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T cell inhibitory pathway

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https://www.readbyqxmd.com/read/28216618/1-2-5-6-dianhydrogalactitol-inhibits-human-glioma-cell-growth-in-vivo-and-in-vitro-by-arresting-the-cell-cycle-at-g2-m-phase
#1
Chun Peng, Xin-Ming Qi, Ling-Ling Miao, Jin Ren
1,2:5,6-dianhydrogalactitol (DAG) is a hexitol epoxide with marked antitumor activity against multiple types of cancer cells, but the molecular mechanisms by which DAG functions as an antitumor agent is largely unknown. In this study, we investigated the inhibitory effects of DAG on human glioma cell growth in vitro and in vivo and uncovered the underlying molecular mechanisms. Treatment with DAG (120 μmol/L) dose-dependently inhibited the proliferation and colony formation in human glioma cell lines LN229, U251, and U87MG in vitro...
February 20, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28213589/sh479-a-betulinic-acid-derivative-ameliorates-experimental-autoimmune-encephalomyelitis-by-regulating-the-th17-treg-balance
#2
Jing Li, Ji Jing, Yang Bai, Zhen Li, Roumei Xing, Binhe Tan, Xueyun Ma, Wenwei Qiu, Changsheng Du, Bing Du, Fan Yang, Jie Tang, Stefan Siwko, Mingyao Liu, Huaqing Chen, Jian Luo
CD4+ T helper cells, especially Th17 cells, combined with immune regulatory network dysfunction, play key roles in autoimmune diseases including multiple sclerosis (MS). Betulinic acid (BA), a natural pentacyclic triterpenoid, has been reported to be involved in anti-inflammation, in particular having an inhibitory effect on pro-inflammatory cytokine IL-17 and IFN-γ production. In this study, we screened BA derivatives and found a BA derivative, SH479, which had a greater inhibitory effect on Th17 differentiation...
February 17, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28201977/targeting-the-immune-niche-within-the-bone-marrow-microenvironment-the-rise-of-immunotherapy-in-multiple-myeloma
#3
Klaus Podar, D Jäger
Multiple Myeloma (MM) cells inhibit the development of an effective anti-MM immune response via defects in T cell function, ineffective antigen presentation; reduced phagocytic capacity; natural killer and dendritic cell dysfunction; decreased responsiveness to IL-2 and defects in B cell immunity; upregulation of inhibitory pathways; and production of excessive pro-inflammatory cytokines. Moreover, immune cells including plasmacytoid dendritic cells and macrophages trigger tumor cell proliferation, survival, and drug resistance...
February 13, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28199983/a-versatile-system-for-rapid-multiplex-genome-edited-car-t-cell-generation
#4
Jiangtao Ren, Xuhua Zhang, Xiaojun Liu, Chongyun Fang, Shuguang Jiang, Carl H June, Yangbing Zhao
The therapeutic potential of CRISPR system has already been demonstrated in many instances and begun to overlap with the rapidly expanding field of cancer immunotherapy, especially on the production of genetically modified T cell receptor or chimeric antigen receptor (CAR) T cells. Efficient genomic disruption of multiple gene loci to generate universal donor cells, as well as potent effector T cells resistant to multiple inhibitory pathways such as PD-1 and CTLA4 is an attractive strategy for cell therapy...
February 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28199198/the-immunological-function-of-gabaergic-system
#5
Chenlu Wu, Xiaobin Qin, Huihui Du, Nengzhang Li, Wenkai Ren, Yuanyi Peng
As a well-known inhibitory neurotransmitter in the central nervous system, gamma-aminobutyric acid also has critical roles in immune system. Immune cells (e.g., lymphocytes, macrophages) express the components of GABAergic system, including GABA receptors, GABA transporters, and GABA metabolic enzymes. The functions of immune cells are highly impacted on GABA signaling. GABAergic components negatively regulate the immune responses, particularly the T cell-mediated immunity, via their effects on production of pro-inflammatory cytokines and activation of signal pathways, like mitogen-activated protein kinase and nuclear factor-kappaB pathways...
March 1, 2017: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28197389/adaptive-resistance-to-anti-pd1-therapy-by-tim-3-upregulation-is-mediated-by-the-pi3k-akt-pathway-in-head-and-neck-cancer
#6
Gulidanna Shayan, Raghvendra Srivastava, Jing Li, Nicole Schmitt, Lawrence P Kane, Robert L Ferris
Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors that are expressed on tumor-infiltrating lymphocytes (TIL) in tumor-bearing mice and humans. As anti-PD-1 single agent response rates are only <20% in head and neck squamous cell carcinoma (HNSCC) patients, it is important to understand how multiple inhibitory checkpoint receptors maintain suppressed cellular immunity. One such receptor, Tim-3, activates downstream proliferative pathways through Akt/S6, and is highly expressed in dysfunctional TIL...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28197369/the-transcriptome-of-lung-tumor-infiltrating-dendritic-cells-reveals-a-tumor-supporting-phenotype-and-a-microrna-signature-with-negative-impact-on-clinical-outcome
#7
Lotte Pyfferoen, Elisabeth Brabants, Celine Everaert, Nancy De Cabooter, Kelly Heyns, Kim Deswarte, Manon Vanheerswynghels, Sofie De Prijck, Glenn Waegemans, Melissa Dullaers, Hamida Hammad, Olivier De Wever, Pieter Mestdagh, Jo Vandesompele, Bart N Lambrecht, Karim Y Vermaelen
Targeting immunomodulatory pathways has ushered a new era in lung cancer therapy. Further progress requires deeper insights into the biology of immune cells in the lung cancer micro-environment. Dendritic cells (DCs) represent a heterogeneous and highly plastic immune cell system with a central role in controlling immune responses. The intratumoral infiltration and activation status of DCs are emerging as clinically relevant parameters in lung cancer. In this study, we used an orthotopic preclinical model of lung cancer to dissect how the lung tumor micro-environment affects tissue-resident DCs and extract novel biologically and clinically relevant information...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28197366/compensatory-upregulation-of-pd-1-lag-3-and-ctla-4-limits-the-efficacy-of-single-agent-checkpoint-blockade-in-metastatic-ovarian-cancer
#8
Ruea-Yea Huang, Ariel Francois, Aj Robert McGray, Anthony Miliotto, Kunle Odunsi
Tumor-associated or -infiltrating lymphocytes (TALs or TILs) co-express multiple immune inhibitory receptors that contribute to immune suppression in the ovarian tumor microenvironment (TME). Dual blockade of PD-1 along with LAG-3 or CTLA-4 has been shown to synergistically enhance T-cell effector function, resulting in a delay in murine ovarian tumor growth. However, the mechanisms underlying this synergy and the relative contribution of other inhibitory receptors to immune suppression in the ovarian TME are unknown...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28181735/the-innervation-of-the-kidney-in-renal-injury-and-inflammation-a-cause-and-consequence-of-deranged-cardiovascular-control
#9
REVIEW
Mohammed H Abdulla, Edward J Johns
Extensive investigations have revealed that renal sympathetic nerves regulate renin secretion, tubular fluid reabsorption and renal haemodynamics which can impact on cardiovascular homoeostasis normally and in pathophysiological states. The significance of the renal afferent innervation and its role in determining the autonomic control of the cardiovascular system is uncertain. The transduction pathways at the renal afferent nerves have been shown to require pro-inflammatory mediators and TRPV1 channels. Reno-renal reflexes have been described, both inhibitory and excitatory, demonstrating that a neural link exists between kidneys and may determine the distribution of excretory and haemodynamic function between the two kidneys...
February 9, 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28165481/targeting-mitochondrial-dysfunction-can-restore-antiviral-activity-of-exhausted-hbv-specific-cd8-t-cells-in-chronic-hepatitis-b
#10
Paola Fisicaro, Valeria Barili, Barbara Montanini, Greta Acerbi, Manuela Ferracin, Francesca Guerrieri, Debora Salerno, Carolina Boni, Marco Massari, M Cristina Cavallo, Glenda Grossi, Tiziana Giuberti, Pietro Lampertico, Gabriele Missale, Massimo Levrero, Simone Ottonello, Carlo Ferrari
Hepatitis B virus (HBV)-specific CD8 T cells are functionally exhausted in chronic hepatitis B infection, and this condition can be corrected only partially through the modulation of inhibitory pathways, which suggests that a more complex molecular interplay underlies T cell exhaustion. To gain broader insight into this process and identify additional targets for the restoration of T cell function, we compared the transcriptome profiles of HBV-specific CD8 T cells from patients with acute and chronic disease with those of HBV-specific CD8 T cells from patients able to resolve HBV infection spontaneously and influenza (FLU)-specific CD8 T cells from healthy participants...
February 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28160290/regulatory-t-cells-and-type-2-innate-lymphoid-cell-dependent-asthma
#11
REVIEW
Jennifer L Aron, Omid Akbari
Group two innate lymphoid cells (ILC2s) are a recently identified group of cells with the potent capability to produce Th2-type cytokines such as interleukin (IL)-5 and IL-13. Several studies suggest that ILC2s play an important role in the development of allergic diseases and asthma. Activation of pulmonary ILC2s in murine models lacking T and B cells induces eosinophilia and airway hyperreactivity (AHR), which are cardinal features of asthma. More importantly, numerous recent studies have highlighted the role of ILC2s in asthma persistence and exacerbation among human subjects and thus, regulation of pulmonary ILC2s is a major area of investigation aimed at curbing allergic lung inflammation and exacerbation...
February 4, 2017: Allergy
https://www.readbyqxmd.com/read/28154184/bax-bak-independent-mitochondrial-depolarization-and-reactive-oxygen-species-induction-by-sorafenib-overcome-resistance-to-apoptosis-in-renal-cell-carcinoma
#12
Bernhard Gillissen, Anja Richter, Antje Richter, Robert Preissner, Klaus Schulze-Osthoff, Frank Essmann, Peter T Daniel
Renal cell carcinoma (RCC) is polyresistant to chemo- and radiotherapy or biologicals including TNF-related apoptosis inducing ligand (TRAIL). Sorafenib, a multikinase inhibitor approved for the treatment of RCC, has been shown to sensitize cancer cells toward TRAIL-induced apoptosis, in particular by downregulation of the Bak-inhibitory Bcl 2 family protein Mcl 1. Here, we demonstrate that sorafenib overcomes TRAIL resistance in RCC by a mechanism that does not rely on Mcl 1 downregulation. Instead, sorafenib induces a rapid dissipation of the mitochondrial membrane potential (Δψm) that is accompanied by the accumulation of reactive oxygen species (ROS)...
February 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28151427/pd-1-modulates-regulatory-t-cell-homeostasis-during-low-dose-il-2-therapy
#13
Takeru Asano, Yusuke Meguri, Takanori Yoshioka, Yuriko Kishi, Miki Iwamoto, Makoto Nakamura, Yasuhisa Sando, Hideo Yagita, John Koreth, Haesook T Kim, Edwin P Alyea, Philippe Armand, Corey S Cutler, Vincent T Ho, Joseph H Antin, Robert J Soiffer, Yoshinobu Maeda, Mitsune Tanimoto, Jerome Ritz, Ken-Ichi Matsuoka
CD4+Foxp3+ regulatory T cells (Tregs) play a central role in the maintainance of immune tolerance after HSCT. We previously reported that low-dose IL-2 therapy increased circulating Tregs and improved clinical symptoms of chronic GVHD, however, the mechanisms which regulate Treg homeostasis during IL-2 therapy have not been well studied. To elucidate these regulatory mechanisms, we examined the role of inhibitory coreceptors on Tregs during IL-2 therapy in a murine model and in patients with chronic GVHD. Murine studies demonstrated that low-dose IL-2 selectively increased Treg and simultaneously enhanced the expression of Programmed death-1 (PD-1), especially on CD44(+)CD62L(+) central-memory Treg, while expression of other inhibitory molecules including CTLA-4, LAG-3 and TIM-3 remained stable...
February 1, 2017: Blood
https://www.readbyqxmd.com/read/28149166/phenolic-composition-and-medicinal-usage-of-psidium-guajava-linn-antifungal-activity-or-inhibition-of-virulence
#14
Maria F B Morais-Braga, Joara N P Carneiro, Antonio J T Machado, Débora L Sales, Antonia T L Dos Santos, Aline A Boligon, Margareth L Athayde, Irwin R A Menezes, Djair S L Souza, José G M Costa, Henrique D M Coutinho
Psidium guajava is a Myrtaceae plant whose medicinal properties are recognized in several locations. The use of teas and tinctures prepared from their leaves has been used to combat infections caused by fungi of the genus Candida. In this study, aqueous extracts of leaves and hydroethanolic were tested to verify the antifungal potential and its chemical composition has been investigated. The microbiological assays were performed by broth microdilution to determine the minimum inhibitory concentration (MIC) and from these the minimum fungicidal concentration was performed (MFC) by subculturing on solid media...
February 2017: Saudi Journal of Biological Sciences
https://www.readbyqxmd.com/read/28130401/distinctive-histogenesis-and-immunological-microenvironment-based-on-transcriptional-profiles-of-follicular-dendritic-cell-sarcomas
#15
Maria Antonella Laginestra, Claudio Tripodo, Claudio Agostinelli, Giovanna Motta, Sylvia Hartmann, Claudia Doring, Maura Rossi, Federica Melle, Maria Rosaria Sapienza, Valentina Tabanelli, Alessandro Pileri, Fabio Fuligni, Anna Gazzola, Claudia Mannu, Carlo Alberto Sagramoso, Silvia Lonardi, Luisa Lorenzi, Francesco Bacci, Elena Sabattini, Anita Borges, Ingrid Simonitsch-Klupp, Jose Cabecadas, Elias Campo, Juan Rosai, Martin-Leo Hansmann, Fabio Facchetti, Stefano Aldo Pileri
: Follicular dendritic cell (FDC) sarcomas are rare mesenchymal tumors (MTs) with variable clinical, morphologic and phenotypic characteristics. Transcriptome analysis was performed on multiple FDC sarcomas and compared to other MTs, microdissected Castleman FDCs, and normal fibroblasts. Using unsupervised analysis, FDC sarcomas clustered with microdissected FDCs, distinct from other MTs and fibroblasts. The specific endowment of FDC-related gene expression programs in FDC sarcomas emerged by applying a gene signature of differentially expressed genes (n=1,289) between microdissected FDCs and fibroblasts...
January 27, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28126464/stimulation-of-renal-afferent-fibers-leads-to-activation-of-catecholaminergic-and-non-catecholaminergic-neurons-in-the-medulla-oblongata
#16
REVIEW
Erika E Nishi, Beatriz S Martins, Maycon I O Milanez, Nathalia R Lopes, Jose F de Melo, Roberto B Pontes, Adriana C Girardi, Ruy R Campos, Cássia T Bergamaschi
Presympathetic neurons in the rostral ventrolateral medulla (RVLM) including the adrenergic cell groups play a major role in the modulation of several reflexes required for the control of sympathetic vasomotor tone and blood pressure (BP). Moreover, sympathetic vasomotor drive to the kidneys influence natriuresis and diuresis by inhibiting the cAMP/PKA pathway and redistributing the Na(+)/H(+) exchanger isoform 3 (NHE3) to the body of the microvilli in the proximal tubules. In this study we aimed to evaluate the effects of renal afferents stimulation on (1) the neurochemical phenotype of Fos expressing neurons in the medulla oblongata and (2) the level of abundance and phosphorylation of NHE3 in the renal cortex...
January 19, 2017: Autonomic Neuroscience: Basic & Clinical
https://www.readbyqxmd.com/read/28124374/the-dental-resin-monomers-hema-and-tegdma-have-inhibitory-effects-on-osteoclast-differentiation-with-low-cytotoxicity
#17
Hiroyuki Inamitsu, Kuniaki Okamoto, Eiko Sakai, Kazuhisa Nishishita, Hiroshi Murata, Takayuki Tsukuba
The dental resin monomers 2-hydroxyethyl methacrylate (HEMA) and triethylene glycol dimethacrylate (TEGDMA) are released from the resin matrix due to unpolymerized monomers; once released, they influence various biological functions and the viability of cells in the oral environment. Although HEMA and TEGDMA have various effects on cells, including inflammation, inhibition of cell proliferation or differentiation, and apoptosis, the effects of these monomers on osteoclasts remain unknown. In this study, we investigated the effects of HEMA and TEGDMA on osteoclast differentiation of bone marrow-derived macrophages or murine monocytic cell line RAW-D...
January 26, 2017: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/28123634/memory-cd4-t-cells-are-suppressed-by-cd8-regulatory-t-cells-in-vitro-and-in-vivo
#18
Xin Long, Qi Cheng, Huifang Liang, Jianping Zhao, Jian Wang, Wei Wang, Stephen Tomlinson, Lin Chen, Carl Atkinson, Bixiang Zhang, Xiaoping Chen, Peng Zhu
BACKGROUND: Acute graft rejection mediated by alloreactive memory CD4(+) T cells is a major obstacle to transplantation tolerance. It has been reported that CD8(+) T regulatory cells (Tregs) have the ability to induce graft tolerance by restraining the function of activated CD4(+) T cells, but not including memory T cells. The aim of this study is to elucidate the effect of CD8(+) Tregs on alloreactive memory CD4(+) T cells. METHODS: We detected Qa-1 expression and performed proliferative assay on memory CD4(+) T cells...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28122336/distinct-patterns-of-infiltrating-cd8-t-cells-in-hpv-and-cd68-macrophages-in-hpv-oropharyngeal-squamous-cell-carcinomas-are-associated-with-better-clinical-outcome-but-pd-l1-expression-is-not-prognostic
#19
Kenneth Oguejiofor, Henry Galletta-Williams, Simon J Dovedi, Darren L Roberts, Peter L Stern, Catharine M L West
Immunotherapies are beginning to revolutionise treatment paradigms in oncology with monoclonal antibodies (mAb) targeting T-cell co-inhibitory (e.g. PD-1/PD-L1) and co-stimulatory pathways (e.g. CTLA-4/CD28) demonstrating clinical utility. Some clinical studies demonstrate that responsiveness to PD-1/PD-L1 mAb therapy is greater in patients with expression of PD-L1 in the tumour microenvironment. However, robust responses have also been observed in patients with low or absent expression of PD-L1. Using multiplex immuno-fluorescent labelling we sought to determine how infiltration of tumours by CD8+ T-cells, their expression of PD-1, and the expression of PD-L1 on both tumours and CD68 cells (macrophages) correlated with HPV status and outcome in a cohort of 124 oropharyngeal squamous cell carcinomas (OPSCC)...
January 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28119073/harnessing-the-immunotherapeutic-potential-of-t-lymphocyte-co-signaling-molecules-in-transplantation
#20
REVIEW
Abdul W Ansari, Mohammad A Khan, Reinhold E Schmidt, Dieter C Broering
Alloantigen-specific T-cell triggered immunopathological events are responsible for rapid allograft rejection. The co-signaling pathways orchestrated by co-stimulatory and co-inhibitory molecules are critical for optimal T-cell effector function. Therefore, selective blockade of pathways that control T-cell immunity may offer an attractive therapeutic strategy to manipulate cell mediated allogenic responses. For example, CD28, CTLA-4 and CD154 receptor blockade have proven beneficial in maintaining T-cell tolerance against transplanted organs in experimental animal models as well as in clinical trials...
March 2017: Immunology Letters
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