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Saeed Mohammadi, Ali Memarian, Sima Sedighi, Nasser Behnampour, Yaghoub Yazdani
Macrophages are versatile phagocytic cells in immune system with immunoregulatory functions. However, the removal of apoptotic cells by macrophages is disturbed in systemic lupus erythematosus (SLE). Aryl hydrocarbon receptor (AhR) is a ligand-activated cytoplasmic receptor and transcription factor with diverse effects on immune response. Indole-3-carbinol (I3C) is an AhR agonist which has been implicated as a beneficial factor in regulating inflammation and cytokine expression in murine models of SLE. However, the molecular mechanisms are not thoroughly studied...
October 5, 2018: Autoimmunity
Xiao-Jun Zhang, Zhong-Wen Yuan, Chang Qu, Xiu-Ting Yu, Tao Huang, Ping Vicky Chen, Zi-Ren Su, Yao-Xing Dou, Jia-Zhen Wu, Hui-Fang Zeng, Ying Xie, Jian-Nan Chen
Inflammatory bowel disease (IBD), majorly include Crohn's disease (CD) and ulcerative colitis (UC), is chronic and relapsing inflammatory disorders of the gastrointestinal tract, which treatment options remain limited. Here we examined the therapeutic effects of an isoquinoline alkaloid, Palmatine (Pal), on mice experimental colitis induced by dextran sulfate sodium (DSS) and explored underlying mechanisms. Colitis was induced in BALB/c mice by administering 3% DSS in drinking water for 7 days. Pal (50 and 100 mg kg-1 ) and the positive drug Sulfasalazine (SASP, 200 mg kg-1 ) were orally administered for 7 days...
September 19, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Lilian Cha, Anderson P Jones, Stephanie Trend, Scott N Byrne, Marzena J Fabis-Pedrini, William M Carroll, Robyn M Lucas, Judith M Cole, David R Booth, Allan G Kermode, Prue H Hart
Objectives: Clinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). A study of circulating cells from patients with CIS may help us understand the transition to, and processes associated with, the development of MS. Methods: As immune cell activity can be determined by flux through metabolic pathways, the mRNA expression of l-tryptophan- and l-arginine-catabolising enzymes, indoleamine 2,3-dioxygenase (IDO) 1 and IDO2 and arginase (ARG) 1 and ARG2, respectively, was compared between peripheral blood mononuclear cells (PBMCs) from healthy controls, and patients with CIS and definite MS...
2018: Clinical & Translational Immunology
Bing Feng, Fangyuan Zhou, Bo Hou, Dangge Wang, Tingting Wang, Yuanlei Fu, Yuting Ma, Haijun Yu, Yaping Li
Checkpoint blockade immunotherapy is promising for clinical treatment of various malignant tumors. However, checkpoint blockade immunotherapy suffers from a low response rate due to insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (ITM). In this study, a tumor-microenvironment-activatable binary cooperative prodrug nanoparticle (BCPN) is rationally designed to improve immunotherapy by synergistically modulating the immune tumor microenvironment. BCPN is purely constructed from a tumor acidity and reduction dual-responsive oxaliplatin (OXA) prodrug for triggering immunogenic cell death (ICD) and eliciting antitumor immunity, and a reduction-activatable homodimer of NLG919 for inactivating indoleamine 2,3-dioxygenase 1, which is a key regulator for ITM...
July 31, 2018: Advanced Materials
Geoffroy Laumet, Jules Daniel Edralin, Angie Chi-An Chiang, Robert Dantzer, Cobi J Heijnen, Annemieke Kavelaars
In humans, depression is often associated with low-grade inflammation, activation of the tryptophan/kynurenine pathway, and mild lymphopenia. Preclinical research confirms that inflammation induces depression-like behavior through activation of the tryptophan/kynurenine pathway. However, the mechanisms governing recovery from depression are unknown. Understanding the pathways leading to resolution of depression will likely lead to identification of novel targets for treatment. We investigated the contribution of T lymphocytes to the resolution of lipopolysaccharide-induced depression-like behavior...
July 16, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Eleonora Da Pozzo, Chiara Giacomelli, Chiara Cavallini, Claudia Martini
The stress hormone cortisol has been recognized as a coordinator of immune response. However, its different ability to modulate the release of inflammatory mediators in males and females has not been clarified yet. Indeed, the dissection of cortisol specific actions may be difficult due to the complex hormonal and physio-pathological individual status. Herein, the release of inflammatory mediators following increasing cortisol concentrations was investigated in an in vitro model of primary human male and female lymphomonocytes...
2018: PloS One
Catherine Rolvering, Andreas D Zimmer, Aurélien Ginolhac, Christiane Margue, Mélanie Kirchmeyer, Florence Servais, Heike M Hermanns, Sabine Hergovits, Petr V Nazarov, Nathalie Nicot, Stephanie Kreis, Serge Haan, Iris Behrmann, Claude Haan
Interleukin-27 (IL27) is a type-I cytokine of the IL6/IL12 family and is predominantly secreted by activated macrophages and dendritic cells. We show that IL27 induces STAT factor phosphorylation in cancerous cell lines of different tissue origin. IL27 leads to STAT1 phosphorylation and recapitulates an IFN-γ-like response in the microarray analyses, with up-regulation of genes involved in antiviral defense, antigen presentation, and immune suppression. Like IFN-γ, IL27 leads to an up-regulation of TAP2 and MHC-I proteins, which mediate increased tumor immune clearance...
July 24, 2018: Journal of Leukocyte Biology
Douglas B Johnson, Jennifer M Bordeaux, Ju-Young Kim, Christine A Vaupel, David L Rimm, Thai H Ho, Richard W Joseph, Adil I Daud, Robert M Conry, Elizabeth M Gaughan, Leonel F Hernandez-Aya, Anastasios Dimou, Pauline Funchain, James W Smithy, John S Witte, Svetlana B McKee, Jennifer Ko, John Wrangle, Bashar Dabbas, Shabnam Tangri, Jelveh Lameh, Jeffrey M Hall, Joseph Markowitz, Justin M Balko, Naveen K Dakappagari
PURPOSE: PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients, therefore, biomarkers of response are needed. We hypothesized quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD1 response. METHODS: Pre-treatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts...
July 18, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Daqing Wang, Wayne Jiang, Fugang Zhu, Xianzhi Mao, Sudhir Agrawal
The objective of cancer immunotherapy is to prime the host's immune system to recognize and attack malignant tumor cells. IMO‑2125, a Toll‑like receptor 9 (TLR9) agonist, exhibited potent antitumor effects in the murine syngeneic A20 lymphoma and the CT26 colon carcinoma models. IMO‑2125 exhibited superior A20 antitumor activity when injected intratumorally (i.t.) compared with equivalent subcutaneous doses. In mice bearing dual CT26 grafts, the i.t. injection of right flank tumors elicited infiltration of cluster of differentiation (CD)3+ T lymphocytes into tumors, resulting in the regression of injected and uninjected left flank tumors...
September 2018: International Journal of Oncology
Ashley Volaric, Ryan Gentzler, Richard Hall, James H Mehaffey, Edward B Stelow, Timothy N Bullock, Linda W Martin, Anne M Mills
The immune regulatory enzyme indoleamine-2,3-dioxygenase (IDO-1) suppresses T cell responses and may reduce efficacy of therapies targeting immune checkpoints such as programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1). Early phase clinical trials combining IDO-1 and PD-1/PD-L1 inhibitors have shown some promise in non-small cell lung cancers (NSCLCs). However, the coexpression of IDO-1 and PD-L1 has not been thoroughly investigated, and the potential for IDO-1 immunohistochemical expression as a therapeutic biomarker is unknown...
September 2018: American Journal of Surgical Pathology
Allison M Garrison, Jennifer M Parrott, Arnulfo Tuñon, Jennifer Delgado, Laney Redus, Jason C O'Connor
Chronic stress or inflammation increases tryptophan metabolism along the kynurenine pathway (KP), and the generation of neuroactive kynurenine metabolites contributes to subsequent depressive-like behaviors. Microglia regulate KP balance by preferentially producing oxidative metabolites, including quinolinic acid. Research has focused on the interplay between cytokines and HPA axis-derived corticosteroids in regulating microglial activity and effects of KP metabolites directly on neurons; however, the potential role that KP metabolites have directly on microglial activity is unknown...
August 2018: Psychoneuroendocrinology
Anthony R Guastella, Sharon K Michelhaugh, Neil V Klinger, Hassan A Fadel, Sam Kiousis, Rouba Ali-Fehmi, William J Kupsky, Csaba Juhász, Sandeep Mittal
INTRODUCTION: There is mounting evidence supporting the role of tryptophan metabolism via the kynurenine pathway (KP) in the pathogenesis of primary brain tumors. Under normal physiological conditions, the KP is the major catabolic pathway for the essential amino acid tryptophan. However, in cancer cells, the KP becomes dysregulated, depletes local tryptophan, and contributes to an immunosuppressive tumor microenvironment. METHODS: We examined the protein expression levels (in 73 gliomas and 48 meningiomas) of the KP rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, and tryptophan 2,3-dioxygenase (TDO2), as well as, the aryl hydrocarbon receptor (AhR), a carcinogenic transcription factor activated by KP metabolites...
September 2018: Journal of Neuro-oncology
K Becker, S Schwaiger, B Waltenberger, D Fuchs, C K Pezzei, H Schennach, H Stuppner, J M Gostner
Several phytochemicals were shown to interfere with redox biology in the human system. Moreover, redox biochemistry is crucially involved in the orchestration of immunological cascades. When screening for immunomodulatory compounds, the two interferon gamma- (IFN- γ -) dependent immunometabolic pathways of tryptophan breakdown via indoleamine 2,3-dioxygenase-1 (IDO-1) and neopterin formation by GTP-cyclohydrolase 1 (GTP-CH-I) represent prominent targets, as IFN- γ -related signaling is strongly sensitive to oxidative triggers...
2018: Oxidative Medicine and Cellular Longevity
Qingdong Guan, Yun Li, Tanner Shpiruk, Swaroop Bhagwat, Donna A Wall
AIM: Establishment of a potency assay in the manufacturing of clinical-grade mesenchymal stromal cells (MSCs) has been a challenge due to issues of relevance to function, timeline and variability of responder cells. In this study, we attempted to develop a potency assay for MSCs. METHODS: Clinical-grade bone marrow-derived MSCs were manufactured. The phenotype and immunosuppressive functions of the MSCs were evaluated based on the International Society for Cellular Therapy guidelines...
May 2018: Cytotherapy
Edwin Roger Parra, Pamela Villalobos, Jiexin Zhang, Carmen Behrens, Barbara Mino, Stephen Swisher, Boris Sepesi, Annika Weissferdt, Neda Kalhor, John Victor Heymach, Cesar Moran, Jianjun Zhang, Jack Lee, Jaime Rodriguez-Canales, Don Gibbons, Ignacio I Wistuba
INTRODUCTION: The understanding of immune checkpoint molecules' co-expression in non-small cell lung carcinoma (NCLC) is important to potentially design combinatorial immunotherapy approaches. METHODS: We studied 225 formalin-fixed, paraffin-embedded tumor tissues from stage I-III NCLCs - 142 adenocarcinomas (ADCs) and 83 squamous cell carcinomas (SCCs) - placed in tissue microarrays. Nine immune checkpoint markers were evaluated; four (programmed death ligand 1 [PD-L1], B7-H3, B7-H4, and indoleamine 2,3-dioxygenase 1 [IDO-1]) expressed predominantly in malignant cells (MCs) and five (inducible T cell costimulator, V-set immunoregulatory receptor, T-cell immunoglobulin mucin family member 3, lymphocyte activating 3, and OX40) expressed mostly in stromal tumor-associated inflammatory cells (TAICs)...
June 2018: Journal of Thoracic Oncology
Andreas Seeber, Gerald Klinglmair, Josef Fritz, Fabian Steinkohl, Kai-Christian Zimmer, Friedrich Aigner, Wolfgang Horninger, Günther Gastl, Bettina Zelger, Andrea Brunner, Renate Pichler
Nivolumab belongs to the standard therapy in the second-line setting of metastatic renal cell carcinoma (mRCC). Although deep and long-lasting responses are seen in some patients, the majority of patients will further progress. PD-L1 is still under critical evaluation as a predictive biomarker. Thus, more accurate biomarkers are clearly warranted. Here, we investigated for the first time the predictive role of IDO-1, a negative immune-regulatory molecule, on clear cell RCC tissues of 15 patients undergoing nivolumab therapy...
May 2018: Cancer Science
Laurence Booth, Jane L Roberts, Rumeesa Rais, John Kirkwood, Francesca Avogadri-Connors, Richard E Cutler, Alshad S Lalani, Andrew Poklepovic, Paul Dent
The irreversible ERBB1/2/4 inhibitor neratinib has been shown in vitro to rapidly reduce the expression of ERBB1/2/4 and RAS proteins via autophagic/lysosomal degradation. We have recently demonstrated that neratinib and valproate interact to suppress the growth of 4T1 mammary tumors but had not defined whether the [neratinib + valproate] drug combination, in a mouse, had altered the biology of the 4T1 cells. Exposure of 4T1 mammary tumors to [neratinib + valproate] for three days resulted, two weeks later, in tumors that expressed less ERBB1, K-RAS, N-RAS, indoleamine-pyrrole 2,3-dioxygenase (IDO-1), ornithine decarboxylase (ODC) and had increased Class I MHCA expression...
January 19, 2018: Oncotarget
Nataša Ilic, Alisa Gruden-Movsesijan, Jelena Cvetkovic, Sergej Tomic, Dragana Bozidar Vucevic, Carmen Aranzamendi, Miodrag Colic, Elena Pinelli, Ljiljana Sofronic-Milosavljevic
Trichinella spiralis , as well as its muscle larvae excretory-secretory products (ES L1), given either alone or via dendritic cells (DCs), induce a tolerogenic immune microenvironment in inbred rodents and successfully ameliorate experimental autoimmune encephalomyelitis. ES L1 directs the immunological balance away from T helper (Th)1, toward Th2 and regulatory responses by modulating DCs phenotype. The ultimate goal of our work is to find out if it is possible to translate knowledge obtained in animal model to humans and to generate human tolerogenic DCs suitable for therapy of autoimmune diseases through stimulation with ES L1...
2018: Frontiers in Immunology
Benjamin Solomon, Richard J Young, Danny Rischin
Head and neck squamous cell carcinoma (HNSCC) comprises a heterogeneous group of tumors that arise from the squamous epithelium of the oral cavity, oropharynx, larynx and hypopharynx. While many HNSCCs are related to classical etiologic factors of smoking and alcohol, a clinically, genomically, and immunologically distinct subgroup of tumors arise from the epithelium of the tonsil and the base of tongue as a result of infection with Human Papilloma Virus (HPV). In this review we describe the genomic and immunologic landscape of HNSCC, highlighting differences between HPV-positive and HPV-negative HNSCC...
October 2018: Seminars in Cancer Biology
Shao-Liang Yang, Tian-Tian Niu, Xue-Lian Li, Da-Jin Li, Ming-Qing Li, Hai-Yan Wang
Recurrent spontaneous abortion (RSA) is a common health problem that affects about 5% of fertile women, when it occurs for unknown reasons, it is called unexplained recurrent spontaneous abortion (URSA). Traditional Chinese medicine, such as Bu-Shen-Yi-Qi formula which consists of Dangshen, Tusizi, Baizhu, Baishuo, Duzhong, Sangjisheng, Sugeng, and Tiaohuangqin, has played an invaluable role in the treatment of RSA since ancient times. However, the mechanism of how it takes effect is still not clear. To identify Bu-Shen-Yi-Qi formula could modulate immune condition at maternal-fetal interface via its effect on trophoblasts, HTR-8 of different treatment were co-cultured with peripheral or decidual natural killer (NK) cells, and the receptors such as NKP30 and NKP46 expression on NK cells were measured by flow cytometry (FCM)...
August 2018: Gynecological Endocrinology
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