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https://www.readbyqxmd.com/read/28808483/therapeutic-immune-monitoring-of-cd4-cd25-t-cells-in-chronic-myeloid-leukemia-patients-treated-with-tyrosine-kinase-inhibitors
#1
Ziyuan Lu, Na Xu, Xuan Zhou, Guanlun Gao, Lin Li, Jixian Huang, Yuling Li, Qisi Lu, Bolin He, Chengyun Pan, Xiaoli Liu
Tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib and nilotinib, are effective forms of therapy for various types of solid cancers and Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia. A number of TKIs have been known to have strong effects on T cells, particularly cluster of differentiation (CD) 4(+)CD25(+) T cells, also known as regulatory T cells (Tregs). There is currently a deficit in the available clinical data regarding this area of study. In the present study, a total of 108 peripheral blood samples were collected from patients with chronic myeloid leukemia (CML) at diagnosis (n=31), and at 3 and 6 months following treatment with TKI [imatinib (n=12), dasatinib (n=11) and nilotinib groups (n=8)] and healthy controls (n=15)...
August 2017: Oncology Letters
https://www.readbyqxmd.com/read/28807056/agonist-anti-gitr-antibody-significantly-enhances-the-therapeutic-efficacy-of-listeria-monocytogenes-based-immunotherapy
#2
Rajeev Shrimali, Shamim Ahmad, Zuzana Berrong, Grigori Okoev, Adelaida Matevosyan, Ghazaleh Shoja E Razavi, Robert Petit, Seema Gupta, Mikayel Mkrtichyan, Samir N Khleif
BACKGROUND: We previously demonstrated that in addition to generating an antigen-specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4(+) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Since Lm-based immunotherapy is able to inhibit the immune suppressive environment, we hypothesized that combining this treatment with agonist antibody to a co-stimulatory receptor that would further boost the effector arm of immunity will result in significant improvement of anti-tumor efficacy of treatment...
August 15, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28806299/the-dynamic-and-transient-immune-microenvironment-in-locally-advanced-esophageal-adenocarcinoma-post-chemoradiation
#3
Ronan J Kelly, Ali H Zaidi, Matthew A Smith, Ashten N Omstead, Juliann E Kosovec, Daisuke Matsui, Samantha A Martin, Christina DiCarlo, E Day Werts, Jan F Silverman, David H Wang, Blair A Jobe
OBJECTIVE: The aim of this study was to assess the impact of chemoradiation on the immune microenvironment to influence and optimally design future neoadjuvant clinical trials. SUMMARY BACKGROUND DATA: Programmed death (PD)-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25% in programmed death ligand-1 (PD-L1+) tumors. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with chemoradiation in earlier stage esophageal cancer may prevent metastatic disease in patients...
August 10, 2017: Annals of Surgery
https://www.readbyqxmd.com/read/28771603/expression-of-pd-l1-and-other-immunotherapeutic-targets-in-thymic-epithelial-tumors
#4
Kathryn C Arbour, Jarushka Naidoo, Keith E Steele, Ai Ni, Andre L Moreira, Natasha Rekhtman, Paul B Robbins, Joyson Karakunnel, Andreas Rimner, James Huang, Gregory J Riely, Matthew D Hellmann
INTRODUCTION: The thymus is a critical organ for the development of the adaptive immune system and thymic epithelial tumors (TETs; thymomas and thymic carcinomas) are often associated with auto-immune paraneoplastic conditions. However, the immunobiology of TETs is not well described. An evaluation of the tumor microenvironment, with particular focus on expression of immunotherapeutic targets, may facilitate and prioritize development of immunotherapy strategies for patients with TETs...
2017: PloS One
https://www.readbyqxmd.com/read/28765225/b-cell-requirement-for-robust-regulatory-t-cell-responses-to-friend-retrovirus-infection
#5
Tyler C Moore, Lorena M Gonzaga, Jennifer M Mather, Ronald J Messer, Kim J Hasenkrug
Regulatory T cells (Tregs) are immunosuppressive cells of the immune system that control autoimmune reactivity. Tregs also respond during immune reactions to infectious agents in order to limit immunopathological damage from potent effectors such as CD8(+) cytolytic T lymphocytes. We have used the Friend virus (FV) model of retroviral infection in mice to investigate how viral infections induce Tregs. During acute FV infection, there is significant activation and expansion of thymus-derived (natural) Tregs that suppress virus-specific CD8(+) T cell responses...
August 1, 2017: MBio
https://www.readbyqxmd.com/read/28761757/mechanisms-of-action-and-rationale-for-the-use-of-checkpoint-inhibitors-in-cancer
#6
REVIEW
Clemence Granier, Eleonore De Guillebon, Charlotte Blanc, Helene Roussel, Cecile Badoual, Elia Colin, Antonin Saldmann, Alain Gey, Stephane Oudard, Eric Tartour
The large family of costimulatory molecules plays a crucial role in regulation of the immune response. These molecules modulate TCR signalling via phosphorylation cascades. Some of the coinhibitory members of this family, such as PD-1 and CTLA-4, already constitute approved targets in cancer therapy and, since 2011, have opened a new area of antitumour immunotherapy. Many antibodies targeting other inhibitory receptors (Tim-3, VISTA, Lag-3 and so on) or activating costimulatory molecules (OX40, GITR and so on) are under evaluation...
2017: ESMO Open
https://www.readbyqxmd.com/read/28758197/enhanced-immune-modulatory-effects-of-thalidomide-and-dexamethasone-co-treatment-on-t-cell-subsets
#7
Eun Jee Kim, Jae Geun Lee, Joon Ye Kim, Seung Hwan Song, Dong Jin Joo, Kyu Ha Huh, Myoung Soo Kim, Beom Seok Kim, Yu Seun Kim
Thalidomide (TM) has been reported to have anti-cancer and anti-inflammatory properties, and dexamethasone (DX) is known to reduce inflammation and inhibit production of inflammatory cytokines. Many studies have reported the combinatorial therapy of TM and DX is clinically used to treat multiple myeloma (MM) and lupus nephritis, but the mechanism responsible for its effects has not been elucidated. In this study, we determined that TM and DX co-treatment had an enhanced immune-modulatory effect on T cells through regulating expression of co-stimulatory molecules...
July 31, 2017: Immunology
https://www.readbyqxmd.com/read/28680744/intratumoral-delivery-of-tumor-antigen-loaded-dc-and-tumor-primed-cd4-t-cells-combined-with-agonist-%C3%AE-gitr-mab-promotes-durable-cd8-t-cell-dependent-antitumor-immunity
#8
Zuqiang Liu, Xingxing Hao, Yi Zhang, Jiying Zhang, Cara D Carey, Louis D Falo, Walter J Storkus, Zhaoyang You
The progressive tumor microenvironment (TME) coordinately supports tumor cell expansion and metastasis, while it antagonizes the survival and (poly-)functionality of antitumor T effector cells. There remains a clear need to develop novel therapeutic strategies that can transform the TME into a pro-inflammatory niche that recruits and sustains protective immune cell populations. While intravenous treatment with tumor-primed CD4(+) T cells combined with intraperitoneal delivery of agonist anti-glucocorticoid-induced TNF receptor (α-GITR) mAb results in objective antitumor responses in murine early stage disease models, this approach is ineffective against more advanced tumors...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28652399/c-rel-and-i%C3%AE%C2%BAbns-govern-common-and-independent-steps-of-regulatory-t-cell-development-from-novel-cd122-expressing-pre-precursors
#9
Marc Schuster, Carlos Plaza-Sirvent, Anne-Marie Matthies, Ulrike Heise, Andreas Jeron, Dunja Bruder, Alexander Visekruna, Jochen Huehn, Ingo Schmitz
Foxp3-expressing regulatory T cells (Tregs) are essential regulators of immune homeostasis and, thus, are prime targets for therapeutic interventions of diseases such as cancer and autoimmunity. c-REL and IκBNS are important regulators of Foxp3 induction in Treg precursors upon γ-chain cytokine stimulation. In c-REL/IκBNS double-deficient mice, Treg numbers were dramatically reduced, indicating that together, c-REL and IκBNS are pivotal for Treg development. However, despite the highly reduced Treg compartment, double-deficient mice did not develop autoimmunity even when aged to more than 1 y, suggesting that c-REL and IκBNS are required for T cell effector function as well...
June 26, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28649380/gitr-ligand-fusion-protein-agonist-enhances-the-tumor-antigen-specific-cd8-t-cell-response-and-leads-to-long-lasting-memory
#10
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
https://www.readbyqxmd.com/read/28638937/anti-gitr-antibody-treatment-increases-tcr-repertoire-diversity-of-regulatory-but-not-effector-t-cells-engaged-in-the-immune-response-against-b16-melanoma
#11
Bozena Scirka, Edyta Szurek, Maciej Pietrzak, Grzegorz Rempala, Pawel Kisielow, Leszek Ignatowicz, Arkadiusz Miazek
Crosslinking of glucocorticoid-induced TNF family-related receptor (GITR) with agonist antibodies restores cancer immunity by enhancing effector T cell (Teff) responses while interfering with intra-tumor regulatory T cell (Treg) stability and/or accumulation. However, how anti-GITR antibody infusion changes T cell receptor (TCR) repertoire of Teffs and Tregs engaged in anti-tumor immune response is unclear. Here, we used a transgenic mouse model (TCRmini) where T cells express naturally generated but limited TCR repertoire to trace the fate of individual T cells recognizing B16 melanoma in tumor-bearing mice, treated or non-treated with an anti-GITR monoclonal antibody DTA-1...
June 21, 2017: Archivum Immunologiae et Therapiae Experimentalis
https://www.readbyqxmd.com/read/28638727/identification-of-an-immunogenic-neo-epitope-encoded-by-mouse-sarcoma-using-cxcr3-ligand-mrnas-as-sensors
#12
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
https://www.readbyqxmd.com/read/28611044/characterization-of-mk-4166-a-clinical-agonistic-antibody-that-targets-human-gitr-and-inhibits-the-generation-and-suppressive-effects-of-t-regulatory-cells
#13
Selvakumar Sukumar, Douglas C Wilson, Ying Yu, Jerelyn Wong, Saraswathi Naravula, Grigori Ermakov, Romina Riener, Bhagyashree Bhagwat, Antoaneta S Necheva, Jeff Grein, Tatyana Churakova, Ruban Mangadu, Peter Georgiev, Denise Manfra, Elaine M Pinheiro, Venkataraman Sriram, Wendy J Bailey, Danuta Herzyk, Terrill K McClanahan, Aarron Willingham, Amy M Beebe, Svetlana Sadekova
GITR is a T-cell costimulatory receptor that enhances cellular and humoral immunity. The agonist anti-mouse GITR antibody DTA-1 has demonstrated efficacy in murine models of cancer primarily by attenuation of Treg-mediated immune suppression, but the translatability to human GITR biology has not been fully explored. Here, we report the potential utility of MK-4166, a humanized GITR mAb selected to bind to an epitope analogous to the DTA-1 epitope, which enhances the proliferation of both naïve and tumor-infiltrating T lymphocytes (TIL)...
August 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28539551/suppression-of-gpi-induced-arthritis-by-oral-administration-of-transgenic-rice-seeds-expressing-altered-peptide-ligands
#14
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
https://www.readbyqxmd.com/read/28536578/expansion-of-cd25-negative-forkhead-box-p3-positive-t-cells-during-hiv-and-mycobacterium-tuberculosis-infection
#15
Matías T Angerami, Guadalupe V Suarez, María B Vecchione, Natalia Laufer, Diego Ameri, Graciela Ben, Hector Perez, Omar Sued, Horacio Salomón, María F Quiroga
Tuberculosis (TB) and HIV alter the immune system, and coinfected (HIV-TB) individuals usually present deregulations of T-lymphocytic immune response. We previously observed an increased frequency of "unconventional" CD4(+)CD25(-)FoxP3(+) Treg (uTreg) population during HIV-TB disease. Therefore, we aimed to explore the phenotype and function of uTreg and conventional CD4(+)CD25(+)FoxP3(+) Treg subsets (cTreg) in this context. We evaluated the expression of CD39, programmed cell death protein 1 (PD1), glucocorticoid-induced tumor necrosis factor receptor (GITR), and the effector/memory distribution by flow cytometry in cTreg and uTreg...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28524007/the-proinflammatory-cytokine-gitrl-contributes-to-trail-mediated-neurotoxicity-in-the-hcn-2-human-neuronal-cell-line
#16
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
#17
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
#18
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
#19
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
#20
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
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