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https://www.readbyqxmd.com/read/28524007/the-proinflammatory-cytokine-gitrl-contributes-to-trail-mediated-neurotoxicity-in-the-hcn-2-human-neuronal-cell-line
#1
Giulia Di Benedetto, Salvatore Saccone, Laurence Lempereur, Nicole Ronsisvalle, Giuseppe Nocentini, Rodolfo Bianchini, Carlo Riccardi, Renato Bernardini, Giuseppina Cantarella
Cytokines belonging to the TNF superfamily play a relevant role in neurodegenerative processes. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), released during neuronal injury, has proven to potently mediate and sustain neurotoxic processes leading to neuronal death. Similarly to TRAIL, the cytokine Glucocorticoid-induced TNF receptor ligand (GITRL) is able to transduce proapoptotic signals. In spite of the array of reports suggesting relationships between TRAIL and other cytokines, scanty data are, so far, available about a GITRL/TRAIL crosstalk...
May 18, 2017: Current Alzheimer Research
https://www.readbyqxmd.com/read/28507805/generation-and-functional-characterization-of-mdsc-like-cells
#2
Annkristin Heine, Stefanie Andrea Erika Held, Jonas Schulte-Schrepping, Julia Friederike Andrea Wolff, Kathrin Klee, Thomas Ulas, Niklas Arndt Schmacke, Solveig Nora Daecke, Kati Riethausen, Joachim L Schultze, Peter Brossart
Myeloid-derived suppressor cells (MDSC) are critical in regulating immune responses by suppressing antigen presenting cells (APC) and T cells. We previously observed that incubation of peripheral blood monocytes with interleukin (IL)-10 during their differentiation to monocyte-derived dendritic cells (moDCs) results in the generation of an APC population with a CD14(+)HLA-DR(low)phenotype (IL-10-APC) with reduced stimulatory capacity similar to human MDSC. Co-incubation experiments now revealed that the addition of IL-10-APC to moDC caused a reduction of DC-induced T-cell proliferation, of the expression of maturation markers, and of secreted cytokines and chemokines such as TNF-α, IL-6, MIP-1α and Rantes...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28446565/murinization-and-h-chain-isotype-matching-of-the-anti-gitr-antibody-dta-1-reduces-immunogenicity-mediated-anaphylaxis-in-c57bl-6-mice
#3
Nicole A Belmar, Sarah W Chan, Melvin I Fox, Josue A Samayoa, Marcia M Stickler, Ninian N Tran, Yoshiko Akamatsu, Diane Hollenbaugh, Fiona A Harding, Hamsell M Alvarez
Recent advances in immuno-oncology have shown that the immune system can be activated to induce long-term, durable antitumor responses. For immuno-oncology drug development, immune activation is often explored using rat Abs in immunocompetent mouse models. Although these models can be used to show efficacy, antidrug immune responses to experimental protein-based therapeutics can arise. Immunogenicity of surrogate Abs may therefore represent an important obstacle to the evaluation of the antitumor efficacy of immunomodulator Abs in syngeneic models...
April 26, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28440511/simultaneously-increased-expression-of-glucocorticoid%C3%A2-induced-tumor-necrosis-factor-receptor-and-its-ligand-contributes-to-increased-interleukin%C3%A2-5-13%C3%A2-producing-group-2-innate-lymphocytes-in-murine-asthma
#4
Mengying Zhang, Jie Wan, Yunyun Xu, Danyi Zhang, Jingjing Peng, Chen Qi, Qi Guo, Sheng Xia, Zhaoliang Su, Shengjun Wang, Huaxi Xu
Glucocorticoid‑induced tumor necrosis factor receptor (GITR) is expressed at high levels on CD4+CD25+ regulatory T cells (Tregs). Following activation by its ligand (GITRL), GITR influences the activity of effector T cells and Tregs and participates in the development of numerous autoimmune and inflammatory diseases, including asthma. However, the GITR/GITRL expression level in lung tissue and its influence on group 2 innate lymphocytes (ILC2s) in asthma remains unclear. The present study detected the number of ILC2s and the expression levels of GITR and GITRL in the lung tissues of asthmatic mice by flow cytometry analysis, immunofluorescence staining and reverse transcription quantitative polymerase chain reaction...
June 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28405505/medi1873-a-potent-stabilized-hexameric-agonist-of-human-gitr-with-regulatory-t-cell-targeting-potential
#5
Natalie J Tigue, Lisa Bamber, John Andrews, Samantha Ireland, James Hair, Edward Carter, Sudharsan Sridharan, Jelena Jovanović, D Gareth Rees, Jeremy S Springall, Emilie Solier, Yi-Ming Li, Matthieu Chodorge, David Perez-Martinez, Daniel R Higazi, Michael Oberst, Maureen Kennedy, Chelsea M Black, Li Yan, Martin Schwickart, Shaun Maguire, Jennifer A Cann, Lolke de Haan, Lesley L Young, Tristan Vaughan, Robert W Wilkinson, Ross Stewart
Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is part of a system of signals involved in controlling T-cell activation. Targeting and agonizing GITR in mice promotes antitumor immunity by enhancing the function of effector T cells and inhibiting regulatory T cells. Here, we describe MEDI1873, a novel hexameric human GITR agonist comprising an IgG1 Fc domain, a coronin 1A trimerization domain and the human GITRL extracellular domain (ECD). MEDI1873 was optimized through systematic testing of different trimerization domains, aglycosylation of the GITRL ECD and comparison of different Fc isotypes...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28388572/combination-gitr-targeting-pd-1-blockade-with-vaccination-drives-robust-antigen-specific-antitumor-immunity
#6
Daniel O Villarreal, Diana Chin, Melissa A Smith, Leopoldo L Luistro, Linda A Snyder
Tumor progression is facilitated immunologically by mechanisms that include low antigen expression, an absence of coimmunostimulatory signals, and the presence of regulatory T cells (Tregs), all of which act to suppress and restrict effector T cells in the tumor. It may be possible to overcome these conditions by a combination of modulatory immunotherapy agents and tumor-antigen targeting to activate and drive effective antitumor T cell responses. Here, we demonstrated that co-administration of aGITR and aPD-1 monoclonal antibodies (mAb) in combination with a peptide vaccine (Vax) in mice bearing established tumors significantly delayed tumor growth and induced complete regression in 50% of the mice...
March 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28349869/modulation-of-regulatory-t-cells-by-intranasal-allergen-immunotherapy-in-an-experimental-rat-model-of-airway-allergy
#7
Saibal Moitra, Ankur Datta, Somnath Mondal, Iman Hazra, Sk Md Omar Faruk, Prasanta K Das, Anjan K Basu, Santanu K Tripathi, Swapna Chaudhuri
Allergic airway diseases such as asthma and allergic rhinitis are increasing in prevalence worldwide. The theory of an altered Th1/Th2 balance in allergic diathesis has recently been termed a "procrustean paradigm" as it failed to explain many preclinical findings. Regulatory T cells (Treg) have now been shown to be critical in T-cell homeostasis and in the maintenance of peripheral tolerance to allergens. Allergen specific immunotherapy (SIT) has been shown to induce regulatory T cells in allergic patients...
March 24, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28335888/second-and-third-generation-drugs-for-immuno-oncology-treatment-the-more-the-better
#8
REVIEW
Wolfram C M Dempke, Klaus Fenchel, Peter Uciechowski, Stephen P Dale
Recent success in cancer immunotherapy (anti-CTLA-4, anti-PD1/PD-L1) has confirmed the hypothesis that the immune system can control many cancers across various histologies, in some cases producing durable responses in a way not seen with many small-molecule drugs. However, only less than 25% of all patients do respond to immuno-oncology drugs and several resistance mechanisms have been identified (e.g. T-cell exhaustion, overexpression of caspase-8 and β-catenin, PD-1/PD-L1 gene amplification, MHC-I/II mutations)...
March 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28300714/biomarkers-and-immunotherapeutic-targets-in-glioblastoma
#9
REVIEW
Alice L Hung, Tomas Garzon-Muvdi, Michael Lim
Glioblastoma (GBM) is an aggressive central nervous system (CNS) cancer with poor prognosis despite maximal therapy. The recent advent of immunotherapy holds great promise for improving GBM survival and has already made great strides towards changing current management strategies. A diverse set of biomarkers has been implicated as immunotherapeutic targets and prognostic indicators in other cancers. Some of the more extensively studied examples include cytokines (IL-4, IL-13, and TGF-ß), checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, CD137, GITR, OX40), and growth/angiogenesis proteins (endoglin and EGFR)...
March 11, 2017: World Neurosurgery
https://www.readbyqxmd.com/read/28283653/antibody-drug-conjugates-bearing-pyrrolobenzodiazepine-or-tubulysin-payloads-are-immunomodulatory-and-synergize-with-multiple-immunotherapies
#10
Jonathan Rios-Doria, Jay Harper, Raymond Rothstein, Leslie Wetzel, Jon Chesebrough, Allison M Marrero, Cui Chen, Patrick Strout, Kathy Mulgrew, Kelly A McGlinchey, Ryan Fleming, Binyam Bezabeh, John Meekin, David Stewart, Maureen Kennedy, Philip Martin, Andrew Buchanan, Nazzareno Dimasi, Emil F Michelotti, Robert E Hollingsworth
Immunogenic cell death (ICD) is the process by which certain cytotoxic drugs induce apoptosis of tumor cells in a manner that stimulates the immune system. In this study, we investigated whether antibody-drug conjugates (ADC) conjugated with pyrrolobenzodiazepine dimer (PBD) or tubulysin payloads induce ICD, modulate the immune microenvironment, and could combine with IO drugs to enhance antitumor activity. We show that these payloads on their own induced an immune response that prevented the growth of tumors following subsequent tumor cell challenge...
March 10, 2017: Cancer Research
https://www.readbyqxmd.com/read/28252048/identification-of-serum-protein-biomarkers-for-utrophin-based-dmd-therapy
#11
Simon Guiraud, Benjamin Edwards, Sarah E Squire, Arran Babbs, Nandini Shah, Adam Berg, Huijia Chen, Kay E Davies
Despite promising therapeutic avenues, there is currently no effective treatment for Duchenne muscular dystrophy (DMD), a lethal monogenic disorder caused by the loss of the large cytoskeletal protein, dystrophin. A highly promising approach to therapy, applicable to all DMD patients irrespective to their genetic defect, is to modulate utrophin, a functional paralogue of dystrophin, able to compensate for the primary defects of DMD restoring sarcolemmal stability. One of the major difficulties in assessing the effectiveness of therapeutic strategies is to define appropriate outcome measures...
March 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28250919/the-role-of-gitr-single-positive-cells-in-immune-homeostasis
#12
Giuseppe Nocentini, Luigi Cari, Graziella Migliorati, Carlo Riccardi
No abstract text is available yet for this article.
March 2017: Immunity, Inflammation and Disease
https://www.readbyqxmd.com/read/28224733/nk1-1-cd4-nkg2d-t-cells-suppress-dss-induced-colitis-in-mice-through-production-of-tgf-%C3%AE
#13
Xingxing Qian, Chunxia Hu, Sen Han, Zhijie Lin, Weiming Xiao, Yanbing Ding, Yu Zhang, Li Qian, Xiaoqing Jia, Guoqiang Zhu, Weijuan Gong
CD4(+) NKG2D(+) T cells are associated with tumour, infection and autoimmune diseases. Some CD4(+) NKG2D(+) T cells secrete IFN-γ and TNF-α to promote inflammation, but others produce TGF-β and FasL to facilitate tumour evasion. Here, murine CD4(+) NKG2D(+) T cells were further classified into NK1.1(-) CD4(+) NKG2D(+) and NK1.1(+) CD4(+) NKG2D(+) subpopulations. The frequency of NK1.1(-) CD4(+) NKG2D(+) cells decreased in inflamed colons, whereas more NK1.1(+) CD4(+) NKG2D(+) cells infiltrated into colons of mice with DSS-induced colitis...
February 22, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28213366/tumor-infiltrating-and-peripheral-blood-t-cell-immunophenotypes-predict-early-relapse-in-localized-clear-cell-renal-cell-carcinoma
#14
Nicolas A Giraldo, Etienne Becht, Yann Vano, Florent Petitprez, Laetitia Lacroix, Pierre Validire, Rafael Sanchez-Salas, Alexandre Ingels, Stephane Marie Oudard, Audrey Moatti, Bénédicte Buttard, Sarah Bourras, Claire Germain, Xavier Cathelineau, Wolf-Herman Fridman, Catherine Sautes-Fridman
PURPOSE: The efficacy of PD-1 Checkpoint Blockade (ChB) as adjuvant therapy in localized clear cell Renal Cell Carcinoma (ccRCC) is currently unknown. The identification of tumor microenvironment (TME) prognostic biomarkers in this setting may help to define which patients could benefit from ChB and to uncover new therapeutic targets. EXPERIMENTAL DESIGN: We performed multiparametric flow cytometry immunophenotypic analysis of T cells isolated from tumor tissue (TIL), adjacent non-malignant renal tissue (RIL) and peripheral blood (PBL), in a cohort of patients (n=40) with localized ccRCC...
February 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28122327/dual-roles-for-regulatory-t-cell-depletion-and-costimulatory-signaling-in-agonistic-gitr-targeting-for-tumor-immunotherapy
#15
Ashley E Mahne, Smita Mauze, Barbara Joyce-Shaikh, Jane Xia, Edward P Bowman, Amy M Beebe, Daniel J Cua, Renu Jain
Agonistic monoclonal antibodies (mAb) targeting the T-cell receptor coregulatory molecule GITR exert potent therapeutic activities in preclinical tumor models. Although anti-GITR mAb are thought to act by depleting and destabilizing the intratumoral T regulatory cell (Treg) population, the precise mechanism of action is obscure. Here, we addressed this issue using a Treg fate-mapping approach, which revealed that Treg loss was primarily due to cell depletion, with minimal evidence of Treg conversion to a non-Foxp3-expressing population...
October 20, 2016: Cancer Research
https://www.readbyqxmd.com/read/28107375/narcolepsy-type-1-is-associated-with-a-systemic-increase-and-activation-of-regulatory-t-cells-and-with-a-systemic-activation-of-global-t-cells
#16
Michel Lecendreux, Guillaume Churlaud, Fabien Pitoiset, Armelle Regnault, Tu Anh Tran, Roland Liblau, David Klatzmann, Michelle Rosenzwajg
Narcolepsy is a rare neurologic disorder characterized by excessive daytime sleepiness, cataplexy and disturbed nocturnal sleep patterns. Narcolepsy type 1 (NT1) has been shown to result from a selective loss of hypothalamic hypocretin-secreting neurons with patients typically showing low CSF-hypocretin levels (<110 pg/ml). This specific loss of hypocretin and the strong association with the HLA-DQB1*06:02 allele led to the hypothesis that NT1 could be an immune-mediated pathology. Moreover, susceptibility to NT1 has recently been associated with several pathogens, particularly with influenza A H1N1 virus either through infection or vaccination...
2017: PloS One
https://www.readbyqxmd.com/read/28101786/evaluation-of-t-regulatory-lymphocytes-transcription-factors-in-htlv-1-associated-myelopathy-tropical-spastic-paraparesis-ham-tsp-patients
#17
Sanaz Ahmadi Ghezeldasht, Hamed Sadeghian, Mahmoud Reza Azarpazhooh, Seyyed Ali Akbar Shamsian, Houshang Rafatpanah, Mahmood Mahmoodi, Seyyed Abdolrahim Rezaee
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an aggressive neurological disease. The CD4(+)CD25(+) T cell population plays pivotal roles in the maintenance of immunological tolerance and prevention of such autoimmune diseases. In the current study, proviral load (PVL), factor forkhead box p3 (Foxp3), and glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) gene expression and regulatory T cells (Tregs) counts of 21 HAM/TSP patients and 16 HTLV-1 healthy carriers (ACs) were measured using real-time PCR, TaqMan method, and flow cytometry...
January 18, 2017: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/28069723/a-novel-murine-gitr-ligand-fusion-protein-induces-antitumor-activity-as-a-monotherapy-which-is-further-enhanced-in-combination-with-an-ox40-agonist
#18
Rebecca Leyland, Amanda Watkins, Kathy Mulgrew, Nicholas Holoweckyj, Lisa Bamber, Natalie J Tigue, Emily Offer, John Andrews, Li Yan, Stefanie Mullins, Michael D Oberst, Jane Coates Ulrichsen, David A Leinster, Kelly A McGlinchey, Lesley Young, Michelle Morrow, Scott A Hammond, Philip R Mallinder, Athula Herath, Ching Ching Leow, Robert W Wilkinson, Ross Stewart
PURPOSE: To generate and characterize a murine GITR ligand fusion protein (mGITRL-FP) designed to maximize valency and the potential to agonize the GITR receptor for cancer immunotherapy. EXPERIMENTAL DESIGN: The EC50 value of the mGITRL-FP was compared to an anti-GITR antibody in an in vitro agonistic cell based reporter assay. We assessed the impact of dose, schedule and Fc isotype on antitumor activity and T-cell modulation in the CT26 tumor model. The activity of the mGITRL-FP was compared to an agonistic murine OX40L-FP targeting OX40, in CT26 and B16F10-Luc2 tumor models...
January 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27942984/lps-treated-bone-marrow-derived-dendritic-cells-induce-immune-tolerance-through-modulating-differentiation-of-cd4-regulatory-t-cell-subpopulations-mediated-by-3g11-and-cd127
#19
Fang Zhou, Guang-Xian Zhang, Abdolmohamad Rostami
Intravenous transfer of LPS-treated bone marrow-derived dendritic cells blocks development of autoimmunity induced by CD4(+) T cells in vivo. However, cellular mechanisms of dendritic cell-mediated immune tolerance have not yet been fully elucidated. Here, we report that there are two new subpopulations of CD4(+)CD25(+)FoxP3(+)GITR(+) regulatory T cells (CD127(+)3G11(+) and CD127(+)3G11(-) cells). LPS-treated dendritic cells facilitate development of CD4(+)CD127(+)3G11(-) regulatory T cells but inhibit that of CD4(+)CD127(+)3G11(+) regulatory T cells...
December 12, 2016: Immunologic Research
https://www.readbyqxmd.com/read/27877174/dna-methyltransferase-inhibitor-promotes-human-cd4-cd25-h-foxp3-regulatory-t-lymphocyte-induction-under-suboptimal-tcr-stimulation
#20
Chun-Hao Lu, Cheng-Jang Wu, Cheng-Chi Chan, Duc T Nguyen, Kuo-Ray Lin, Syh-Jae Lin, Li-Chen Chen, Jeffrey Jong-Yong Yen, Ming-Ling Kuo
The "master transcription factor" FOXP3 regulates the differentiation, homeostasis, and suppressor function of CD4(+) regulatory T (Treg) cells, which are critical in maintaining immune tolerance. Epigenetic regulation of FOXP3 expression has been demonstrated to be important to Treg cell development, but the induction of human Treg cells through epigenetic modification has not been clearly described. We report that the combination of the DNA methyltransferase inhibitor 5-azacytidine (5-Aza) and suboptimal T cell receptor (TCR) stimulation promoted CD4(+)CD25(h)FOXP3(+) T cell induction from human CD4(+)CD25(-) T cells...
2016: Frontiers in Immunology
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