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Costimulatory

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https://www.readbyqxmd.com/read/28642092/chemokine-ccl17-is-expressed-by-dendritic-cells-in-the-cns-during-experimental-autoimmune-encephalomyelitis-and-promotes-pathogenesis-of-disease
#1
Christina Ruland, Hannes Renken, Ivan Kuzmanov, Arezoo Fattahi Mehr, Kathrin Schwarte, Manuela Cerina, Alexander Herrmann, David-Marian Otte, Andreas Zimmer, Nicholas Schwab, Sven G Meuth, Volker Arolt, Luisa Klotz, Irmgard Förster, Stefanie Scheu, Judith Alferink
The CC chemokine ligand 17 (CCL17) and its cognate CC chemokine receptor 4 (CCR4) are known to control leukocyte migration, maintenance of TH17 cells, and regulatory T cell (Treg) expansion in vivo. In this study we characterized the expression and functional role of CCL17 in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). Using a CCL17/EGFP reporter mouse model, we could show that CCL17 expression in the CNS can be found in a subset of classical dendritic cells (DCs) that immigrate into the CNS during the effector phase of MOG-induced EAE...
June 19, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28637095/selective-cd28-blockade-results-in-superior-inhibition-of-donor-specific-t-follicular-helper-cell-and-antibody-responses-relative-to-ctla-4-ig
#2
I R Badell, G M La Muraglia, D Liu, M E Wagener, G Ding, M L Ford
Donor-specific antibodies (DSA) are a barrier to improved long-term outcomes following kidney transplantation. Costimulation blockade with CTLA-4-Ig has shown promise as a potential therapeutic strategy to control DSA. T follicular helper (Tfh) cells, a subset of CD4(+) T cells required for optimum antibody production, are reliant on the CD28 costimulatory pathway. We have previously shown that selective CD28 blockade leads to superior allograft survival through improved control of CD8(+) T cells relative to CTLA-4-Ig, but the impact of CD28-specific blockade on CD4(+) Tfh cells is unknown...
June 21, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28634588/antitumor-effect-of-kml-b-treated-dendritic-cells-via-induction-of-lymphocyte-activation
#3
Jong-Jin Kim, Yun-Ho Hwang, Kyung-Yun Kang, Sung-Ju Lee, Jong-Bae Kim, Jina Choi, Sung-Tae Yee
Lectins are carbohydrate-binding proteins with various biological activities, such as antitumor and immunomodulatory effects. Although lectins have various biological activities, they are still limited by cytotoxicity in normal cells. To overcome this problem, we used the noncytotoxic part of Korean mistletoe lectin B-chain (KML-B) to induce maturation of dendritic cells (DCs). A previous study reported that KML-B induces DC maturation by triggering TLR-4, including expression of costimulatory molecules (CD40, CD80, and CD86), MHC II, and secretion of cytokines in DCs...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28634420/characterization-of-the-proinflammatory-profile-of-synovial-fluid-derived-exosomes-of-patients-with-osteoarthritis
#4
Rossana Domenis, Rossella Zanutel, Federica Caponnetto, Barbara Toffoletto, Adriana Cifù, Cinzia Pistis, Paolo Di Benedetto, Araldo Causero, Massimo Pozzi, Fabrizio Bassini, Martina Fabris, Kayvan R Niazi, Patrick Soon-Shiong, Francesco Curcio
The purpose of this study is to characterize synovial fluid- (SF-) derived exosomes of patients with gonarthrosis comparing two methods of isolation and to investigate their immune regulatory properties. Extracellular vesicles (EVs) have been isolated from inflamed SF by polymer precipitation method and quantified by Exocet kit and by nanoparticle tracking analysis. Vesicles expressed all the specific exosomal markers by immunoblot and FACS. After isolation with Exoquick, a relevant contamination by immune complexes was detected, which required further magnetic bead-based purification to remove...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28634283/phase-ib-study-of-utomilumab-pf-05082566-a-4-1bb-cd137-agonist-in-combination-with-pembrolizumab-mk-3475-in-patients-with-advanced-solid-tumors
#5
Anthony W Tolcher, Mario Sznol, Siwen Hu-Lieskovan, Kyriakos P Papadopoulos, Amita Patnaik, Drew Rasco, Donna Di Gravio, Bo Huang, Dhiraj Gambhire, Ying Chen, Aron Thall, Nuzhat Pathan, Emmett V Schmidt, Laura Q M Chow
Purpose:  This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors. <p>Experimental Design:  Utomilumab (0.45-5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event-continual reassessment method...
June 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28631301/prevention-of-lupus-nephritis-development-in-nzb-nzw-mice-by-selective-blockade-of-cd28
#6
Laetitia Laurent, Awena Lefur, Rozenn Le Bloas, Mélanie Néel, Caroline Mary, Anne Moreau, Nicolas Poirier, Bernard Vanhove, Fadi Fakhouri
Systemic Lupus Erythematosus (SLE) is a chronic systemic inflammatory disease. Autoantibodies (autoAbs) against double-stranded DNA (ds DNA), the hallmark of lupus, are produced and maintained by the interaction between auto-reactive B cells and CD4(+) T cells. This interplay is controlled by the CD28/CD80-86/CTLA-4 axis. Here we investigated whether selective blockade of CD28-CD80/86 co-stimulatory interactions abrogates lupus nephritis development in a murine model of SLE. To this aim, NZB/NZW F1 mice were treated for 3 months, either with an anti-CD28 Fab' fragment or a control Fab'-IgG...
June 20, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28630103/up-regulation-of-ep2-and-ep3-receptors-in-human-tolerogenic-dendritic-cells-boost-the-immunosuppressive-activity-of-pge2
#7
Georgina Flórez-Grau, Raquel Cabezón, Kyra J E Borgman, Carolina España, Juan Jose Lozano, Maria F Garcia-Parajo, Daniel Benítez-Ribas
Dendritic cells (DCs) are APCs essential in regulating the immune response. PGE2, produced during inflammation, has a pivotal role in the maturation of DCs and, therefore, is vital for the immune response. The large variety of biologic functions governed by PGE2 is mediated by its signaling through 4 distinct E-type prostanoid (EP) receptors. Immunogenic DCs express EP2 and EP4, which mediate the PGE2 signaling. However, the expression and function of EP receptors in human tolerogenic DCs (tol-DCs), which present an inhibitory phenotype, have not yet, to our knowledge, been assessed...
June 19, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28628831/analysis-of-immunostimulatory-activity-of-polysaccharide-extracted-from-yu-ping-feng-in-vitro-and-in-vivo
#8
Wentao Fan, Pimiao Zheng, Yang Wang, Pan Hao, Jianzhu Liu, Xiaona Zhao
As a traditional Chinese multiherbal formula, Yu-Ping-Feng (YPF) is frequently used to treat cold, flu and inflammation-associated diseases. We aimed to evaluate the immunostimulatory effects of polysaccharide isolated from YPF (YPF-PS) in vitro and in vivo. In in vitro experiment, macrophage cell proliferation, phagocytosis rate, cytokine and costimulatory molecule release, T lymphocyte proliferation, cell cycle distribution, CD4(+) and CD8(+) T cell percentages were determined. To investigate the in vivo effects of YPF-PS treatment, different doses YPF-PS were administered to chicken vaccinated against Newcastle disease...
June 16, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28620390/belatacept-does-not-inhibit-follicular-t-cell-dependent-b-cell-differentiation-in-kidney-transplantation
#9
Gretchen N de Graav, Dennis A Hesselink, Marjolein Dieterich, Rens Kraaijeveld, Wenda Verschoor, Dave L Roelen, Nicolle H R Litjens, Anita S Chong, Willem Weimar, Carla C Baan
Humoral alloreactivity has been recognized as a common cause of kidney transplant dysfunction. B-cell activation, differentiation, and antibody production are dependent on IL-21(+)CXCR5(+)follicular T-helper (Tfh) cells. Here, we studied whether belatacept, an inhibitor of the costimulatory CD28-CD80/86-pathway, interrupts the crosstalk between Tfh- and B-cells more efficiently than the calcineurin inhibitor tacrolimus. The suppressive effects of belatacept and tacrolimus on donor antigen-driven Tfh-B-cell interaction were functionally studied in peripheral blood mononuclear cells from 40 kidney transplant patients randomized to a belatacept- or tacrolimus-based immunosuppressive regimen...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28619138/newcastle-disease-virus-like-particles-induce-dc-maturation-through-tlr4-nf-%C3%AE%C2%BAb-pathway-and-facilitate-dc-migration-by-ccr7-ccl19-ccl21-axis
#10
Jing Qian, Xiaohong Xu, Jiaxin Ding, Renfu Yin, Yixue Sun, Cong Xue, Jianzhong Wang, Chan Ding, Shengqing Yu, Xiufan Liu, Shunlin Hu, Chunfeng Wang, Yanlong Cong, Zhuang Ding
Newcastle disease virus-like particles (NDV VLPs) are a potential candidate vaccine, as shown by eliciting specific immune response against NDV in mice and chickens. Activation of dendritic cells (DCs) is critical to initiate immune response. However, the mechanism of how NDV VLPs induce DC maturation and migration remains elusive. In this study, we found that NDV VLPs are efficient in DC activation by up-regulating surface MHC II and costimulatory molecules, and proinflammatory cytokines through the TLR4/NF-κB pathway...
May 2017: Veterinary Microbiology
https://www.readbyqxmd.com/read/28613437/t-cell-subsets-predicting-belatacept-resistant-rejection-finding-the-root-where-the-trouble-starts
#11
EDITORIAL
T Wekerle
The potential of costimulation blockade to revolutionize post-transplant immunosuppression has remained largely unfulfilled to date. Belatacept, the only costimulation blocker approved in organ transplant recipients, has not replaced the 30-plus-year-old CNIs as the mainstay of immunosuppression and is currently used infrequently. Modulating pathogenic immune responses through the interruption of costimulatory signals, which a naïve T cell requires for its full activation, has captivated immunologists since the demonstration that such costimulation blockade leads to antigen-specific immunomodulation (at least in vitro)...
June 14, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28612747/pathogenetic-insights-from-the-treatment-of-rheumatoid-arthritis
#12
REVIEW
Iain B McInnes, Georg Schett
Rheumatoid arthritis is a chronic autoimmune disease that causes progressive articular damage, functional loss, and comorbidity. The development of effective biologics and small-molecule kinase inhibitors in the past two decades has substantially improved clinical outcomes. Just as understanding of pathogenesis has led in large part to the development of drugs, so have mode-of-action studies of these specific immune-targeted agents revealed which immune pathways drive articular inflammation and related comorbidities...
June 10, 2017: Lancet
https://www.readbyqxmd.com/read/28612217/ox40-promotes-obesity-induced-adipose-inflammation-and-insulin-resistance
#13
Bing Liu, Hengchi Yu, Guangyong Sun, Xiaojing Sun, Hua Jin, Chunpan Zhang, Wen Shi, Dan Tian, Kai Liu, Hufeng Xu, Xinmin Li, Jie Yin, Xu Hong, Dong Zhang
Adaptive immunity plays a critical role in IR and T2DM development; however, the biological mechanisms linking T cell costimulation and glucose metabolism have not been fully elucidated. In this study, we demonstrated that the costimulatory molecule OX40 controls T cell activation and IR development. Inflammatory cell accumulation and enhanced proinflammatory gene expression, as well as high OX40 expression levels on CD4(+) T cells, were observed in the adipose tissues of mice with diet-induced obesity. OX40-KO mice exhibited significantly less weight gain and lower fasting glucose levels than those of WT mice, without obvious adipose tissue inflammation...
June 13, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28611775/inhibition-of-myeloid-differentiation-factor-88-reduces-human-and-mouse-t-cell-interleukin-17-and-ifn%C3%AE-production-and-ameliorates-experimental-autoimmune-encephalomyelitis-induced-in-mice
#14
Shira Dishon, Shmuel J Cohen, Irun R Cohen, Gabriel Nussbaum
Myeloid differentiation factor 88 (MyD88) recruits signaling proteins to the intracellular domain of receptors belonging to the toll-like/interleukin-1 (IL-1) receptor superfamily. Mice lacking MyD88 are highly susceptible to infectious diseases, but tend to resist experimentally induced autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and manifest diminished allograft rejection. We reasoned that inhibition of MyD88 should influence the cytokine profile of responding T cells by blocking costimulatory molecule expression by antigen-presenting cells (APCs) and by inhibiting T-cell responses to IL-18...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28606939/transcriptional-and-epigenetic-regulation-of-t-cell-hyporesponsiveness
#15
REVIEW
Renata M Pereira, Patrick G Hogan, Anjana Rao, Gustavo J Martinez
Naive CD8(+) T cells differentiate into effector and memory cytolytic T cells (CTLs) during an acute infection. In contrast, in scenarios of persistent antigen stimulation, such as chronic infections and cancer, antigen-specific CTLs show a gradual decrease in effector function, a phenomenon that has been termed CD8(+) T cell "exhaustion" or "dysfunction." Another hyporesponsive state, termed anergy, is observed when T cells are activated in the absence of positive costimulatory signals. Among the many negative regulators induced in hyporesponsive T cells are inhibitory cell-surface receptors, such as PD-1, LAG-3, CTLA-4, and TIM-3; "checkpoint blockade" therapies that involve treatment of patients with cancer with blocking antibodies to those receptors show considerable promise in the clinic because the blocking antibodies can mitigate hyporesponsiveness and promote tumor rejection...
June 12, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28600225/b7-h4-is-a-prognostic-biomarker-for-poor-survival-in-patients-with-pancreatic-cancer
#16
Lingwei Shen, Yun Qian, Weigen Wu, Tianhao Weng, Frederick X C Wang, Bo Hong, Zhigang Wu, Qi Wang, Yiwen Sang, Hong Zhang, Xinhui Zhou, Hangping Yao
B7-H4 belongs to the immune costimulatory B7 family and is thought to negatively regulate T-cell mediated immunity, and may contribute an important role in tumor immune evasion. Although the expression of B7-H4 has been observed in human pancreatic cancer, the prognostic significance of this expression is poorly understood. This present study explored the prognostic value of B7-H4 in pancreatic cancer. Patients with pancreatic cancer and healthy controls were recruited at the Second Affiliated Hospital to Zhejiang University from January 2011 to December 2014...
June 6, 2017: Human Pathology
https://www.readbyqxmd.com/read/28599483/effects-of-programmed-death-ligand-1-expression-on-ok-432-immunotherapy-following-transurethral-resection-in-non-muscle-invasive-bladder-cancer
#17
Zhi-Hua Liu, Fu-Fu Zheng, Yu-Ling Mao, Lie-Fu Ye, Jun Bian, De-Hui Lai, Yun-Lin Ye, Yu-Ping Dai
The present study aimed to investigate the effect of the negative costimulatory molecule programmed death-ligand 1 (PD-L1) on immunotherapy with OK-432, following transurethral resection of bladder tumors in non-muscle invasive bladder cancer (NMIBC), and to elucidate the underlying mechanism. PD-L1 was detected by immunohistochemical staining in tumor specimens from 55 cases of NMIBC following postoperative immunotherapy with OK-432. The PD-L1 mRNA and protein expression levels were measured in the bladder cancer T24 cell line and the human uroepithelial SV-HUC-1 cell line, following treatment with interleukin (IL)-2, interferon (IFN)-α and IFN-γ, by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, respectively...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28589497/frequency-of-dendritic-cells-and-their-expression-of-costimulatory-molecules-in-children-with-autism-spectrum-disorders
#18
Khaled Saad, Asmaa M Zahran, Khalid I Elsayh, Ahmed A Abdel-Rahman, Abdulrahman A Al-Atram, Almontaser Hussein, Yasmin G El-Gendy
The aim of our study was to evaluate the frequencies of myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) in children with ASD. Subjects were 32 children with ASD and 30 healthy children as controls. The numbers of mDCs and pDCs and the expression of CD86 and CD80 on the entire DCs were detected by flow cytometry. ASD children had significantly higher percentages of mDCs and pDCs when compared to controls. We found significant inverse relationships between serum 25-hydroxyvitamin D levels and the frequencies of mDCs and pDCs in autistic children...
June 7, 2017: Journal of Autism and Developmental Disorders
https://www.readbyqxmd.com/read/28584241/e-coli-promotes-human-v%C3%AE-9v%C3%AE-2%C3%A2-t-cell-transition-from-cytokine-producing-bactericidal-effectors-to-professional-phagocytic-killers-in-a-tcr-dependent-manner
#19
M Barisa, A M Kramer, Y Majani, D Moulding, L Saraiva, M Bajaj-Elliott, J Anderson, K Gustafsson
γδT cells provide immune-surveillance and host defense against infection and cancer. Surprisingly, functional details of γδT cell antimicrobial immunity to infection remain largely unexplored. Limited data suggests that γδT cells can phagocytose particles and act as professional antigen-presenting cells (pAPC). These potential functions, however, remain controversial. To better understand γδT cell-bacterial interactions, an ex vivo co-culture model of human peripheral blood mononuclear cell (PBMC) responses to Escherichia coli was employed...
June 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28580358/belatacept-as-an-alternative-to-calcineurin-inhibitors-in-patients-with-solid-organ-transplants
#20
REVIEW
Dhiren Kumar, Spencer LeCorchick, Gaurav Gupta
The goal of immunosuppression in transplantation has shifted to improving long-term outcomes, reducing drug-induced toxicities while preserving the already excellent short-term outcomes. Long-term gains in solid organ transplantation have been limited at least partly due to the nephrotoxicity and metabolic side effects of calcineurin inhibitors (CNIs). The alloimmune response requires activation of the costimulatory pathway for T cell proliferation and amplification. Belatacept is a molecule that selectively blocks T cell costimulation...
2017: Frontiers in Medicine
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