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Tamara Pérez-Jeldres, Christopher J Tyler, Joshua D Boyer, Thangaraj Karuppuchamy, Giorgos Bamias, Parambir S Dulai, Brigid S Boland, William J Sandborn, Derek R Patel, Jesús Rivera-Nieves
After 20 years of successful targeting of pro-inflammatory cytokines for the treatment of IBD, an alternative therapeutic strategy has emerged, based on several decades of advances in understanding the pathogenesis of IBD. The targeting of molecules involved in leukocyte traffic has recently become a safe and effective alternative. With 2 currently approved drugs (ie, natalizumab, vedolizumab) and several others in phase 3 trials (eg, etrolizumab, ozanimod, anti-MAdCAM-1), the blockade of trafficking molecules has firmly emerged as a new therapeutic era for IBD...
August 24, 2018: Inflammatory Bowel Diseases
Z Vrablicova, K Soltys, A Krajcovicova, I Sturdik, T Koller, M Huorka, J Payer, S Stuchlik, Z Killinger, P Jackuliak, M Stuchlikova, H Drahovska, T Hlavaty
The aim of this study was to analyze the influence of 25(OH)VD serum concentration on the expression of mRNA cytokines (IL-6, IL-8, IL-12, IL-17, IL-23, TNFα, CCR1, CCR2, CCR5, CCR9, CCL5, TLR2, TLR4, TLR5, CD207 ,CD206, FoxP3) in mucosa of IBD patients. The cohort consisted of 86 IBD patients (48 CD and 38 UC) followed at the IBD center of University Hospital Bratislava-Ruzinov. We performed colonoscopy in each patient and took biopsies from mucosa of sigma and terminal ileum. Serum concentration of 25(OH)VD was assessed at the time of colonoscopy...
2018: Bratislavské Lekárske Listy
Palak J Trivedi, David H Adams
The principal targets for anti-chemokine therapy in inflammatory bowel disease (IBD) have been the receptors CCR9 and CXCR3 and their respective ligands CCL25 and CXCL10. More recently CCR6 and its ligand CCL20 have also received attention, the expression of the latter in enterocytes being manipulated through Smad7 signalling. These pathways, selected based on their fundamental role in regulating mucosal immunity, have led to the development of several therapeutic candidates that have been tested in early phase clinical trials with variable clinical efficacy...
August 22, 2018: Journal of Crohn's & Colitis
Zongguo Yang, Yuquan Tao, Xin Xu, Feng Cai, Yongchun Yu, Lifang Ma
OBJECTIVE: This study aimed to evaluate functions of APOBEC3F gene in biological process of hepatocellular carcinoma (HCC) and anti-tumor mechanisms of bufalin. METHODS: Effect of APOBEC3F and bufalin on cell proliferation and migration abilities were evaluated by CCK-8, wounding healing tests and transwell assays in SK-Hep1 and Bel-7404 cells. Bioinformatic analysis were also used to compare APOBEC3F expression levels, detect coexpressed genes and enrichment of pathways...
September 10, 2018: Biochemical and Biophysical Research Communications
Cong Wang, Zhenghuan Liu, Zhihui Xu, Xian Wu, Dongyang Zhang, Ziqi Zhang, Jianqin Wei
Chemokine ligand 25 (CCL25) and chemokine receptor 9 (CCR9) are important regulators of migration, proliferation and apoptosis in leukocytes and cancer cells. Blocking of the CCR9/CCL25 signal has been demonstrated to be a potential novel cancer therapy. Research into CCR9 and CCL25 has revealed their associated upstream and downstream signaling pathways; CCR9 is regulated by several immunological factors, including NOTCH, interleukin 2, interleukin 4 and retinoic acid. NOTCH in particular, has been revealed to be a crucial upstream regulator of CCR9...
August 2018: Oncology Letters
Yufei Xia, Jie Wu, Yiqun Du, Chunyu Miao, Zhiguo Su, Guanghui Ma
As peripheral lymphocytes are typically excluded from the gastrointestinal lymph tissues, current parenteral vaccinations fail to simultaneously induce systemic and mucosal responses. To break the natural barrier, "immunoticket" capsules are developed and heralded, which are designed with positive charged shells and oily core to spatiotemporally deliver antigens and all-trans retinoic acid (RA). After intramuscular vaccinations, these capsules function as an immunoticket to cultivate peripheral dendritic cells (DCs) with gut-homing receptors (CCR9)...
August 2018: Advanced Materials
Divyanshu Malhotra, Jimann Shin, Lilianna Solnica-Krezel, Erez Raz
Chemokines are secreted proteins that regulate a range of processes in eukaryotic organisms. Interestingly, different chemokine receptors control distinct biological processes, and the same receptor can direct different cellular responses, but the basis for this phenomenon is not known. To understand this property of chemokine signaling, we examined the function of the chemokine receptors Cxcr4a, Cxcr4b, Ccr7, Ccr9 in the context of diverse processes in embryonic development in zebrafish. Our results reveal that the specific response to chemokine signaling is dictated by cell-type-specific chemokine receptor signal interpretation modules (CRIM) rather than by chemokine-receptor-specific signals...
June 6, 2018: ELife
Francesco Ciccia, Giuliana Guggino, Michael Zeng, Ranjeny Thomas, Vidya Ranganathan, Arifur Rahman, Riccardo Alessandro, Aroldo Rizzo, Laura Saieva, Federica Macaluso, Sergio Peralta, Diana Di Liberto, Francesco Dieli, Paola Cipriani, Roberto Giacomelli, Dominique Baeten, Nigil Haroon
OBJECTIVE: Gut derived ILC3 have been demonstrated to participate in AS pathogenesis. CX3CR1+ mononuclear phagocytes (MNP) have been demonstrated to modulate ILC3 function in the gut. The aim of this study was to study the role of pro-inflammatory CX3CR1+ CD59+ MNP in modulating ILC3 function in AS patients. METHODS: MNP subsets in blood were analysed by flow cytometry in AS patients and controls. Tissue presence of CX3CR1+ CD59+ cells was confirmed by confocal microscopy...
June 5, 2018: Arthritis & Rheumatology
Mpala Mwanza-Lisulo, Mumba S Chomba, Mubanga Chama, Ellen C Besa, Evelyn Funjika, Kanekwa Zyambo, Rose Banda, Mercy Imikendu, Sandie Sianongo, Robert E W Hancock, Amy Lee, Roma Chilengi, Andy J Stagg, Boniface Namangala, Paul M Kelly
All-trans retinoic acid (ATRA) up-regulates, in laboratory animals, the expression of the gut homing markers α4β7 integrin and CCR9 on lymphocytes, increasing their gut tropism. Here, we show that, in healthy adult volunteers, ATRA induced an increase of these gut homing markers on T cells in vivo in a time dependent manner. The coordinated increase of α4β7 and CCR9 by ATRA was seen in 57% (12/21) of volunteers and only when given together with an oral Vivotif vaccine. When this coordinated response to ATRA and Vivotif vaccine was present, it was strongly correlated with the gut immunoglobulin A (IgA) specific response to vaccine LPS (ρ = 0...
June 27, 2018: Vaccine
Emilie J Cosway, Izumi Ohigashi, Karin Schauble, Sonia M Parnell, William E Jenkinson, Sanjiv Luther, Yousuke Takahama, Graham Anderson
During αβ T cell development in the thymus, migration of newly selected CD4+ and CD8+ thymocytes into medullary areas enables tolerance mechanisms to purge the newly selected αβ TCR repertoire of autoreactive specificities. Thymic dendritic cells (DC) play key roles in this process and consist of three distinct subsets that differ in their developmental origins. Thus, plasmacytoid DC and Sirpα+ conventional DC type 2 are extrathymically derived and enter into the thymus via their respective expression of the chemokine receptors CCR9 and CCR2...
July 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
R E Hoeppli, K N MacDonald, P Leclair, V C W Fung, M Mojibian, J Gillies, S M R Rahavi, A I M Campbell, S K Gandhi, A M Pesenacker, G Reid, C J Lim, M K Levings
Cell-based therapy with CD4+ FOXP3+ regulatory T cells (Tregs) is a promising strategy to limit organ rejection and graft-vs-host disease. Ongoing clinical applications have yet to consider how human Tregs could be modified to direct their migration to specific inflammation sites and/or tissues for more targeted immunosuppression. We show here that stable, homing-receptor-tailored human Tregs can be generated from thymic Tregs isolated from pediatric thymus or adult blood. To direct migration to Th1-inflammatory sites, addition of interferon-γ and IL-12 during Treg expansion produced suppressive, epigenetically stable CXCR3+ TBET+ FOXP3+ T helper (Th)1-Tregs...
May 15, 2018: American Journal of Transplantation
Keiko Igaki, Yusaku Komoike, Yoshiki Nakamura, Takeshi Watanabe, Masashi Yamasaki, Paul Fleming, Lili Yang, Dulce Soler, Eric Fedyk, Noboru Tsuchimori
C-C chemokine receptor 9 (CCR9) is the homing receptor for C-C motif chemokine ligand 25 (CCL25), and contributes to the maintenance of mucosal immunity and pathogenesis of inflammatory bowel disease (IBD) through the recruitment of T cells into the gut mucosa. Recent reports suggest that the interaction of CCR9 and CCL25 in the large intestine correlate with disease severity of colonic IBD. MLN3126 is an orally available small molecular compound with potent and selective CCR9 antagonist activity. MLN3126 inhibited CCL25-induced calcium mobilization in human CCR9 transfected cells and CCL25-induced chemotaxis of mouse primary thymocytes in a dose-dependent manner...
July 2018: International Immunopharmacology
Satoshi Koga, Katsuto Hozumi, Ken-Ichi Hirano, Masaki Yazawa, Tommy Terooatea, Aki Minoda, Takashi Nagasawa, Shigeo Koyasu, Kazuyo Moro
Group 2 innate lymphoid cells (ILC2s) are derived from common lymphoid progenitors (CLPs) via several specific precursors, and the transcription factors essential for ILC2 differentiation have been extensively studied. However, the external factors regulating commitment to the ILC lineage as well as the sites and stromal cells that constitute the optimal microenvironment for ILC2-specific differentiation are not fully defined. In this study, we demonstrate that three key external factors, the concentration of interleukin 7 (IL-7) and strength and duration of Notch signaling, coordinately determine the fate of CLP toward the T, B, or ILC lineage...
June 4, 2018: Journal of Experimental Medicine
Erich Piovan, Valeria Tosello, Alberto Amadori, Paola Zanovello
The NOTCH signaling pathway is a conserved signaling cascade that regulates many aspects of development and homeostasis in multiple organ systems. Aberrant activity of this signaling pathway is linked to the initiation and progression of several hematological malignancies, exemplified by T-cell acute lymphoblastic leukemia (T-ALL). Interestingly, frequent non-mutational activation of NOTCH1 signaling has recently been demonstrated in B-cell chronic lymphocytic leukemia (B-CLL), significantly extending the pathogenic significance of this pathway in B-CLL...
2018: Frontiers in Immunology
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...
April 2018: Journal of Computer-aided Molecular Design
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
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
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...
July 2018: Mucosal Immunology
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
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
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