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https://www.readbyqxmd.com/read/29582229/in-silico-guided-discovery-of-novel-ccr9-antagonists
#1
Xin Zhang, Jason B Cross, Jan Romero, Alexander Heifetz, Eric Humphries, Katie Hall, Yuchuan Wu, Sabrina Stucka, Jing Zhang, Haoqun Chandonnet, Blaise Lippa, M Dominic Ryan, J Christian Baber
Antagonism of CCR9 is a promising mechanism for treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. There is limited experimental data on CCR9 and its ligands, complicating efforts to identify new small molecule antagonists. We present here results of a successful virtual screening and rational hit-to-lead campaign that led to the discovery and initial optimization of novel CCR9 antagonists. This work uses a novel data fusion strategy to integrate the output of multiple computational tools, such as 2D similarity search, shape similarity, pharmacophore searching, and molecular docking, as well as the identification and incorporation of privileged chemokine fragments...
March 26, 2018: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29523306/validation-of-runx1-as-a-potential-target-for-treating-circadian-clock-induced-obesity-through-preventing-migration-of-group-3-innate-lymphoid-cells-into-intestine
#2
Fangjia Lu, Qingyang Liu
The impact of unrhythmic circadian clock on obesity has started to be increasingly appreciated nowadays. Recently it was discovered that interaction between intestinal microbiota and unrhythmic circadian clock plays a key role in such a process. It involves relaying signals from microbiota through dendritic cells to group 3 innate lymphoid cells in the intestine and in the end impacting some of the key transcription factors of circadian clock. Breaking such a signal relay may prove to be an effective way reducing unrhythmic circadian clock-induced obesity...
April 2018: Medical Hypotheses
https://www.readbyqxmd.com/read/29483908/cow-s-milk-and-immune-function-in-the-respiratory-tract-potential-mechanisms
#3
REVIEW
Olaf Perdijk, Marloes van Splunter, Huub F J Savelkoul, Sylvia Brugman, R J Joost van Neerven
During the last decades, the world has witnessed a dramatic increase in allergy prevalence. Epidemiological evidence shows that growing up on a farm is a protective factor, which is partly explained by the consumption of raw cow's milk. Indeed, recent studies show inverse associations between raw cow's milk consumption in early life and asthma, hay fever, and rhinitis. A similar association of raw cow's milk consumption with respiratory tract infections is recently found. In line with these findings, controlled studies in infants with milk components such as lactoferrin, milk fat globule membrane, and colostrum IgG have shown to reduce respiratory infections...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29467446/oral-cholera-vaccination-promotes-homing-of-iga-memory-b-cells-to-the-large-intestine-and-the-respiratory-tract
#4
M van Splunter, E van Hoffen, E G Floris-Vollenbroek, H Timmerman, E Lucas-van de Bos, B Meijer, L H Ulfman, B Witteman, J M Wells, S Brugman, H F J Savelkoul, R J J van Neerven
Oral cholera vaccination is used to induce immune responses in the intestines to protect against cholera infection. However, oral vaccination may also affect immune responses in other mucosal tissues. To study this, tissue-specific homing potential and kinetics of B-cell responses were characterized after oral cholera vaccination. Healthy adult volunteers received two doses of Dukoral® and blood, saliva, nasal wash, and fecal samples were collected over time to detect vaccine-specific antibodies. Additionally, homing potential of lymphocytes to small intestine, colon, airways, skin, and periphery was measured by expression of Integrin β1 and β7, CCR9, CCR10, CCR7, and CLA...
February 21, 2018: Mucosal Immunology
https://www.readbyqxmd.com/read/29434597/92r-monoclonal-antibody-inhibits-human-ccr9-leukemia-cells-growth-in-nsg-mice-xenografts
#5
Beatriz Somovilla-Crespo, Maria Teresa Martín Monzón, Maria Vela, Isabel Corraliza-Gorjón, Silvia Santamaria, Jose A Garcia-Sanz, Leonor Kremer
CCR9 is as an interesting target for the treatment of human CCR9+-T cell acute lymphoblastic leukemia, since its expression is limited to immature cells in the thymus, infiltrating leukocytes in the small intestine and a small fraction of mature circulating T lymphocytes. 92R, a new mouse mAb (IgG2a isotype), was raised using the A-isoform of hCCR9 as immunogen. Its initial characterization demonstrates that binds with high affinity to the CCR9 N-terminal domain, competing with the previously described 91R mAb for receptor binding...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29343500/cbf%C3%AE-2-controls-differentiation-of-and-confers-homing-capacity-to-prethymic-progenitors
#6
Mari Tenno, Satoshi Kojo, Divine-Fondzenyuy Lawir, Isabell Hess, Katsuyuki Shiroguchi, Takashi Ebihara, Takaho A Endo, Sawako Muroi, Rumi Satoh, Hiroshi Kawamoto, Thomas Boehm, Ichiro Taniuchi
Multipotent hematopoietic progenitors must acquire thymus-homing capacity to initiate T lymphocyte development. Despite its importance, the transcriptional program underlying this process remains elusive. Cbfβ forms transcription factor complexes with Runx proteins, and here we show that Cbfβ2, encoded by an RNA splice variant of the Cbfb gene, is essential for extrathymic differentiation of T cell progenitors. Furthermore, Cbfβ2 endows extrathymic progenitors with thymus-homing capacity by inducing expression of the principal thymus-homing receptor, Ccr9...
January 17, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29338773/chemokine-ligand-receptor-interactions-critically-regulate-cutaneous-wound-healing
#7
Erich Bünemann, Norman-Philipp Hoff, Bettina Alexandra Buhren, Ulrike Wiesner, Stephan Meller, Edwin Bölke, Anja Müller-Homey, Robert Kubitza, Thomas Ruzicka, Albert Zlotnik, Bernhard Homey, Peter Arne Gerber
BACKGROUND: Wound healing represents a dynamic process involving directional migration of different cell types. Chemokines, a family of chemoattractive proteins, have been suggested to be key players in cell-to-cell communication and essential for directed migration of structural cells. Today, the role of the chemokine network in cutaneous wound healing is not fully understood. Unraveling the chemokine-driven communication pathways in this complex process could possibly lead to new therapeutic strategies in wound healing disorders...
January 16, 2018: European Journal of Medical Research
https://www.readbyqxmd.com/read/29315632/food-allergen-sensitized-ccr9-lymphocytes-enhance-airways-allergic-inflammation-in-mice
#8
L Castan, M-A Cheminant, L Colas, S Brouard, A Magnan, G Bouchaud
BACKGROUND: The mechanisms of the atopic march, characterized by a natural progression from food and cutaneous allergies to rhinitis and asthma, are still unknown. However, as several organs can be involved, chemokines and their receptors might be implicated in this process and may be instrumental factors. OBJECTIVES: We hypothesized that the T-cell gut-homing receptor CCR9 could be implicated in the evolution of allergic diseases. METHODS: We characterized the immune response and the role of CCR9 in a murine model combining food allergy to wheat gliadin and a model of acute airways inflammation in response to house dust mite...
January 9, 2018: Allergy
https://www.readbyqxmd.com/read/29163684/novel-peptide-screened-from-a-phage-display-library-antagonizes-the-activity-of-cc-chemokine-receptor-9
#9
Yi Hu, Aiping Ma, Shan Lin, Yang Yang, Guolin Hong
CC chemokine receptor 9 (CCR9) serves a role in the drug resistance and metastasis of tumors. In the present study, a peptide specifically bound to CCR9 was obtained and the effect on tumor cells was observed. A Ph.D.-12 phage display peptide library was used to screen for peptides binding specifically to the second extracellular loop of CCR9. The ratios of the input and output of phage clones increased gradually following three rounds of biopanning. A total of 8 positive phage clones were identified from DNA analysis...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29154408/chemokine-c-c-motif-ligand-25-expressed-by-trophoblast-cells-and-leukocytes-bearing-its-receptor-ccr9-an-alliance-during-embryo-implantation
#10
Rodrigo Barbano Weingrill, Mara S Hoshida, Ciro Dresch Martinhago, Simone Correa-Silva, Elaine Cardoso, Patrícia Palmeira, Claudio Romero Farias Marinho, Estela Bevilacqua
PROBLEM: We hypothesized that trophoblast expression of Ccl25 attracts a specific leukocyte cell population to the implantation site for local regulation. METHOD OF STUDY: Mice blastocysts, ectoplacental cones, and decidua at gestational days 3.5-7.5 were evaluated for Ccl25 and Ccr9 expressions. Peripheral availability and characterization of Ccr9+ leukocytes were determined by flow cytometry. Leukocyte chemotaxis was assessed in the presence of Ccl25 recombinant protein and embryos using antisense oligomers (ODNs) to Ccl25 and Ccr9 neutralizing antibody...
January 2018: American Journal of Reproductive Immunology: AJRI
https://www.readbyqxmd.com/read/29106985/the-chemokine-receptor-ccr2-maintains-plasmacytoid-dendritic-cell-homeostasis
#11
Oriane Cédile, Line Østerby Jørgensen, Ida Frank, Agnieszka Wlodarczyk, Trevor Owens
Thymic dendritic cells (DC) play a role in central tolerance. Three thymic DC subtypes have been described: plasmacytoid DC (pDC) and two conventional DC (cDC), CD8α(+) Sirpα(-) DC and Sirpα(+) CD8α(-) cDC. Both pDC and Sirpα(+) cDC can take up antigen in periphery and migrate into the thymus in response to chemokine signaling via CCR9 and CCR2 respectively. CCL2 is a major ligand for CCR2 and we previously showed that it was constitutively expressed in thymus, and that mice overexpressing CCL2 in thymus had reduced numbers of autoreactive T cells but elevated numbers of pDC...
October 26, 2017: Immunology Letters
https://www.readbyqxmd.com/read/29097494/gut-microbiome-influences-efficacy-of-pd-1-based-immunotherapy-against-epithelial-tumors
#12
Bertrand Routy, Emmanuelle Le Chatelier, Lisa Derosa, Connie P M Duong, Maryam Tidjani Alou, Romain Daillère, Aurélie Fluckiger, Meriem Messaoudene, Conrad Rauber, Maria P Roberti, Marine Fidelle, Caroline Flament, Vichnou Poirier-Colame, Paule Opolon, Christophe Klein, Kristina Iribarren, Laura Mondragón, Nicolas Jacquelot, Bo Qu, Gladys Ferrere, Céline Clémenson, Laura Mezquita, Jordi Remon Masip, Charles Naltet, Solenn Brosseau, Coureche Kaderbhai, Corentin Richard, Hira Rizvi, Florence Levenez, Nathalie Galleron, Benoit Quinquis, Nicolas Pons, Bernhard Ryffel, Véronique Minard-Colin, Patrick Gonin, Jean-Charles Soria, Eric Deutsch, Yohann Loriot, François Ghiringhelli, Gérard Zalcman, François Goldwasser, Bernard Escudier, Matthew D Hellmann, Alexander Eggermont, Didier Raoult, Laurence Albiges, Guido Kroemer, Laurence Zitvogel
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so...
January 5, 2018: Science
https://www.readbyqxmd.com/read/29077981/tissue-specific-differences-in-immune-cell-subsets-located-in-the-naso-oropharyngeal-associated-lymphoid-tissues
#13
M Bankvall, M Jontell, A Wold, S Östman
Defining the immune cells within the naso-oropharyngeal-associated lymphoid tissues would promote the development of efficient orally and nasally delivered immunotherapies. The aim was to compare murine antigen-presenting cells (APCs) and T cell subsets in the nose-associated lymphoid tissues (NALT), cervical lymph nodes (CLN), mesenteric lymph nodes (MLN) and peripheral lymph nodes (PLN) using flow cytometry and in vitro proliferation assays. Overall, the NALT contained a higher proportion of APCs and a lower proportion of T cells compared to the CLN, MLN and PLN...
January 2018: Scandinavian Journal of Immunology
https://www.readbyqxmd.com/read/29073082/transcription-factor-isx-mediates-the-cross-talk-between-diet-and-immunity
#14
Made Airanthi K Widjaja-Adhi, Grzegorz Palczewski, Kali Dale, Elizabeth A Knauss, Mary E Kelly, Marcin Golczak, Alan D Levine, Johannes von Lintig
The intestinal epithelium is a major site for the conversion of dietary β-carotene to retinaldehyde by the enzyme BCO1. The majority of retinaldehyde is further metabolized to retinol (vitamin A), esterified and packaged into triacylglycerol-rich chylomicrons for bodily distribution. Some serve on-site for the synthesis of retinoic acid, a hormone-like compound, which exerts pleiotropic and dominant effects on gastrointestinal immunity. We report here that the intestine-specific homeobox protein ISX is critical to control the metabolic flow of β-carotene through this important branching point of vitamin A metabolism...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29020986/colorectal-cancer-infiltrating-t-lymphocytes-display-a-distinct-chemokine-receptor-expression-profile
#15
Ann-Britt Löfroos, Mohammad Kadivar, Sabina Resic Lindehammer, Jan Marsal
BACKGROUND: T lymphocytes exert important homeostatic functions in the healthy intestinal mucosa, whereas in case of colorectal cancer (CRC), infiltration of T lymphocytes into the tumor is crucial for an effective anti-tumor immune response. In both situations, the recruitment mechanisms of T lymphocytes into the tissues are essential for the immunological functions deciding the outcome. The recruitment of T lymphocytes is largely dependent on their expression of various chemokine receptors...
October 11, 2017: European Journal of Medical Research
https://www.readbyqxmd.com/read/28986277/upregulation-of-peripheral-cxc-and-cc-chemokine-receptor-expression-on-cd4-t-cells-is-associated-with-immune-dysregulation-in-children-with-autism
#16
Sheikh F Ahmad, Mushtaq A Ansari, Ahmed Nadeem, Saleh A Bakheet, Laila Yousef Al-Ayadhi, Sabry M Attia
Autism spectrum disorders (ASD) are characterized by disturbances in social interactions and communication, restricted repetitive interests, and stereotyped behavior. Cumulative evidence recommends that there are immune alterations in ASD. Chemokine receptors are known to play an important role in the central nervous system (CNS) and in many neuro inflammatory disorders. The main objective of this study was to explore the role of CXC and CC chemokine receptors signaling in children with autism. We examined chemokine receptor production of CXCR2, CXCR3, CXCR5, and CXCR7 in all peripheral blood mononuclear cells (PBMCs) and in CD4(+) T cells of typically developing control children (TD) and autistic children (AU)...
October 3, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/28961803/anti-madcam-antibody-increases-%C3%A3-7-t-cells-and-ccr9-gene-expression-in-the-peripheral-blood-of-patients-with-crohn-s-disease
#17
Mina Hassan-Zahraee, Anindita Banerjee, John B Cheng, Weidong Zhang, Alaa Ahmad, Karen Page, David von Schack, Baohong Zhang, Steven W Martin, Satyaprakash Nayak, Padma Reddy, Li Xi, Hendrik Neubert, Mireia Fernandez Ocana, Ken Gorelick, Robert Clare, Michael Vincent, Fabio Cataldi, Kenneth Hung
Objective: To define pharmacodynamic biomarkers in the peripheral blood of patients with Crohn's disease [CD] after treatment with PF-00547659, an anti-human mucosal addressin cell adhesion molecule-1 [MAdCAM-1] monoclonal antibody. Methods: In this Phase 2, randomised, double-blind, controlled study [OPERA], blood samples were analysed from patients with moderate to severe active CD who received placebo or 22.5 mg, 75 mg, or 225 mg of PF-00547659 subcutaneously at baseline and at Weeks 4 and 8, with follow-up at Week 12...
January 5, 2018: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/28951425/differential-t-cell-homing-to-colon-vs-small-intestine-is-imprinted-by-local-cd11c-apcs-that-determine-homing-receptors
#18
Amiran Dzutsev, Alison Hogg, Yongjun Sui, Shahram Solaymani-Mohammadi, Huifeng Yu, Blake Frey, Yichuan Wang, Jay A Berzofsky
Mechanisms that imprint T cell homing to the small intestine have been well studied; however, those for homing to the colon are poorly understood. Recently, we found that these are distinct subcompartments of the gut mucosal immune system, which implies differential homing. Here, we show that colonic CD11c+ APCs imprint CD8+ T cell preferential homing to the colon, in contrast to those from the small intestine that imprint CD8+ T cell homing to the small intestine, and that the differences are related to the variable ability of APCs to induce α4β7-integrin and CCR9 expression on T cells...
December 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28903065/inflammation-polymorphisms-and-prostate-cancer-risk-in-jamaican-men-role-of-obesity-body-size
#19
Bhawna Dubey, Maria D Jackson, Charnita Zeigler-Johnson, Karthik Devarajan, Rafael E Flores-Obando, Norma McFarlane-Anderson, Marshall K Tulloch-Reid, William Aiken, Kevin Kimbro, Dominique Z Jones, LaCreis R Kidd, Camille Ragin
African ancestry and obesity are associated with higher risk of prostate cancer (PC). In a pilot study, we explored interactions between obesity (as measured by waist to hip ratio (WHR)) and inflammatory SNPs in relation to PC risk among Jamaican men. This study evaluated 87 chemokine and cytokine associated SNPs in obese and normal weight cases (N=109) and controls (N=102) using a stepwise penalized logistic regression approach in multivariable analyses. Upon stratification by WHR (normal weight (WHR<0...
December 15, 2017: Gene
https://www.readbyqxmd.com/read/28833046/ahr-activation-increases-il-2-production-by-alloreactive-cd4-t-cells-initiating-the-differentiation-of-mucosal-homing-tim3-lag3-tr1-cells
#20
Allison K Ehrlich, Jamie M Pennington, Susan Tilton, Xisheng Wang, Nikki B Marshall, Diana Rohlman, Castle Funatake, Sumit Punj, Edmond O'Donnell, Zhen Yu, Siva K Kolluri, Nancy I Kerkvliet
Activation of the aryl hydrocarbon receptor (AhR) by immunosuppressive ligands promotes the development of regulatory T (Treg) cells. Although AhR-induced Foxp3+ Treg cells have been well studied, much less is known about the development and fate of AhR-induced Type 1 Treg (AhR-Tr1) cells. In the current study, we identified the unique transcriptional and functional changes in murine CD4+ T cells that accompany the differentiation of AhR-Tr1 cells during the CD4+ T-cell-dependent phase of an allospecific cytotoxic T lymphocyte (allo-CTL) response...
November 2017: European Journal of Immunology
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