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Costimulatory t cells

Nina Jain, Jeffrey B Doyon, Jacob E Lazarus, Inga-Marie Schaefer, Melanie E Johncilla, Agoston T Agoston, Anuj K Dalal, Gustavo E Velásquez
Biologic agents are effective treatments for rheumatoid arthritis but are associated with important risks, including severe infections. Tumor Necrosis Factor (TNF) α inhibitors are known to increase the risk of systemic fungal infections such as disseminated histoplasmosis. Abatacept is a biologic agent with a mechanism different from that of TNFα inhibitors: It suppresses cellular immunity by competing for the costimulatory signal on antigen-presenting cells. The risk of disseminated histoplasmosis for patients on abatacept is not known...
March 12, 2018: Journal of General Internal Medicine
Jie Wang, Lina Yang, Xiaohe Mao, Zaiye Li, Xiaoyu Lin, Canhua Jiang
It has been shown that the peripheral blood mononuclear cells (PBMCs) from oral squamous cell carcinoma (OSCC) patients presented cytotoxic CD8 T cell response against Streptococcus salivarius (S. salivarius), of which the frequency was positively associated with recurrence-free survival in OSCC patients. To identify the conditions required for regulating S. salivarius-specific CD8 T cell-mediated cytotoxicity, we selectively depleted individual components of the PBMCs, and observed that the depletion of monocytes/macrophages, but not other immune cell subsets, significantly downregulated the S...
March 9, 2018: Experimental Cell Research
Mário R Martins, Rogério L D Santos, Kleber D N Jatahy, Marina C D Matta, Thales P Batista, José Iran C Júnior, Maria D F S Begnami, Leuridan C Torres
BACKGROUND AND OBJECTIVES: OX40, a membrane-bound molecule of the tumor-necrosis-factor-receptor superfamily, is a critical costimulatory receptor during the immune response, especially to T cells, but studies described their presence of OX-40 on neutrophils and monocytes, suggesting a potential role in the activation of immune response. Our aim was to characterize costimulatory receptors OX40 expression on circulating leukocytes in gastric cancer to identify novel targets for immunotherapy...
March 12, 2018: Journal of Surgical Oncology
Juliana Ruiz Fernandes, Cibele Cristine Berto Marques da Silva, Aline Grandi da Silva, Regina Maria de Carvalho Pinto, Alberto José da Silva Duarte, Celso Ricardo Carvalho, Gil Benard
Exercise training has been shown to reduce symptoms and exacerbations in COPD patients; however, the exercise effect on patients' immune response is poorly known. We thus verified if an exercise program (EP) impacted on proliferative T cell response of COPD patients. Fourteen non-O2 dependent COPD patients on standard treatment were studied. EP consisted in 24 sessions of aerobic and muscular training. Peripheral blood mononuclear cells were stimulated with the mitogen phytohemagglutinin and antigens from Haemophilus influenzae and cytomegalovirus, and the lymphocyte proliferative response (LPR) was assessed through the expression of Ki67 before and after the EP...
March 10, 2018: Lung
Kelly R Rhodes, Jordan J Green
Exciting developments in cancer nanomedicine include the engineering of nanocarriers to deliver drugs locally to tumors, increasing efficacy and reducing off-target toxicity associated with chemotherapies. Despite nanocarrier advances, metastatic cancer remains challenging to treat due to barriers that prevent nanoparticles from gaining access to remote, dispersed, and poorly vascularized metastatic tumors. Instead of relying on nanoparticles to directly destroy every tumor cell, immunotherapeutic approaches target immune cells to train them to recognize and destroy tumor cells, which, due to the amplification and specificity of an adaptive immune response, may be a more effective approach to treating metastatic cancer...
March 7, 2018: Molecular Immunology
Rebeca Hid Cadena, Wayel H Abdulahad, G A P Hospers, T T Wind, Annemieke M H Boots, Peter Heeringa, Elisabeth Brouwer
Age-associated changes in the immune system including alterations in surface protein expression are thought to contribute to an increased susceptibility for autoimmune diseases. The balance between the expression of coinhibitory and costimulatory surface protein molecules, also known as immune checkpoint molecules, is crucial in fine-tuning the immune response and preventing autoimmunity. The activation of specific inhibitory signaling pathways allows cancer cells to evade recognition and destruction by the host immune system...
2018: Frontiers in Immunology
Pascal J H Kusters, Tom T P Seijkens, Linda Beckers, Dirk Lievens, Holger Winkels, Vivian de Waard, Adriaan Duijvestijn, Moritz Lindquist Liljeqvist, Joy Roy, Alan Daugherty, Andrew Newby, Norbert Gerdes, Esther Lutgens
OBJECTIVE: The mechanisms underlying formation of arterial aneurysms remain incompletely understood. Because inflammation is a common feature during the progressive degeneration of the aortic wall, we studied the role of the costimulatory molecule CD40L, a major driver of inflammation, in aneurysm formation. APPROACH AND RESULTS: Transcriptomics data obtained from human abdominal aortic aneurysms and normal aortas revealed increased abundance of both CD40L and CD40 in media of thrombus-free and thrombus-covered human abdominal aortic aneurysms samples...
March 8, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Ashley V Menk, Nicole E Scharping, Dayana B Rivadeneira, Michael J Calderon, McLane J Watson, Deanna Dunstane, Simon C Watkins, Greg M Delgoffe
Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to these therapies. The tumor microenvironment can impose metabolic restrictions on T cell function, creating a resistance mechanism to immunotherapy. We have previously shown tumor-infiltrating T cells succumb to progressive loss of metabolic sufficiency, characterized by repression of mitochondrial activity that cannot be rescued by PD-1 blockade. 4-1BB, a costimulatory molecule highly expressed on exhausted T cells, has been shown to influence metabolic function...
March 6, 2018: Journal of Experimental Medicine
Gap Ryol Lee
T helper type 17 (Th17) cells and pTreg cells, which share a common precursor cell (the naïve CD4 T cell), require a common tumor growth factor (TGF)-β signal for initial differentiation. However, terminally differentiated cells fulfill opposite functions: Th17 cells cause autoimmunity and inflammation, whereas Treg cells inhibit these phenomena and maintain immune homeostasis. Thus, unraveling the mechanisms that affect the Th17/Treg cell balance is critical if we are to better understand autoimmunity and tolerance...
March 3, 2018: International Journal of Molecular Sciences
Zhi Cheng, Runhong Wei, Qiuling Ma, Lin Shi, Feng He, Zixiao Shi, Tao Jin, Ronglin Xie, Baofeng Wei, Jing Chen, Hongliang Fang, Xiaolu Han, Jennifer A Rohrs, Paul Bryson, Yarong Liu, Qi-Jing Li, Bo Zhu, Pin Wang
Several recent clinical trials have successfully incorporated a costimulatory domain derived from either CD28 or 4-1BB with the original CD3ζ T cell activating domain to form second-generation chimeric antigen receptors (CARs) that can increase the responsiveness and survival of CAR-engineered T (CAR-T) cells. However, a rigorous assessment of the individual benefits of these costimulatory components relative to the in vivo performance of infused T cells in patients is still lacking. Therefore, we have designed a study that allows us to investigate and compare the impact of different costimulatory signal domains on CAR-T cells in vivo...
February 2, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Deniz Genç, Noushin Zibandeh, Ercan Nain, Muazzez Gökalp, Ahmet Oğuzhan Özen, Mehmet Kamil Göker, Tunç Akkoç
BACKGROUND: Asthma is a chronic inflammatory disease in which inflammatory responses have the polarization of CD4+ T cells to Th2 cells. Dental follicle mesenchymal stem cells (DFSCs) have strong anti-inflammatory properties comparable to other mesenchymal stem cells. OBJECTIVE: We investigated the immunomodulatory effects of DFSCs on CD4+ T helper cell responses of asthmatic patients and compared the results with those obtained with asthmatic subjects on immunotherapy and with healthy individuals...
March 2, 2018: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
Yuk Pheel Park, Linchun Jin, Katie B Bennett, Dunrui Wang, Kristianna M Fredenburg, Jennifer E Tseng, Lung-Ji Chang, Jianping Huang, Edward K L Chan
OBJECTIVES: In accordance with the Precision Medicine Initiative, new treatment strategies for head and neck squamous cell carcinoma (HNSCC) are needed to yield better therapeutic outcomes. The purpose of this study was to establish and validate chimeric antigen receptor (CAR)-T cells targets in HNSCC. METHODS: Putative CAR-T antigens were identified in The Cancer Genome Atlas database. To validate antigen suitability, quantitative RT-PCR, flow cytometry, and immunofluorescent staining were performed...
March 2018: Oral Oncology
Sebastian Thieme, Alexander Holzbaur, Ralf Wiedemuth, Aline Binner, Katrin Navratiel, Konstantinos Anastassiadis, Sebastian Brenner, Cornelia Richter
Plasmacytoid dendritic cells (pDC) constitute a very rare blood cell population and play a significant role in immune response and immune-mediated disorders. Investigations on primary pDCs are hindered not only due to their rarity but also because they represent a heterogeneous cell population which is difficult to culture ex vivo. We generated a conditionally immortalized pDC line (Dox-pDC) from mice with Doxycycline-inducible SV40 Large T Antigen with a comparable immune profile to primary pDCs. The Dox-pDC secrete pro- and anti-inflammatory cytokines upon Toll-like receptor 9 stimulation and upregulate their MHCI, MHCII and costimulatory molecules...
2018: PloS One
Sakthivel Subramaniam, Christopher Overend, Danielle M Yugo, C Lynn Heffron, Shannon R Matzinger, Adam J Rogers, Debin Tian, Qian M Cao, Scott P Kenney, Xiang-Jin Meng
CD137 is a costimulatory molecule transiently expressed on activated T cells after mitogen or antigen stimulation that can be exploited for isolating antigen-specific T cells as reported in mouse models. By utilizing an antiporcine CD137 monoclonal antibody (mAb, clone 3B9) developed in our laboratory, we isolated virus-specific CD8β T cells from peripheral blood of pigs experimentally infected with different porcine reproductive and respiratory syndrome virus (PRRSV) strains. Similar to mouse, porcine CD8β T cells also express CD137 transiently upon Concavalin A stimulation while the unstimulated cells did not...
February 28, 2018: Viral Immunology
Alyssa K Kosmides, Kevin Necochea, John W Hickey, Jonathan P Schneck
T cell activation requires the coordination of a variety of signaling molecules including T cell receptor-specific signals and costimulatory signals. Altering the composition and distribution of costimulatory molecules during stimulation greatly affects T cell functionality for applications such as adoptive cell therapy (ACT), but the large diversity in these molecules complicates these studies. Here, we develop and validate a reductionist T cell activation platform that enables streamlined customization of stimulatory conditions...
February 28, 2018: Nano Letters
Rajesh Parmar, Hardik Patel, Naveen Yadav, Ritika Parikh, Khyati Patel, Aditi Mohankrishnan, Vishakha Bhurani, Urja Joshi, Sarat Kumar Dalai
Immunization with radiation-attenuated sporozoites (RAS) shown to confer complete sterile protection against Plasmodia liver-stage (LS) infection that lasts about 6 to 9 months in mice. We have found that the intermittent infectious sporozoite challenge to immune mice following RAS vaccination extends the longevity of sterile protection by maintaining CD8+ T cell memory responses to LS infection. It is reported that CD8α+ dendritic cells (DCs) are involved in the induction of LS-specific CD8+ T cells following RAS or genetically attenuated parasite (GAP) vaccination...
2018: Frontiers in Immunology
Hidetoshi Tsuda, Charles A Su, Toshiaki Tanaka, Katayoun Ayasoufi, Booki Min, Anna Valujskikh, Robert L Fairchild
Recipient endogenous memory T cells with donor reactivity pose an important barrier to successful transplantation and costimulatory blockade-induced graft tolerance. Longer ischemic storage times prior to organ transplantation increase early posttransplant inflammation and negatively impact early graft function and long-term graft outcome. Little is known about the mechanisms enhancing endogenous memory T cell activation to mediate tissue injury within the increased inflammatory environment of allografts subjected to prolonged cold ischemic storage (CIS)...
February 22, 2018: JCI Insight
Lyndsay Avery, Jessica Filderman, Andrea L Szymczak-Workman, Lawrence P Kane
Tim-3 is highly expressed on a subset of T cells during T cell exhaustion in settings of chronic viral infection and tumors. Using lymphocytic choriomeningitis virus (LCMV) Clone 13, a model for chronic infection, we found that Tim-3 was neither necessary nor sufficient for the development of T cell exhaustion. Nonetheless, expression of Tim-3 was sufficient to drive resistance to PD-L1 blockade therapy during chronic infection. Strikingly, expression of Tim-3 promoted the development of short-lived effector T cells, at the expense of memory precursor development, after acute LCMV infection...
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
Kathleen Yates, Kevin Bi, W Nicholas Haining, Harvey Cantor, Hye-Jung Kim
Regulatory T cells (Tregs) are key modulators of immune tolerance, capable of suppressing inflammatory immune responses and promoting nonlymphoid tissue homeostasis. Helios, a transcription factor (TF) that is selectively expressed by Tregs, has been shown to be essential for the maintenance of Treg lineage stability in the face of inflammatory conditions that include autoimmune disease and cancer. Helios-deficient Tregs within tumors acquire effector T cell function and contribute to immune responses against cancer...
February 9, 2018: Proceedings of the National Academy of Sciences of the United States of America
J Benzaquen, C-H Marquette, N Glaichenhaus, S Leroy, P Hofman, M Ilié
INTRODUCTION: Immunotherapy aims to promote the immune system's activity against malignant cells by stimulating the response to several tumor antigens. STATE OF THE ART: Immunosurveillance may adjust the immunogenicity of tumors. To be effective, immunity must induce the specific activation of CD4+ and CD8+ T lymphocytes, as well as activation of innate immunity. Activator and inhibitory costimulatory molecules regulate T lymphocyte activation at immunity checkpoints such as PD-1/PD-L1 and CTLA-4...
February 7, 2018: Revue des Maladies Respiratoires
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