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GITR Ligand

Nick M Durham, Nick Holoweckyj, Randall S MacGill, Kelly McGlinchey, Ching Ching Leow, Scott H Robbins
BACKGROUND: The expansion of antigen-specific CD8 T cells is important in generating an effective and long-lasting immune response to tumors and viruses. Glucocorticoid-induced tumor necrosis factor receptor family-related receptor (GITR) is a co-stimulatory receptor that binds the GITR ligand (GITRL). Agonism of GITR can produce important signals that drive expansion of effector T cell populations. METHODS: We explored two separate murine tumor models, CT26 and TC-1, for responsiveness to GITR Ligand Fusion Protein(GITRL-FP) monotherapy...
2017: Journal for Immunotherapy of Cancer
Keisuke Fujii, Yoshihiro Miyahara, Naozumi Harada, Daisuke Muraoka, Mitsuhiro Komura, Rui Yamaguchi, Hideo Yagita, Junko Nakamura, Sahoko Sugino, Satoshi Okumura, Seiya Imoto, Satoru Miyano, Hiroshi Shiku
The CXCR3 ligands CXCL9, 10, and 11 play critical roles in the amplification of immune responses by recruiting CXCR3(+) immune effector cells to the tumor site. Taking advantage of this property of CXCR3 ligands, we aimed to establish a novel approach to identify immunogenic mutated-antigens. We examined the feasibility of using CXCR3 ligand mRNAs as sensors for detection of specific immune responses in human and murine systems. We further investigated whether this approach is applicable for the identification of immunogenic mutated-antigens by using murine sarcoma lines...
2017: Oncoimmunology
Tomoya Hirota, Hiroto Tsuboi, Hiroyuki Takahashi, Hiromitsu Asashima, Masaru Ohta, Yuhya Wakasa, Isao Matsumoto, Fumio Takaiwa, Takayuki Sumida
OBJECTIVE: To investigate the effects and mechanisms of transgenic rice seeds expressing the altered peptide ligand (APL) of human glucose-6-phosphate-isomerase (hGPI325-339) in mice model of GPI induced arthritis (GIA). METHODS: We generated transgenic rice expressing APL12 which was analog peptide of hGPI325-339. The transgenic rice seeds were orally administered prophylactically before the induction of GIA. The severity of arthritis and titers of serum anti-GPI antibodies were evaluated...
2017: Nihon Rinshō Men'eki Gakkai Kaishi, Japanese Journal of Clinical Immunology
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
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
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
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
Rebecca Leyland, Amanda Watkins, Kathy A 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 McGlinchey, Lesley Young, Michelle Morrow, Scott A Hammond, Philip 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 with 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 with 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
Deborah A Knee, Becker Hewes, Jennifer L Brogdon
Over the past decade, our understanding of cancer immunotherapy has evolved from assessing peripheral responses in the blood to monitoring changes in the tumour microenvironment. Both preclinical and clinical experience has taught us that modulation of the tumour microenvironment has significant implications to generating robust antitumour immunity. Clinical benefit has been well documented to correlate with a tumour microenvironment that contains a dense infiltration of CD8(+)CD45RO(+) T effectors and a high ratio of CD8(+) T cells to FoxP3(+) regulatory T cells (Tregs)...
November 2016: European Journal of Cancer
Tomoya Hirota, Hiroto Tsuboi, Mana Iizuka-Koga, Hiroyuki Takahashi, Hiromitsu Asashima, Masahiro Yokosawa, Yuya Kondo, Masaru Ohta, Yuhya Wakasa, Isao Matsumoto, Fumio Takaiwa, Takayuki Sumida
OBJECTIVE: To investigate the effects of transgenic rice seeds expressing the altered peptide ligand (APL) of human glucose-6-phosphate-isomerase (hGPI325-339) in mice model of GPI-induced arthritis (GIA). METHODS: We generated transgenic rice expressing T-cell epitope of hGPI325-339 and APL12 contained in the seed endosperm. The transgenic rice seeds were orally administered prophylactically before the induction of GIA. The severity of arthritis and titers of serum anti-GPI antibodies were evaluated...
May 2017: Modern Rheumatology
Joerg U Schmohl, Tina Nuebling, Julia Wild, Tanja Kroell, Lothar Kanz, Helmut R Salih, Helga Schmetzer
Costimulatory ligands (COLs) and their receptors (COR) regulate immune reactions and cellular survival and might be relevant in acute myeloid leukemia (AML). This study evaluated the clinical relevance of 4-1BBL, glucocorticoid-induced TNFR-related protein (GITR) and ligand (GITRL), CD80, and CD86 in case of expression on AML blasts. 98 patients were evaluated at initial diagnosis. Immunophenotypically evaluated specific fluorescence index (SFI) levels of COR and COL on blasts were correlated with morphological, cytogenetic, and several prognostic parameters...
July 7, 2016: Journal of Investigative Medicine: the Official Publication of the American Federation for Clinical Research
Jie Ma, Dingqi Feng, Yancai Wei, Jie Tian, Xinyi Tang, Ke Rui, Liwei Lu, Huaxi Xu, Shengjun Wang
Recent studies have shown that glucocorticoid-induced tumor necrosis factor-receptor-related protein (GITR) and its ligand (GITRL) are critically involved in the pathogenesis of autoimmune arthritis, but the role of GITRL/GITR signaling in modulating CD4(+) follicular helper T (Tfh) cell response during autoimmune arthritis remains largely unclear. We showed that splenic Tfh cells from mice with collagen-induced arthritis expressed higher levels of GITR compared with non-Tfh cells. In vitro, GITRL treatment markedly enhanced the percentage and number of Tfh cells...
June 2016: American Journal of Pathology
Dominika J Nowakowska, Stephan Kissler
PTPN22 gene variation associates with multiple autoimmune diseases, including type 1 diabetes and rheumatoid arthritis. Loss of function studies have demonstrated that PTPN22 impinges on the homeostatic behavior of regulatory T (Treg) cells, a lineage critical for immune tolerance. The frequency and absolute number of Treg cells is increased in Ptpn22-deficient mice, but the mechanism driving this increase is unknown. In this study, we show that Ptpn22 knockdown (KD) promoted the expansion of the Treg cell compartment by upregulating the glucocorticoid-induced TNFR family-related protein (GITR) and increasing GITR signaling...
March 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Yanyi Yao, Jieping Song, Weipeng Wang, Nian Liu
Adaptation of the maternal immune response to accommodate the semiallogeneic fetus is necessary for pregnancy success. However, the mechanisms by which the fetus avoids rejection despite expression of paternal alloantigens remain incompletely understood. Regulatory T cells (Treg cells) are pivotal for maintaining immune homeostasis, preventing autoimmune disease and fetus rejection. In this study, we found that maternal decidual vascular endothelial cells (DVECs) sustained Foxp3 expression in resting Treg cells in vitro...
May 2016: Immunology and Cell Biology
Xinyi Tang, Jie Tian, Jie Ma, Jiemin Wang, Chen Qi, Ke Rui, Yungang Wang, Huaxi Xu, Liwei Lu, Shengjun Wang
The glucocorticoid-induced TNFR family-related protein (GITR) and its ligand play a critical role in the pathogenesis of autoimmune arthritis by enhancing the Th17 cell response, but their molecular mechanisms remain largely unclear. This study aims to define the role of p38 mitogen-activated protein kinases (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling in GITRL-induced Th17 cells in autoimmune arthritis. We found that the p38 phosphorylation was enhanced by GITRL in activated CD4+T cells, and the p38 inhibitor restrained the GITRL-induced Th17 cell expansion in a dose-dependent manner...
February 23, 2016: Oncotarget
Wei-Jun Chen, Xiao-Fan Hu, Min Yan, Wen-Yong Zhang, Xiao-Bo Mao, Yan-Wen Shu
BACKGROUND: Atherosclerosis (AS) is a chronic inflammation characterized by massive infiltration of inflammatory cells in arterial wall plaques. Programmed death ligand-1 (PD-L1), a co-stimulatory molecule, plays a vital role in regulating immune responses. We investigated the role and mechanisms of PD-L1 expressed on oxidized low-density lipoprotein (ox-LDL)-impaired human umbilical vein endothelial cells (HUVECs) in promoting activation and cytokine production of CD4(+)CD25(+) forkhead box P3 (FoxP3) regulatory T cells (Tregs)...
January 2016: Atherosclerosis
Alexander Pedroza-Gonzalez, Guoying Zhou, Simar Pal Singh, Patrick Pc Boor, Qiuwei Pan, Dirk Grunhagen, Jeroen de Jonge, Tc Khe Tran, Cornelis Verhoef, Jan Nm IJzermans, Harry LA Janssen, Katharina Biermann, Jaap Kwekkeboom, Dave Sprengers
In liver cancer tumor-infiltrating regulatory T cells (Ti-Treg) are potent suppressors of tumor-specific T-cell responses and express high levels of the Treg-associated molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor (GITR). In this study, we have evaluated the capacity of GITR-ligation, CTLA-4-blockade and a combination of both treatments to alleviate immunosuppression mediated by Ti-Treg. Using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC) we show that treatment with a soluble form of the natural ligand of GITR (GITRL), or with blocking antibodies to CTLA-4, reduces the suppression mediated by human liver tumor-infiltrating CD4(+)Foxp3+ Treg, thereby restoring proliferation and cytokine production by effector T cells...
December 2015: Oncoimmunology
Young H Kim, Su M Shin, Beom K Choi, Ho S Oh, Chang H Kim, Seung J Lee, Kwang H Kim, Don G Lee, Sang H Park, Byoung S Kwon
The glucocorticoid-induced TNFR family-related protein (GITR, TNFRSF18, CD357) is expressed on effector and regulatory T (Treg) cells. Previous studies demonstrated that GITR triggering by anti-GITR mAb enhanced T and B cell-mediated immune responses. GITR-deficient T cells, however, also proliferate more than normal T cells, and this effect is unexplained. Because the activities of mAbs are controlled by their Fc regions, the true effect of GITR signaling needs to be determined by examining its interaction with authentic ligand...
November 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Jonathan Rios-Doria, Nicholas Durham, Leslie Wetzel, Raymond Rothstein, Jon Chesebrough, Nicholas Holoweckyj, Wei Zhao, Ching Ching Leow, Robert Hollingsworth
Based on the previously described roles of doxorubicin in immunogenic cell death, both doxorubicin and liposomal doxorubicin (Doxil) were evaluated for their ability to boost the antitumor response of different cancer immunotherapies including checkpoint blockers (anti-PD-L1, PD-1, and CTLA-4 mAbs) and TNF receptor agonists (OX40 and GITR ligand fusion proteins) in syngeneic mouse models. In a preventative CT26 mouse tumor model, both doxorubicin and Doxil synergized with anti-PD-1 and CTLA-4 mAbs. Doxil was active when CT26 tumors were grown in immunocompetent mice but not immunocompromised mice, demonstrating that Doxil activity is increased in the presence of a functional immune system...
August 2015: Neoplasia: An International Journal for Oncology Research
Miguel F Sanmamed, Fernando Pastor, Alfonso Rodriguez, Jose Luis Perez-Gracia, Maria E Rodriguez-Ruiz, Maria Jure-Kunkel, Ignacio Melero
T and natural killer (NK) lymphocytes are considered the main effector players in the immune response against tumors. Full activation of T and NK lymphocytes requires the coordinated participation of several surface receptors that meet their cognate ligands through structured transient cell-to-cell interactions known as immune synapses. In the case of T cells, the main route of stimulation is driven by antigens as recognized in the form of short polypeptides associated with major histocompatibility complex (MHC) antigen-presenting molecules...
August 2015: Seminars in Oncology
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