell-anergy-in-type-1-diabetes-is-associated-with-high-risk-hla-and-non-hla-disease-susceptibility-alleles
#11
Mia J Smith, Marynette Rihanek, Clive Wasserfall, Clayton E Mathews, Mark A Atkinson, Peter A Gottlieb, John C Cambier
Although B cells reactive with islet autoantigens are silenced by tolerance mechanisms in healthy individuals, they can become activated and contribute to development of type 1 diabetes. We previously demonstrated that high-affinity insulin-binding B cells (IBCs) occur exclusively in the anergic (BND) compartment in peripheral blood of healthy subjects. Consistent with their activation early in disease development, high-affinity IBCs are absent from the BND compartment of some first-degree relatives (FDRs) as well as all autoantibody positive pre-diabetic and new-onset type 1 diabetes patients, a time when they are found in pancreatic islets...
January 17, 2018: Diabetes
https://www.readbyqxmd.com/read/29339767/regulatory-t-cells-trigger-effector-t-cell-dna-damage-and-senescence-caused-by-metabolic-competition
#12
Xia Liu, Wei Mo, Jian Ye, Lingyun Li, Yanping Zhang, Eddy C Hsueh, Daniel F Hoft, Guangyong Peng
Defining the suppressive mechanisms used by regulatory T (Treg) cells is critical for the development of effective strategies for treating tumors and chronic infections. The molecular processes that occur in responder T cells that are suppressed by Treg cells are unclear. Here we show that human Treg cells initiate DNA damage in effector T cells caused by metabolic competition during cross-talk, resulting in senescence and functional changes that are molecularly distinct from anergy and exhaustion. ERK1/2 and p38 signaling cooperate with STAT1 and STAT3 to control Treg-induced effector T-cell senescence...
January 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29325640/selective-egf-receptor-inhibition-in%C3%A2-cd4-%C3%A2-t%C3%A2-cells-induces-anergy-and%C3%A2-limits%C3%A2-atherosclerosis
#13
Lynda Zeboudj, Mikael Maître, Lea Guyonnet, Ludivine Laurans, Jeremie Joffre, Jeremie Lemarie, Simon Bourcier, Wared Nour-Eldine, Coralie Guérin, Jonas Friard, Abdelilah Wakkach, Elizabeth Fabre, Alain Tedgui, Ziad Mallat, Pierre-Louis Tharaux, Hafid Ait-Oufella
BACKGROUND: Several epidermal growth factor receptor (EGFR) inhibitors have been successfully developed for the treatment of cancer, limiting tumor growth and metastasis. EGFR is also expressed by leukocytes, but little is known about its role in the modulation of the immune response. OBJECTIVES: The aim of this study was to determine whether EGFR expressed on CD4+ T cells is functional and to address the consequences of EGFR inhibition in atherosclerosis, a T cell-mediated vascular chronic inflammatory disease...
January 16, 2018: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/29282254/continuous-activity-of-foxo1-is-required-to-prevent-anergy-and-maintain-the-memory-state-of-cd8-t-cells
#14
Arnaud Delpoux, Rodrigo Hess Michelini, Shilpi Verma, Chen-Yen Lai, Kyla D Omilusik, Daniel T Utzschneider, Alec J Redwood, Ananda W Goldrath, Chris A Benedict, Stephen M Hedrick
Upon infection with an intracellular pathogen, cytotoxic CD8+ T cells develop diverse differentiation states characterized by function, localization, longevity, and the capacity for self-renewal. The program of differentiation is determined, in part, by FOXO1, a transcription factor known to integrate extrinsic input in order to specify survival, DNA repair, self-renewal, and proliferation. At issue is whether the state of T cell differentiation is specified by initial conditions of activation or is actively maintained...
December 27, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29275462/cancer-immunotherapy-targets-based-on-understanding-the-t-cell-inflamed-versus-non-t-cell-inflamed-tumor-microenvironment
#15
Thomas F Gajewski, Leticia Corrales, Jason Williams, Brendan Horton, Ayelet Sivan, Stefani Spranger
Most cancers express tumor antigens that can be recognized by T cells of the host. The fact that cancers become clinically evident nonetheless implies that immune escape must occur. Two major subsets of human melanoma metastases have been identified based on gene expression profiling. One subgroup has a T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN signature. In contrast, the other major subset lacks this phenotype and has been designated as non-T cell-inflamed...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29260623/pd-1-pd-l1-in-disease
#16
Nyanbol Kuol, Lily Stojanovska, Kulmira Nurgali, Vasso Apostolopoulos
AIM: Expression of PD-1 on T/B cells regulates peripheral tolerance and autoimmunity. Binding of PD-1 to its ligand, PD-L1, leads to protection against self-reactivity. In contrary, tumor cells have evolved immune escape mechanisms whereby overexpression of PD-L1 induces anergy and/or apoptosis of PD-1 positive T cells by interfering with T cell receptor signal transduction. PD-L1 and PD-1 blockade using antibodies are in human clinical trials as an alternative cancer treatment modality...
February 2018: Immunotherapy
https://www.readbyqxmd.com/read/29251774/altered-toll-like-receptor-responsiveness-underlies-a-dominant-heritable-defect-in-b%C3%A2-cell-tolerance-in-autoimmune-new-zealand-black-mice
#17
Amy G Clark, Elizabeth S Buckley, Mary H Foster
Systemic lupus erythematosus is a debilitating autoimmune disease in which autoantibodies and autoreactive T cells destroy kidneys and other organs. Disease is clinically and genetically heterogeneous, suggesting that underlying mechanisms vary between patients. We previously used an autoantibody transgenic mouse reporter system to examine the effect of different autoimmune backgrounds on B-cell tolerance, failure of which is a fundamental defect in lupus. We identified a defect consistent with reversible anergy induced by endotoxin stimulation of B cells from Ig transgenic New Zealand Black (NZB) mice...
December 18, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/29233566/activation-of-thyroid-antigen-reactive-b-cells-in-recent-onset-autoimmune-thyroid-disease-patients
#18
Mia J Smith, Marynette Rihanek, Brianne M Coleman, Peter A Gottlieb, Virginia D Sarapura, John C Cambier
Autoimmune thyroid disease (AITD), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), is the most common autoimmune disorder in the United States, affecting over 20 million people. At the time of diagnosis, both HD and GD are characterized by the accumulation of B and T lymphocytes in the thyroid gland and production of autoantibodies targeting the thyroid, indicating that a breach in tolerance of autoreactive lymphocytes has occurred. However, few studies have sought to understand the underlying pathogenesis of AITD that ultimately leads to production of autoantibodies and loss of thyroid function...
December 9, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/29221580/mechanisms-of-allergen-immunotherapy-for-inhaled-allergens-and-predictive-biomarkers
#19
REVIEW
Mohamed H Shamji, Stephen R Durham
Allergen immunotherapy is effective in patients with IgE-dependent allergic rhinitis and asthma. When immunotherapy is given continuously for 3 years, there is persistent clinical benefit for several years after its discontinuation. This disease-modifying effect is both antigen-specific and antigen-driven. Clinical improvement is accompanied by decreases in numbers of effector cells in target organs, including mast cells, basophils, eosinophils, and type 2 innate lymphoid cells. Immunotherapy results in the production of blocking IgG/IgG4 antibodies that can inhibit IgE-dependent activation mediated through both high-affinity IgE receptors (FcεRI) on mast cells and basophils and low-affinity IgE receptors (FcεRII) on B cells...
December 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29203543/a-novel-mechanism-behind-the-immunopathogenesis-of-vulvovaginal-candidiasis-neutrophil-anergy
#20
Junko Yano, Brian M Peters, Mairi C Noverr, Paul L Fidel
For over three decades, investigators have studied the pathogenesis of vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) through clinical studies and animal models. While there was considerable consensus that susceptibility was not associated with any apparent deficiencies in adaptive immunity, protective immune mechanisms and the role of innate immunity remained elusive. It was not until an innovative live challenge design was conducted in women that a fuller understanding of the natural history of infection/disease was achieved...
December 4, 2017: Infection and Immunity
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