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Sandra Schöniger, Hilke Gräfe, Franziska Richter, Heinz-Adolf Schoon
The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) acts immunomodulatory and restricts bacterial growth. In the uterus of women and mice, it likely contributes to tissue homeostasis and disease pathogenesis. Pregnancy failure in mares is often caused by endometritis and endometrosis. The pathogenesis of nonsuppurative endometritis and endometrosis is still uncertain. To the authors' knowledge, no information on IDO1 expression in the equine endometrium is published. Aim of this study was to examine the presence of IDO1 as transcripts and proteins in the healthy and diseased endometrium of 25 mares and to determine its cellular expression...
March 5, 2018: Research in Veterinary Science
Micah T Nelp, Patrick A Kates, John T Hunt, John A Newitt, Aaron Balog, Derrick Maley, Xiao Zhu, Lynn Abell, Alban Allentoff, Robert Borzilleri, Hal A Lewis, Zeyu Lin, Steven P Seitz, Chunhong Yan, John T Groves
For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N -formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors...
March 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Soo Jung Lee, Sun-Young Jun, In Hee Lee, Byung Woog Kang, Su Yeon Park, Hye Jin Kim, Jun Seok Park, Gyu-Seog Choi, Ghilsuk Yoon, Jong Gwang Kim
PURPOSE: This study attempted to reveal the prognostic impact of microsatellite instability-high (MSI-H) colon cancer with tumor-infiltrating immune cells (TIICs) and immune checkpoint protein expression, which are good candidates for immunotherapy. MATERIALS AND METHODS: The study included 89 patients with MSI-H colon cancer who underwent curative surgery at Kyungpook National University Chilgok Hospital. The expression status of specific inhibitory receptors, such as CD274 (programmed death-ligand 1, PD-L1), PDCD1 (programmed cell death 1, PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), and indolamine 2'3'-dioxygenase 1 (IDO1), was retrospectively analyzed using immunohistochemistry (IHC)...
March 8, 2018: Journal of Cancer Research and Clinical Oncology
Carlos R Dostal, Megan Carson Sulzer, Keith W Kelley, Gregory G Freund, Robert H McCusker
Stressors activate the hypothalamic-pituitary-adrenal (HPA) axis and immune system eliciting changes in cognitive function, mood and anxiety. An important link between stress and altered behavior is stimulation of the Kynurenine Pathway which generates neuroactive and immunomodulatory kynurenines. Tryptophan entry into this pathway is controlled by rate-limiting indoleamine/tryptophan 2,3-dioxygenases (DOs: Ido1, Ido2, Tdo2). Although implicated as mediating changes in behavior, detecting stress-induced DO expression has proven inconsistent...
December 2017: Neurobiology of Stress
Rebecca Liu, Jonathan Merola, Thomas D Manes, Lingfeng Qin, Gregory T Tietjen, Francesc López-Giráldez, Verena Broecker, Caodi Fang, Catherine Xie, Ping-Min Chen, Nancy C Kirkiles-Smith, Dan Jane-Wit, Jordan S Pober
Early acute rejection of human allografts is mediated by circulating alloreactive host effector memory T cells (TEM). TEM infiltration typically occurs across graft postcapillary venules and involves sequential interactions with graft-derived endothelial cells (ECs) and pericytes (PCs). While the role of ECs in allograft rejection has been extensively studied, contributions of PCs to this process are largely unknown. This study aimed to characterize the effects and mechanisms of interactions between human PCs and allogeneic TEM...
March 8, 2018: JCI Insight
Anne C Knol, Jean-Michel Nguyen, Marie-Christine Pandolfino, Marc G Denis, Amir Khammari, Brigitte Dréno
Prognostic biomarkers for melanoma patients after lymph node resection are of clinical relevance and could thus enable the identification of patients who therefore would most benefit from adjuvant treatment. The aim of this work was to determine, using an in vitro model, whether immune-related biomarkers such as MHC-class I and II, melanoma associated antigens, IDO1 and PD-L1, could also be relevant to predict the risk of relapse of stage III melanoma patients after lymph node resection. We established tumor cell lines from metastatic lymph nodes of 50 melanoma patients...
March 5, 2018: Experimental Dermatology
N M Kapranov, Yu O Davydova, I V Gal'tseva, N A Petinati, M V Bakshinskaitė, N I Drize, L A Kuz'mina, E N Parovichnikova, V G Savchenko
We studied the effect of autologous and allogeneic lymphocytes on multipotent mesenchymal stromal cells in co-culture. It is shown that changes in multipotent mesenchymal stromal cells and in lymphocytes did not depend on the source of lymphocytes. Contact with lymphocytes triggers expression of HLA-DR molecules on multipotent mesenchymal stromal cells and these cells lose their immune privilege. In multipotent mesenchymal stromal cells, the relative level of expression of factors involved in immunomodulation (IDO1, PTGES, and IL-6) and expression of adhesion molecule ICAM1 increased, while expression of genes involved in the differentiation of multipotent mesenchymal stromal cells remained unchanged...
March 4, 2018: Bulletin of Experimental Biology and Medicine
Erik Ladomersky, Lijie Zhai, Alicia Lenzen, Kristen L Lauing, Jun Qian, Denise M Scholtens, Galina Gritsina, Xuebing Sun, Ye Liu, Fenglong Yu, Wenfeng Gong, Yong Liu, Beibei Jiang, Zhiyu Tang, Ricky Patel, Leonidas C Platanias, C David James, Roger Stupp, Rimas V Lukas, David C Binder, Derek A Wainwright
PURPOSE: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults with a median survival of 15-20 months. Numerous approaches and novel therapeutics for treating GBM have been investigated in the setting of phase III clinical trials, including a recent analysis of the immune checkpoint inhibitor, Nivolumab (anti-PD-1), which failed to improve recurrent GBM patient survival. However, rather than abandoning immune checkpoint inhibitor treatment for GBM, which has shown promise in other types of cancer, ongoing studies are currently evaluating this therapeutic class when combined with other agents...
March 2, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sarvenaz Metghalchi, Marie Vandestienne, Yacine Haddad, Bruno Esposito, Julien Dairou, Alain Tedgui, Ziad Mallat, Stephane Potteaux, Soraya Taleb
AIMS: Abdominal aortic aneurysm (AAA) is an age-associated disease characterized by chronic inflammation, vascular cell apoptosis and metalloproteinase-mediated extracellular matrix degradation. Despite considerable progress in identifying targets involved in these processes, therapeutic approaches aiming to reduce aneurysm growth and rupture are still scarce. Indoleamine 2-3 dioxygenase 1 (IDO) is the first and rate-limiting enzyme involved in the conversion of tryptophan (Trp) into kynurenine (Kyn) pathway...
2018: PloS One
Xin Lu, Si-Yu He, Qi Li, Hongyu Yang, Xueyang Jiang, Hongzhi Lin, Yao Chen, Wei Qu, Feng Feng, Yaoyao Bian, You Zhou, Haopeng Sun
In our endeavor towards the development of potent multi-target ligands for the treatment of Alzheimer's disease, miconazole was identified to show BuChE-IDO1 dual-target inhibitory effects. Morris water maze test indicated that miconazole obviously ameliorated the cognitive function impaired by scopolamine. Furthermore, it showed good safety in primary hepatotoxicity evaluation. Based on these results, we designed, synthesized, and evaluated a series of miconazole derivatives as BuChE-IDO1 dual-target inhibitors...
February 13, 2018: Bioorganic & Medicinal Chemistry
Jae Eun Cheong, Anil Ekkati, Lijun Sun
Indoleamine 2,3-dioxygenase 1 (IDO1) is overexpressed by cancer cells and the antigen presenting dendritic cells in the tumor microenvironment (TME). Activation of IDO1 depletes tryptophan and produces kynurenine, which induces T cell anergy and suppresses tumor control by the immune system. When combined with an immune checkpoint inhibitor, IDO1 inhibitors have shown promising anticancer activity in preclinical tumor models as well as in early stage clinical trials. Areas covered: IDO1 inhibitors disclosed in the patent literature from 2013-2017 are categorized, when applicable, according to their structural similarity to the clinical development candidates indoximod and PF-06840003, navoximod, epacadostat, KHK2455 and aryl-1,2-diamines, and BMS-986205 among others, respectively...
February 23, 2018: Expert Opinion on Therapeutic Patents
Michael G Brant, Jake Goodwin-Tindall, Kurt R Stover, Paul M Stafford, Fan Wu, Autumn R Meek, Paolo Schiavini, Stephanie Wohnig, Donald F Weaver
Inhibition of indoleamine 2,3-dioxygenase (IDO1) is an attractive immunotherapeutic approach for the treatment of a variety of cancers. Dysregulation of this enzyme has also been implicated in other disorders including Alzheimer's disease and arthritis. Herein, we report the structure-based design of two related series of molecules: N 1-substituted 5-indoleimidazoles and N 1-substituted 5-phenylimidazoles. The latter (and more potent) series was accessed through an unexpected rearrangement of an imine intermediate during a Van Leusen imidazole synthesis reaction...
February 8, 2018: ACS Medicinal Chemistry Letters
Lilla Hornyák, Nikoletta Dobos, Gábor Koncz, Zsolt Karányi, Dénes Páll, Zoltán Szabó, Gábor Halmos, Lóránt Székvölgyi
Tumors are composed of abnormally transformed cell types and tissues that differ from normal tissues in their genetic and epigenetic makeup, metabolism, and immunology. Molecular compounds that modulate the immune response against neoplasms offer promising new strategies to combat cancer. Inhibitors targeting the indoleamine-2,3-dioxygenase 1 enzyme (IDO1) represent one of the most potent therapeutic opportunities to inhibit tumor growth. Herein, we assess the biochemical role of IDO1 in tumor metabolism and immune surveillance, and review current diagnostic and therapeutic approaches that are intended to increase the effectiveness of immunotherapies against highly aggressive and difficult-to-treat IDO-expressing cancers...
2018: Frontiers in Immunology
George C Prendergast, William J Malachowski, Arpita Mondal, Peggy Scherle, Alexander J Muller
The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization, and metastasis. IDO1 suppresses local CD8+ T effector cells and natural killer cells and induces CD4+ T regulatory cells (iTreg) and myeloid-derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression. Lastly, emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated iTreg and contribute to B-cell inflammed states in certain cancers...
2018: International Review of Cell and Molecular Biology
George C Prendergast, Arpita Mondal, Souvik Dey, Lisa D Laury-Kleintop, Alexander J Muller
We discuss how small-molecule inhibitors of the tryptophan (Trp) catabolic enzyme indoleamine 2,3-dioxygenase (IDO) represent a vanguard of new immunometabolic adjuvants to safely enhance the efficacy of cancer immunotherapy, radiotherapy, or 'immunogenic' chemotherapy by leveraging responses to tumor neoantigens. IDO inhibitors re-program inflammatory processes to help clear tumors by blunting tumor neovascularization and restoring immunosurveillance. Studies of regulatory and effector pathways illuminate IDO as an inflammatory modifier...
January 2018: Trends in Cancer
Barbara Dillinger, Sarah Ahmadi-Erber, Manuel Lau, Markus A Hoelzl, Friedrich Erhart, Birgit Juergens, Dietmar Fuchs, Andreas Heitger, Stephan Ladisch, Alexander M Dohnal
Gangliosides shed by tumors into their microenvironment (TME) are immunoinhibitory. Interferon-γ (IFN-γ) may boost antitumor immune responses. Thus we wondered whether IFN-γ would counteract tumor ganglioside-mediated immune suppression. To test this hypothesis, we exposed human monocyte-derived LPS-activated dendritic cells (DC) to IFN-γ and to a highly purified ganglioside, GD1a. DC ganglioside exposure decreased TLR-dependent p38 signaling, explaining the previously observed ganglioside-induced down-modulation of pro-inflammatory surface markers and cytokines...
February 2, 2018: Cellular Immunology
Alessia Griglio, Enza Torre, Marta Serafini, Alice Bianchi, Roberta Schmid, Giulia Coda Zabetta, Alberto Massarotti, Giovanni Sorba, Tracey Pirali, Silvia Fallarini
Indoleamine 2,3-dioxygenase plays a crucial role in immune tolerance and has emerged as an attractive target for cancer immunotherapy. In this study, the Passerini and Ugi multicomponent reactions have been employed to assemble a small library of imidazothiazoles that target IDO1. While the p-bromophenyl and the imidazothiazole moieties have been kept fixed, a full SAR study has been performed on the side-chain, leading to the discovery of nine compounds with sub-micromolar IC50 values in the enzyme-based assay...
February 2, 2018: Bioorganic & Medicinal Chemistry Letters
David K Williams, Jay A Markwalder, Aaron J Balog, Bin Chen, Libing Chen, Jennifer Donnell, Lauren Haque, Amy C Hart, Sunil K Mandal, Andrew Nation, Weifang Shan, Gregory D Vite, Kelly Covello, John T Hunt, Maria N Jure-Kunkel, Steven P Seitz
A novel series of o-phenylenediamine-based inhibitors of indoleamine 2,3-dioxygenase (IDO) has been identified. IDO is a heme-containing enzyme, overexpressed in the tumor microenvironment of many cancers, which can contribute to the suppression of the host immune system. Synthetic modifications to a previously described diarylether series resulted in an additional degree of molecular diversity which was exploited to afford compounds that demonstrated significant potency in the HeLa human cervical cancer IDO1 assay...
January 11, 2018: Bioorganic & Medicinal Chemistry Letters
Lijie Zhai, Erik Ladomersky, Alicia Lenzen, Brenda Nguyen, Ricky Patel, Kristen L Lauing, Meijing Wu, Derek A Wainwright
Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting metabolic enzyme that converts the essential amino acid tryptophan (Trp) into downstream catabolites known as kynurenines. Coincidently, numerous studies have demonstrated that IDO1 is highly expressed in multiple types of human cancer. Preclinical studies have further introduced an interesting paradox: while single-agent treatment with IDO1 enzyme inhibitor has a negligible effect on decreasing the established cancer burden, approaches combining select therapies with IDO1 blockade tend to yield a synergistic benefit against tumor growth and/or animal subject survival...
January 29, 2018: Cellular & Molecular Immunology
Matthew W Rosenbaum, Benjamin J Gigliotti, Sara I Pai, Sareh Parangi, Heather Wachtel, Mari Mino-Kenudson, Viswanath Gunda, William C Faquin
Poorly differentiated thyroid carcinoma (PDTC) is an aggressive form of thyroid cancer that currently has limited effective treatment options. Immune checkpoint inhibitors (ICIs) have shown to be an effective treatment for a variety of carcinomas. In this study, we explore whether immune checkpoint pathways, such as programmed cell death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1), are activated in a cohort of patients with PDTC to determine whether ICIs may be an effective therapy for these patients...
January 25, 2018: Endocrine Pathology
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