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Zhou Zhou, Ming-Jiang Xu, Yan Cai, Wei Wang, Joy X Jiang, Zoltan V Varga, Dechun Feng, Pal Pacher, George Kunos, Natalie J Torok, Bin Gao
Background & Aims: Hepatic infiltration of neutrophils is a hallmark of steatohepatitis; however, the role of neutrophils in the progression of steatohepatitis remains unknown. Methods: A clinically relevant mouse model of steatohepatitis induced by high-fat diet (HFD) plus binge ethanol feeding was used. Liver fibrosis was examined. In vitro cell culture was used to analyze the interaction of hepatic stellate cells (HSCs) and neutrophils. Results: HFD plus one binge ethanol (HFD+1B) feeding induced significant hepatic neutrophil infiltration, liver injury, and fibrosis...
March 2018: Cellular and Molecular Gastroenterology and Hepatology
Lucía Fernández, Alejandra Leivas, Jaime Valentín, Adela Escudero, Dolores Corral, Raquel de Paz, Maria Vela, David Bueno, Rebeca Rodríguez, Juan Manuel Torres, Mariana Díaz-Almirón, Eduardo López-Collazo, Joaquin Martinez-Lopez, Antonio Pérez-Martínez
BACKGROUND: Cancer immunotherapy involving natural killer (NK) cells has gained interest. Here we report two methods to obtain interleukin (IL)-15-activated NK cells for clinical use. STUDY DESIGN AND METHODS: IL-15-activated NK cell products were obtained after 1) enrichment from healthy haploidentical donors' peripheral blood mononuclear cells (PBMNCs) collected by nonmobilized apheresis by a two-step magnetic procedure, depletion of CD3+ cells followed by selection of CD56+ cells and ex vivo overnight stimulation with IL-15 (NKIL15); and 2) expansion using the K562-mb15-41BBL cell line (NKAE), from autologous PBMNCs from patients with multiple myeloma or expansion from healthy haploidentical PBMNCs obtained from whole blood using the same previous cell line...
March 14, 2018: Transfusion
Pilvi Laurikka, Katri Lindfors, Mikko Oittinen, Heini Huhtala, Teea Salmi, Marja-Leena Lähdeaho, Tuire Ilus, Markku Mäki, Katri Kaukinen, Kalle Kurppa
GOALS: The aim of this study was to investigate the role of dietary factors, distinct small-bowel mucosal immune cell types, and epithelial integrity in the perpetuation of gastrointestinal symptoms in treated celiac disease patients. BACKGROUND: For unexplained reasons, many celiac disease patients suffer from persistent symptoms, despite a strict gluten-free diet (GFD) and recovered intestinal mucosa. STUDY: We compared clinical and serological data and mucosal recovery in 22 asymptomatic and 25 symptomatic celiac patients on a long-term GFD...
March 2, 2018: Journal of Clinical Gastroenterology
Johannes Fessler, Rusmir Husic, Verena Schwetz, Elisabeth Lerchbaum, Felix Aberer, Patrizia Fasching, Anja Ficjan, Barbara Obermayer-Pietsch, Christina Duftner, Winfried Graninger, Martin Helmut Stradner, Christian Dejaco
Objective: T-cells are critical players in the pathogenesis of osteoporosis in patients with rheumatoid arthritis (RA). Premature senescence of lymphocytes including the accumulation of senescent CD4+ T-cells is a hallmark feature of RA. Whether T-cell senescence is associated with bone loss in RA patients is elusive so far. Methods: This includes a prospective study of consecutive patients with RA ( n  = 107), patients with primary osteopenia/-porosis ( n  = 75), and healthy individuals ( n  = 38)...
2018: Frontiers in Immunology
Cristina Bergamaschi, Dionysios C Watson, Antonio Valentin, Jenifer Bear, Cody J Peer, William D Figg, Barbara K Felber, George N Pavlakis
The common γ-chain cytokine interleukin-15 (IL-15) plays a significant role in regulating innate and adaptive lymphocyte homeostasis and can stimulate anti-tumor activity of leukocytes. We have previously shown that the circulating IL-15 in the plasma is the heterodimeric form (hetIL-15), produced upon co-expression of IL-15 and IL-15 Receptor alpha (IL-15Rα) polypeptides in the same cell, heterodimerization of the two chains and secretion. We investigated the pharmacokinetic and pharmacodynamic profile and toxicity of purified human hetIL-15 cytokine upon injection in rhesus macaques...
February 2, 2018: Cytokine
Gabriela M Webb, Shengbin Li, Gwantwa Mwakalundwa, Joy M Folkvord, Justin M Greene, Jason S Reed, Jeffery J Stanton, Alfred W Legasse, Theodore Hobbs, Lauren D Martin, Byung S Park, James B Whitney, Emily K Jeng, Hing C Wong, Douglas F Nixon, R Brad Jones, Elizabeth Connick, Pamela J Skinner, Jonah B Sacha
Sequestering of latent HIV in follicular helper T cells within B-cell follicles that largely exclude cytotoxic T cells is a major barrier to cellular immune-based approaches to eradicate HIV. Here, we show that the clinical-grade human interleukin-15 (IL-15) superagonist ALT-803 activates and redirects simian immunodeficiency virus (SIV)-specific CD8+ T cells from the peripheral blood into B-cell follicles. In agreement with the increased trafficking of SIV-specific cytotoxic T cells to sites of cryptic viral replication, lymph nodes of elite controlling macaques contained fewer cells expressing SIV RNA or harboring SIV DNA post-ALT-803 treatment...
January 23, 2018: Blood Advances
Maria Carmen Ochoa, Luna Minute, Ascensión López, Elisabeth Pérez-Ruiz, Celia Gomar, Marcos Vasquez, Susana Inoges, Iñaki Etxeberria, Inmaculada Rodriguez, Saray Garasa, Jan-Peter Andreas Mayer, Peter Wirtz, Ignacio Melero, Pedro Berraondo
Enhancement of antibody-dependent cellular cytotoxicity (ADCC) may potentiate the antitumor efficacy of tumor-targeted monoclonal antibodies. Increasing the numbers and antitumor activity of NK cells is a promising strategy to maximize the ADCC of standard-of-care tumor-targeted antibodies. For this purpose, we have preclinically tested a recombinant chimeric protein encompassing the sushi domain of the IL15Rα, IL-15, and apolipoprotein A-I (Sushi-IL15-Apo) as produced in CHO cells. The size-exclusion purified monomeric fraction of this chimeric protein was stable and retained the IL-15 and the sushi domain bioactivity as measured by CTLL-2 and Mo-7e cell proliferation and STAT5 phosphorylation in freshly isolated human NK and CD8+ T cells...
2018: Oncoimmunology
Jun-Ying Ding, Zhi-Hua Wang, Zheng-Zheng Zhang, Xu-Ran Cui, Yan-Ying Hong, Qing-Quan Liu
Interleukin 15 (IL-15) is a cytokine exhibiting antitumor characteristic similar to that of IL-2. However, in human tissues and cells, IL-15 expression and secretion is very limited, suggesting IL-15 functions mainly intracellularly. In the present study, we assessed the effects of transfecting NCI-H446 small cell lung cancer cells with genes encoding three IL-15 variants: prototypical IL-15, mature IL-15 peptide, and modified IL-15 in which the IL-2 signal peptide is substituted for the native signal peptide...
December 8, 2017: Oncotarget
Stefano Garofalo, Alessandra Porzia, Fabrizio Mainiero, Silvia Di Angelantonio, Barbara Cortese, Bernadette Basilico, Francesca Pagani, Giorgio Cignitti, Giuseppina Chece, Roberta Maggio, Eve Tremblay, Julie Savage, Kanchan Bisht, Vincenzo Esposito, Giovanni Bernardini, Thomas Seyfried, Jakub Mieczkowski, Karolina Stepniak, Bozena Kaminska, Angela Santoni, Cristina Limatola
In glioma, microglia and infiltrating macrophages are exposed to factors that force them to produce cytokines and chemokines, contributing to tumor growth and maintaining a pro-tumorigenic, immunosuppressed microenvironment. We demonstrate that housing glioma-bearing mice in enriched environment (EE) reverts the immunosuppressive phenotype of infiltrating myeloid cells, by modulating inflammatory gene expression. Under these conditions, branching and patrolling activity of myeloid cells is increased, and their phagocytic activity is promoted...
December 29, 2017: ELife
Ikumi Katano, Chiyoko Nishime, Ryoji Ito, Tsutomu Kamisako, Takuma Mizusawa, Yuyo Ka, Tomoyuki Ogura, Hiroshi Suemizu, Yutaka Kawakami, Mamoru Ito, Takeshi Takahashi
We generated a novel mouse strain expressing transgenic human interleukin-15 (IL-15) using the severe immunodeficient NOD/Shi-scid-IL-2Rγnull (NOG) mouse genetic background (NOG-IL-15 Tg). Human natural killer (NK) cells, purified from the peripheral blood (hu-PB-NK) of normal healthy donors, proliferated when transferred into NOG-IL-15 Tg mice. In addition, the cell number increased, and the hu-PB-NK cells persisted for 3 months without signs of xenogeneic graft versus host diseases (xGVHD). These in vivo-expanded hu-PB-NK cells maintained the original expression patterns of various surface antigens, including NK receptors and killer cell immunoglobulin-like receptor (KIR) molecules...
December 8, 2017: Scientific Reports
Jeffrey S Miller, Chihiro Morishima, Douglas G McNeel, Manish R Patel, Holbrook E K Kohrt, John A Thompson, Paul M Sondel, Heather A Wakelee, Mary L Disis, Judith C Kaiser, Martin A Cheever, Howard Streicher, Steven P Creekmore, Thomas A Waldmann, Kevin C Conlon
Purpose: Preclinical data established IL15 as a homeostatic factor and powerful stimulator of NK and CD8+ T-cell function, the basis for clinical testing. Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday-Friday) subcutaneous injections of rhIL15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL15 and immune biomarkers were evaluated...
December 4, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Rebecca Kohnken, Jing Wen, Bethany Mundy-Bosse, Kathleen McConnell, Ashleigh Keiter, Leah Grinshpun, Alex Hartlage, Max Yano, Betina McNeil, Nitin Chakravarti, Basem William, James E Bradner, Michael A Caligiuri, Pierluigi Porcu, Anjali Mishra
MicroRNA (miRNA) dysregulation is a hallmark of cutaneous T-cell lymphoma (CTCL), an often-fatal malignancy of skin-homing CD4+ T cells for which there are few effective therapies. The role of microRNAs (miRs) in controlling epigenetic modifier-dependent transcriptional regulation in CTCL is unknown. In this study, we characterize a novel miR dysregulation that contributes to overexpression of the epigenetic reader bromodomain-containing protein 4 (BRD4). We used patient CD4+ T cells to show diminished levels of miR-29b compared with healthy donor cells...
February 15, 2018: Blood
Joo Young Huh
Exercise has beneficial effects in ameliorating metabolic disorders, and a combined therapeutic regimen of regular exercise and pharmaceutical treatment is often recommended. Exercise biology is complex and it involves various metabolic and molecular changes that translate into changes in substrate utilization, enzyme activation, and alternatively, improvement in exercise performance. Besides the effect of exercise on muscle metabolism, it has recently been discovered that contracting muscle can induce secretion of molecules called myokines...
January 2018: Archives of Pharmacal Research
D He, Z Jiang, Y Tian, H Han, M Xia, W Wei, L Zhang, J Chen
Intramuscular fat (IMF) content is a key aspect of pork quality. Elucidation of intramuscular adipocyte regulation mechanisms is important for improving IMF content. Intramuscular adipocytes are dispersed among muscle fibers, so they are inclined to be affected by muscle-derived factors. Interleukin-15 is a major muscle-secreted factor. In this study, the genetic and physiological impacts of IL15 on adipogenesis is investigated. The promoter region of IL15 was scanned by comparative sequencing using two DNA pools of high- and low-IMF individuals...
November 22, 2017: Animal Genetics
Renfang Han, Xiao Yang, Mengya Chen, Xu Zhang, Yaping Yuan, Xingxing Hu, Mengmeng Wang, Rui Liu, Yubo Ma, Jiajia Yang, Shengqian Xu, Zongwen Shuai, Shanqun Jiang, Faming Pan
The aim of our study was to explore the relationship between circulating T cells and ankylosing spondylitis (AS) and to find the role of the CD8+CD122+ T cells in the pathogenesis and progression of AS. With the method of case-control design, flow cytometry was performed to quantitatively determine the percentage of circulating CD8(+)CD122(+) T cells in peripheral blood mononuclear cells from established AS patients and age- and gender-matched healthy controls. Serum levels of inflammatory cytokines like interleukin-2, interleukin-10, interleukin-15, TGF-β1, and TNF-ɑ were detected by enzyme-linked immunosorbent assay...
November 6, 2017: Clinical Rheumatology
Jian-Xin Lin, Ning Du, Peng Li, Majid Kazemian, Tesfay Gebregiorgis, Rosanne Spolski, Warren J Leonard
Interleukin-15 (IL-15) is essential for the development and maintenance of natural killer (NK) cells. IL-15 activates STAT5 proteins, which can form dimers or tetramers. We previously found that NK cell numbers are decreased in Stat5a-Stat5b tetramer-deficient double knockin (DKI) mice, but the mechanism was not investigated. Here we show that STAT5 dimers are sufficient for NK cell development, whereas STAT5 tetramers mediate NK cell maturation and the expression of maturation-associated genes. Unlike the defective proliferation of Stat5 DKI CD8+ T cells, Stat5 DKI NK cells have normal proliferation to IL-15 but are susceptible to death upon cytokine withdrawal, with lower Bcl2 and increased active caspases...
November 6, 2017: Nature Communications
Sayaka Akieda-Asai, Takanori Ida, Mikiya Miyazato, Kenji Kangawa, Yukari Date
Recently we found that guanylin (Gn) and its receptor, guanylyl cyclase C (GC-C), are uniquely expressed in the mesenteric macrophages of some diet-resistant rats and that double-transgenic (dTg) rats overexpressing Gn and GC-C in macrophages demonstrate reduced fatty acid synthase and fat accumulation in fat tissue even when fed a high-fat diet (HFD). Lipid accumulation and fatty acid synthase mRNA levels in cocultured dTg rat adipocytes and macrophages were reduced compared with those in adipocytes cultured with WT rat macrophages...
January 2018: Peptides
Dietmar Herndler-Brandstetter, Liang Shan, Yi Yao, Carmen Stecher, Valerie Plajer, Melanie Lietzenmayer, Till Strowig, Marcel R de Zoete, Noah W Palm, Jie Chen, Catherine A Blish, Davor Frleta, Cagan Gurer, Lynn E Macdonald, Andrew J Murphy, George D Yancopoulos, Ruth R Montgomery, Richard A Flavell
Immunodeficient mice reconstituted with a human immune system represent a promising tool for translational research as they may allow modeling and therapy of human diseases in vivo. However, insufficient development and function of human natural killer (NK) cells and T cell subsets limit the applicability of humanized mice for studying cancer biology and therapy. Here, we describe a human interleukin 15 ( IL15 ) and human signal regulatory protein alpha ( SIRPA ) knock-in mouse on a Rag2-/- Il2rg-/- background (SRG-15)...
November 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
Ahmet Yalcin, Kamile Silay, Ahmet Rifat Balik, Gamze Avcioğlu, Almila Senat Aydin
BACKGROUND AND AIM: Sarcopenia is a geriatric syndrome in which there is a decrease in muscle mass, muscle strength, and muscle function. Interleukin-15 (IL-15), a myokine released by skeletal muscle, has effects on both muscle and adipose tissue. We evaluated the relationship between plasma IL-15 level and sarcopenia. METHODS: We evaluated a total of 160 outpatient older people, and 80 of whom had sarcopenia. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People criteria...
October 25, 2017: Aging Clinical and Experimental Research
Margaret Bublitz, Suzanne De La Monte, Susan Martin, Lucia Larson, Ghada Bourjeily
BACKGROUND: Women with childhood maltreatment histories are at increased risk for adverse birth outcomes. Mechanisms explaining this link are poorly understood. Past research is limited by sampling pregnant women at low risk for adverse maternal and neonatal outcomes. METHODS: This pilot study was a secondary data analysis of 24 women with gestational diabetes mellitus; 17% of the sample also reported a maltreatment history. Women provided a blood sample to measure inflammatory cytokines and insulin resistance, and saliva samples to measure diurnal cortisol...
September 2017: Obstetric Medicine
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