DOCSLIB.ORG

WO 2017/087708 Al 26 May 2017 (26.05.2017) P O P C T

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
WO 2017/087708 Al 26 May 2017 (26.05.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/087708 Al 26 May 2017 (26.05.2017) P O P C T (51) International Patent Classification: (72) Inventors: KUCHROO, Vijay K.; 30 Fairhaven Road, A61K 38/17 (2006.01) A61P 17/00 (2006.01) Newton, Massachusetts 02459 (US). WANG, Chao; 6 A61K 38/20 (2006.01) Canal Park, Unit 302, Cambridge, Massachusetts 02141 (US). REGEV, Aviv; 15a Ellsworth Ave, Cambridge, (21) International Application Number: Massachusetts 02139 (US). SHEKHAR, Karthik; 415 PCT/US2016/062592 Main Street, Cambridge, Massachusetts 02142 (US). (22) International Filing Date: (74) Agents: TALAPATRA, Sunk et al; Foley & Lardner 17 November 2016 (17.1 1.2016) LLP, 3000 K Street, Suite 600, Washington, District of (25) Filing Language: English Columbia 20007 (US). (26) Publication Language: English (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (30) Priority Data: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 62/257,589 1 November 2015 (19. 11.2015) US BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (71) Applicants: THE BRIGHAM AND WOMEN'S HOS¬ DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PITAL, INC. [US/US]; 75 Francis Street, Boston, M as HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, sachusetts 021 15 (US). THE BROAD INSTITUTE, INC. KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, [US/US]; 415 Main Street, Cambridge, Massachusetts MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 02142 (US). MASSACHUSETTS INSTITUTE OF OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, Cambridge, Massachusetts 02139 (US). TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, [Continued on nextpage] (54) Title: LYMPHOCYTE ANTIGEN CD5-LIKE (CD5L)-INTERLEUKIN 12B (P40) HETERODIMERS IN IMMUNITY (57) Abstract: Described herein are methods for sup pressing an immune response in a subject, e.g., a sub n = 106 {DE out of 312: nanostring) ject with an autoimmune disease, by administering to the subject a therapeutically effective amount of re combinant CD5L, CD5L homodimers and/or a CD5L:p40 heterodimers, or nucleic acids encoding o ό any of these. Also described are methods for enhan Reversal cing an immune response in a subject, e.g., a subject Q Novel (soluble) U with cancer, infection, or an immune deficiency, by administering to the subject a therapeutically effective Opposite amount of an antibody or antigen-binding fragment thereof that binds specifically to CD5L, D5L homodi Novel (intrinsic) mers and/or CD5L:p40 heterodimers, and inhibits their binding to the IL-23 receptor, or inhibits forma tion of the CD5L homodimer and/or CD5L:p40 het- erodimer, or inhibitory nucleic acids that target CD5L and/or p40. o00 l o00 FIG. 1 o w o 2017/087708 AI II II II I III IIII II III I II II III I III II I II DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, before the expiration of the time limit for amending the LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, claims and to be republished in the event of receipt of SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, amendments (Rule 48.2(h)) GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: Lymphocyte Antigen CD5-Like (CD5L)-Interleukin 12B p40 Heterodimers in Immunity FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under Grant Nos. POl AI056299, POl AI039671, POl AI073748, and 5P01 AI045757 awarded by the National Institutes of Health. The Government has certain rights in the invention. TECHNICAL FIELD Described herein are methods for suppressing or enhancing an immune response in a subject. BACKGROUND The cytokine environment influences immune cell differentiation, function and plasticity. IL-23 has been identified as key player in inflammatory diseases, contributing largely to mucosal inflammation. It was discovered as a susceptibility gene in GWAS and is widely implicated in autoimmune diseases and cancer such as melanoma and colorectal carcinoma (Burkett et al., 2015; Cho and Feldman, 2015; Teng et al., 2015; Wang and Karin, 2015). SUMMARY The present invention is based, at least in part, on the discovery that CD5L and p40 form heterodimers in vivo, and that these heterodimers modulate the immune response. CD5L exists as a monomer, and is also able to form dimers; both forms may also serve as immunomodulators. Some embodiments comprise methods for modulating an immune response or suppressing an immune response (e.g., an inflammatory immune response) in a subject, the method comprising administering to the subject a therapeutically effective amount of recombinant soluble CD5L, a CD5L:CD5L homodimer, a CD5L:p40 heterodimer, or one or more nucleic acids encoding the same. In some embodiments, the subject has an autoimmune disease, e.g., Multiple Sclerosis (MS), Irritable Bowel Disease (IBD), Crohn's disease, spondyloarthritides, Systemic Lupus Erythematosus (SLE), Vitiligo, rheumatoid arthritis, psoriasis, Sjogren's syndrome, or diabetes. In some embodiments, the subject has an inflammation-related cancer, e.g., colorectal cancer, carcinogen-induced skin papilloma, fibrosarcoma, or mammary carcinomas. Some embodiments comprise methods of suppressing an immune response in a subject, the method comprising administering to the subject a therapeutically effective amount of one or more of: a recombinant soluble CD5L and/or a nucleic acid encoding CD5L; a recombinant soluble CD5L:CD5L homodimer and/or a nucleic acid encoding a CD5L homodimer; and a recombinant soluble CD5L:p40 heterodimer and/or nucleic acids encoding CD5L and p40. In some embodiments the subject has an autoimmune disease, such as Multiple Sclerosis (MS), Irritable Bowel Disease (IBD), Crohn's disease, spondyloarthritides, Systemic Lupus Erythematosus (SLE), Vitiligo, rheumatoid arthritis, psoriasis, Sjogren's syndrome, or diabetes. In some embodiments, subject has an inflammation-related cancer, such as colorectal cancer, carcinogen-induced skin papilloma, fibrosarcoma, or mammary carcinomas. Some embodiments comprise administering the CD4L:p40 heterodimer. Some embodiments comprise administering the CD5L:CD5L homodimer. Some embodiments relate to methods of enhancing an immune response in a subject, the method comprising administering to the subject a therapeutically effective amount of an agent that: (a) inhibits CD5L, a CD5L:CD5L homodimer, and/or a CD5L:p40 heterodimer from binding to an IL-23 receptor; and/or (b) inhibits formation of the CD5L:CD5L homodimer and/or the CD5L:p40 heterodimer. In some embodiments, the agent comprises an antibody, or an antigen binding fragment thereof, that binds to one or more of the CD5L, the CD5L homodimer, or the CD5L:p40 heterodimer. In some embodiments, the agent comprises inhibitory nucleic acids that target the CD5L and/or the p40. In some embodiments, the subject has cancer that is not inflammation related. Some embodiments comprise administering an anti-cancer immunotherapy to the subject, such as checkpoint inhibitors, PD-l/PDL-1, anti-cancer vaccines, adoptive T cell therapy, and/or combination of two or more thereof. In embodiments that comprise administering inhibitory nucleic acids, the nucleic acids can include small interfering RNAs (e.g., shRNA), antisense oligonucleutides (e.g. antisense RNAs), and/or CRISPR-Cas. In some embodiments, the subject has an immune deficiency, e.g., a primary or secondary immune deficiency. In some embodiments, the subject has an infection with a pathogen, e.g., viral, bacterial, or fungal pathogen. Some embodiments comprised methods of modulating CD8+ T cell exhaustion in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent that: (a) inhibits CD5L, a CD5L:CD5L homodimer, and/or a CD5L:p40 heterodimer from binding to an IL-23 receptor; and/or (b) inhibits formation of the CD5L:CD5L homodimer and/or the CD5L:p40 heterodimer. In some embodiments, said administering reduces CD8+ T cell exhaustion. In some embodiments the subject has cancer, such as a non-inflammatory cancer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. DESCRIPTION OF DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. Figure 1. Soluble CD5L can regulate T cell function, largely reversing CD5L deficiency-induced gene expression pattern in T cells. WT or CD5L-/- naive T cells were sorted and activated under ThO condition and treated with either PBS or soluble CD5L (50nM).
Load more

Recommended publications
  • UNIVERSITY of CALIFORNIA, SAN DIEGO Towards an Understanding of Inflammation in Macrophages a Dissertation Submitted in Partial
    UNIVERSITY OF CALIFORNIA, SAN DIEGO Towards an Understanding of Inflammation in Macrophages A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biomedical Sciences by Dawn Xiaobin Zhang Committee in charge: Professor Christopher L. Glass, Chair Professor Jack Bui Professor Ronald M. Evans Professor Richard L. Gallo Professor Joseph L. Witztum 2014 Copyright Dawn Xiaobin Zhang, 2014 All rights reserved. This Dissertation of Dawn Xiaobin Zhang is approved, and it is acceptable in quality and form for publication on microfilm and electronically: Chair University of California, San Diego 2014 iii DEDICATION To my family and the love of my life, Matthew. iv EPIGRAPH How often have I said to you that when you have eliminated the impossible, whatever remains, however improbable, must be the truth? -Sherlock Holmes, From The Sign of the Four, Sir Arthur Conan Doyle v TABLE OF CONTENTS Signature Page ……………………………………………………………….. iii Dedication ……………………………………………………….…………….. iv Epigraph ……………………………………………………………………….. v Table of Contents ………………………………………………………….….. vi List of Figures ………………………………………………………….………. viii List of Tables ………………………………………………………….…….…. x Acknowledgements …………………………………….…………………..…. xi Vita …………………………………….……………………………………..…. xiii Abstract of the Dissertation ………………………………..…………………. xv Chapter I: Introduction: Towards an Understanding of Cell-Specific Function of Signal-Dependent Transcription Factors ……....…....…... 1 A. Abstract ……....…....………………………………...…………….. 2 B. Introduction
    [Show full text]
  • Transcriptional and Post-Transcriptional Regulation of ATP-Binding Cassette Transporter Expression
    Transcriptional and Post-transcriptional Regulation of ATP-binding Cassette Transporter Expression by Aparna Chhibber DISSERTATION Submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pharmaceutical Sciences and Pbarmacogenomies in the Copyright 2014 by Aparna Chhibber ii Acknowledgements First and foremost, I would like to thank my advisor, Dr. Deanna Kroetz. More than just a research advisor, Deanna has clearly made it a priority to guide her students to become better scientists, and I am grateful for the countless hours she has spent editing papers, developing presentations, discussing research, and so much more. I would not have made it this far without her support and guidance. My thesis committee has provided valuable advice through the years. Dr. Nadav Ahituv in particular has been a source of support from my first year in the graduate program as my academic advisor, qualifying exam committee chair, and finally thesis committee member. Dr. Kathy Giacomini graciously stepped in as a member of my thesis committee in my 3rd year, and Dr. Steven Brenner provided valuable input as thesis committee member in my 2nd year. My labmates over the past five years have been incredible colleagues and friends. Dr. Svetlana Markova first welcomed me into the lab and taught me numerous laboratory techniques, and has always been willing to act as a sounding board. Michael Martin has been my partner-in-crime in the lab from the beginning, and has made my days in lab fly by. Dr. Yingmei Lui has made the lab run smoothly, and has always been willing to jump in to help me at a moment’s notice.
    [Show full text]
  • The Viral Oncoproteins Tax and HBZ Reprogram the Cellular Mrna Splicing Landscape
    bioRxiv preprint doi: https://doi.org/10.1101/2021.01.18.427104; this version posted January 18, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape Charlotte Vandermeulen1,2,3, Tina O’Grady3, Bartimee Galvan3, Majid Cherkaoui1, Alice Desbuleux1,2,4,5, Georges Coppin1,2,4,5, Julien Olivet1,2,4,5, Lamya Ben Ameur6, Keisuke Kataoka7, Seishi Ogawa7, Marc Thiry8, Franck Mortreux6, Michael A. Calderwood2,4,5, David E. Hill2,4,5, Johan Van Weyenbergh9, Benoit Charloteaux2,4,5,10, Marc Vidal2,4*, Franck Dequiedt3*, and Jean-Claude Twizere1,2,11* 1Laboratory of Viral Interactomes, GIGA Institute, University of Liege, Liege, Belgium.2Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.3Laboratory of Gene Expression and Cancer, GIGA Institute, University of Liege, Liege, Belgium.4Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. 5Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.6Laboratory of Biology and Modeling of the Cell, CNRS UMR 5239, INSERM U1210, University of Lyon, Lyon, France.7Department of Pathology and Tumor Biology, Kyoto University, Japan.8Unit of Cell and Tissue Biology, GIGA Institute, University of Liege, Liege, Belgium.9Laboratory of Clinical and Epidemiological Virology, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, Catholic University of Leuven, Leuven, Belgium.10Department of Human Genetics, CHU of Liege, University of Liege, Liege, Belgium.11Lead Contact. *Correspondence: [email protected]; [email protected]; [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2021.01.18.427104; this version posted January 18, 2021.
    [Show full text]
  • Combined DNA Methylation and Transcriptomic Assessments to Determine a Prognostic Model for PD-1-Negative Hepatocellular Carcinoma
    fcell-09-708819 August 9, 2021 Time: 10:32 # 1 ORIGINAL RESEARCH published: 11 August 2021 doi: 10.3389/fcell.2021.708819 Combined DNA Methylation and Transcriptomic Assessments to Determine a Prognostic Model for PD-1-Negative Hepatocellular Carcinoma Lixu Zhu1,2,3,4 and Wenzhi Guo1,2,3,4* 1 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China, 2 Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China, 3 Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China, 4 Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China Edited by: Ritu Kulshreshtha, Hepatocellular carcinoma (HCC) has the highest incidence and mortality of any Indian Institute of Technology Delhi, malignancy in the world. Immunotherapy has been a major breakthrough for HCC India treatment, but immune checkpoint inhibitors (ICIs) are effective in only a small Reviewed by: Hernando Lopez Bertoni, percentage of HCC patients. In the present study, we screened programmed cell death Johns Hopkins Medicine, protein 1 (PD-1) -negative HCC samples, which are frequently resistant to ICIs, and United States Jingying Zhou, identified their methylation and transcription characteristics through the assessment The Chinese University of Hong Kong, of differential gene methylation and gene expression. We also screened for potential China targeted therapeutic drugs using the DrugBank database. Finally, we used a LASSO *Correspondence: (least absolute shrinkage and selection operator) regression analysis to construct Wenzhi Guo [email protected] a prognostic model based on three differentially methylated and expressed genes (DMEGs).
    [Show full text]
  • Apoptosis Inhibitor of Macrophage (AIM) Is Required for Obesity-Associated Recruitment of Inflammatory Macrophages Into Adipose Tissue
    Apoptosis inhibitor of macrophage (AIM) is required for obesity-associated recruitment of inflammatory macrophages into adipose tissue Jun Kurokawaa, Hiromichi Naganoa, Osamu Oharab, Naoto Kubotac, Takashi Kadowakic, Satoko Araia, and Toru Miyazakia,1 aLaboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan; bDepartment of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan; and cDepartment of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan Edited* by Tadatsugu Taniguchi, University of Tokyo, Tokyo, Japan, and approved June 14, 2011 (received for review February 3, 2011) Infiltration of inflammatory macrophages into adipose tissues with macrophages against different types of apoptosis-inducing stimuli the progression of obesity triggers insulin resistance and obesity- (13). AIM is a direct target for regulation by nuclear receptor liver related metabolic diseases. We recently reported that macrophage- X receptor/retinoid X receptor (LXR/RXR) heterodimers (15, derived apoptosis inhibitor of macrophage (AIM) protein is in- 16) and is solely produced by tissue macrophages. As a secreted molecule, AIM is detected in both human and mouse blood at creased in blood in line with obesity progression and is incorporated – into adipocytes, thereby inducing lipolysis in adipose tissue. Here various levels (13, 16 19) and increases in blood with the pro- we show that such a response is required for the recruitment of gression of obesity in mice fed a high-fat diet (HFD) (14). The augmented blood AIM induced lipolysis, as evident by the fact adipose tissue macrophages.
    [Show full text]
  • Peripheral Nerve Single-Cell Analysis Identifies Mesenchymal Ligands That Promote Axonal Growth
    Research Article: New Research Development Peripheral Nerve Single-Cell Analysis Identifies Mesenchymal Ligands that Promote Axonal Growth Jeremy S. Toma,1 Konstantina Karamboulas,1,ª Matthew J. Carr,1,2,ª Adelaida Kolaj,1,3 Scott A. Yuzwa,1 Neemat Mahmud,1,3 Mekayla A. Storer,1 David R. Kaplan,1,2,4 and Freda D. Miller1,2,3,4 https://doi.org/10.1523/ENEURO.0066-20.2020 1Program in Neurosciences and Mental Health, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada, 2Institute of Medical Sciences University of Toronto, Toronto, Ontario M5G 1A8, Canada, 3Department of Physiology, University of Toronto, Toronto, Ontario M5G 1A8, Canada, and 4Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1A8, Canada Abstract Peripheral nerves provide a supportive growth environment for developing and regenerating axons and are es- sential for maintenance and repair of many non-neural tissues. This capacity has largely been ascribed to paracrine factors secreted by nerve-resident Schwann cells. Here, we used single-cell transcriptional profiling to identify ligands made by different injured rodent nerve cell types and have combined this with cell-surface mass spectrometry to computationally model potential paracrine interactions with peripheral neurons. These analyses show that peripheral nerves make many ligands predicted to act on peripheral and CNS neurons, in- cluding known and previously uncharacterized ligands. While Schwann cells are an important ligand source within injured nerves, more than half of the predicted ligands are made by nerve-resident mesenchymal cells, including the endoneurial cells most closely associated with peripheral axons. At least three of these mesen- chymal ligands, ANGPT1, CCL11, and VEGFC, promote growth when locally applied on sympathetic axons.
    [Show full text]
  • Signatures of Adaptive Evolution in Platyrrhine Primate Genomes 5 6 Hazel Byrne*, Timothy H
    1 2 Supplementary Materials for 3 4 Signatures of adaptive evolution in platyrrhine primate genomes 5 6 Hazel Byrne*, Timothy H. Webster, Sarah F. Brosnan, Patrícia Izar, Jessica W. Lynch 7 *Corresponding author. Email [email protected] 8 9 10 This PDF file includes: 11 Section 1: Extended methods & results: Robust capuchin reference genome 12 Section 2: Extended methods & results: Signatures of selection in platyrrhine genomes 13 Section 3: Extended results: Robust capuchins (Sapajus; H1) positive selection results 14 Section 4: Extended results: Gracile capuchins (Cebus; H2) positive selection results 15 Section 5: Extended results: Ancestral Cebinae (H3) positive selection results 16 Section 6: Extended results: Across-capuchins (H3a) positive selection results 17 Section 7: Extended results: Ancestral Cebidae (H4) positive selection results 18 Section 8: Extended results: Squirrel monkeys (Saimiri; H5) positive selection results 19 Figs. S1 to S3 20 Tables S1–S3, S5–S7, S10, and S23 21 References (94 to 172) 22 23 Other Supplementary Materials for this manuscript include the following: 24 Tables S4, S8, S9, S11–S22, and S24–S44 1 25 1) Extended methods & results: Robust capuchin reference genome 26 1.1 Genome assembly: versions and accessions 27 The version of the genome assembly used in this study, Sape_Mango_1.0, was uploaded to a 28 Zenodo repository (see data availability). An assembly (Sape_Mango_1.1) with minor 29 modifications including the removal of two short scaffolds and the addition of the mitochondrial 30 genome assembly was uploaded to NCBI under the accession JAGHVQ. The BioProject and 31 BioSample NCBI accessions for this project and sample (Mango) are PRJNA717806 and 32 SAMN18511585.
    [Show full text]
  • The Macrophage Soluble Receptor AIM/Api6/CD5L Displays a Broad Pathogen Recognition Spectrum and Is Involved in Early Response to Microbial Aggression
    Cellular & Molecular Immunology (2014) 11, 343–354 ß 2014 CSI and USTC. All rights reserved 1672-7681/14 $32.00 www.nature.com/cmi RESEARCH ARTICLE The macrophage soluble receptor AIM/Api6/CD5L displays a broad pathogen recognition spectrum and is involved in early response to microbial aggression Vanesa G. Martinez1,6, Cristina Escoda-Ferran1,6, Ineˆs Tadeu Simo˜es1, Satoko Arai2, Marc Orta Mascaro´ 1, Esther Carreras1, Mario Martı´nez-Florensa1, Jose´ Yelamos3, Toru Miyazaki2 and Francisco Lozano1,4,5 Apoptosis inhibitor of macrophages (AIMs), a homologue of human Spa, is a mouse soluble member of the scavenger receptor cysteine-rich superfamily (SRCR-SF). This family integrates a group of proteins expressed by innate and adaptive immune cells for which no unifying function has yet been described. Pleiotropic functions have been ascribed to AIM, from viability support in lymphocytes during thymic selection to lipid metabolism and anti-inflammatory effects in autoimmune pathologies. In the present report, the pathogen binding properties of AIM have been explored. By using a recombinant form of AIM (rAIM) expressed in mammalian cells, it is shown that this protein is able to bind and aggregate Gram-positive and Gram-negative bacteria, as well as pathogenic and saprophytic fungal species. Importantly, endogenous AIM from mouse serum also binds to microorganisms and secretion of AIM was rapidly induced in mouse spleen macrophages following exposure to conserved microbial cell wall components. Cytokine release induced by well-known bacterial and fungal Toll-like receptor (TLR) ligands on mouse splenocytes was also inhibited in the presence of rAIM. Furthermore, mouse models of pathogen-associated molecular patterns (PAMPs)-induced septic shock of bacterial and fungal origin showed that serum AIM levels changed in a time-dependent manner.
    [Show full text]
  • Cao Science 2020.Pdf
    RESEARCH ◥ CONCLUSION: The single-cell data resource RESEARCH ARTICLE SUMMARY presented here is notable for its scale, its fo- cus on human fetal development, the breadth HUMAN GENOMICS of tissues analyzed, and the parallel gener- ation of gene expression (this study) and chro- A human cell atlas of fetal gene expression matin accessibility data (Domcke et al.,this issue). We furthermore consolidate the tech- Junyue Cao, Diana R. O’Day, Hannah A. Pliner, Paul D. Kingsley, Mei Deng, Riza M. Daza, nical framework for individual laboratories to Michael A. Zager, Kimberly A. Aldinger, Ronnie Blecher-Gonen, Fan Zhang, Malte Spielmann, generate and analyze gene expression and James Palis, Dan Doherty, Frank J. Steemers, Ian A. Glass, Cole Trapnell*, Jay Shendure* chromatin accessibility data from millions of single cells. Looking forward, we envision that the somewhat narrow window of mid- INTRODUCTION: A reference atlas of human cell 72 to 129 days in estimated postconceptual age gestational human development studied here typesisamajorgoalforthefield.Here,weset and representing 15 organs, altogether profiling will be complemented by additional atlases out to generate single-cell atlases of both gene 4 million single cells. We developed and applied of earlier and later time points, as well as expression (this study) and chromatin acces- a framework for quantifying cell type specificity, similarly comprehensive profiling and inte- sibility (Domcke et al., this issue) using diverse identifying 657 cell subtypes, which we prelimi- gration of data from model organisms. The human tissues obtained during midgestation. narily annotated based on cross-matching to continued development and application of mouse cell atlases.
    [Show full text]
  • CD5L Promotes M2 Macrophage Polarization Through Autophagy-Mediated Upregulation Of
    ORIGINAL RESEARCH published: 12 March 2018 doi: 10.3389/fimmu.2018.00480 CD5L Promotes M2 Macrophage Polarization through Autophagy- Mediated Upregulation of ID3 Lucía Sanjurjo1,2, Gemma Aran1, Érica Téllez1, Núria Amézaga1, Carolina Armengol3,4, Daniel López5, Clara Prats5 and Maria-Rosa Sarrias1,3* 1 Innate Immunity Group, Germans Trias i Pujol Health Sciences Research Institute (IGTP), Barcelona, Spain, 2 Network for Biomedical Research in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain, 3 Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain, 4 Childhood Liver Oncology Group, Program of Predictive and Personalized Medicine of Cancer (PMPCC), Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona, Spain, 5 Departament de Física, Escola Superior d’Agricultura de Barcelona, Universitat Politècnica de Catalunya – BarcelonaTech Castelldefels, Barcelona, Spain CD5L (CD5 molecule-like) is a secreted glycoprotein that controls key mechanisms in inflammatory responses, with involvement in processes such as infection, atherosclero- sis, and cancer. In macrophages, CD5L promotes an anti-inflammatory cytokine profile in response to TLR activation. In the present study, we questioned whether CD5L is able to influence human macrophage plasticity, and drive its polarization toward any Edited by: Liwu Li, specific phenotype. We compared CD5L-induced phenotypic and functional changes Virginia Tech, United States to those caused by IFN/LPS, IL4, and IL10 in human monocytes. Phenotypic markers Reviewed by: were quantified by RT-qPCR and flow cytometry, and a mathematical algorithm was Charles E. McCall, Wake Forest Baptist Medical Center, built for their analysis. Moreover, we compared ROS production, phagocytic capacity, United States and inflammatory responses to LPS.
    [Show full text]
  • CD5L‑Induced Activation of Autophagy Is Associated with Hepatoprotection in Ischemic Reperfusion Injury Via the CD36/ATG7 Axis
    2588 EXPERIMENTAL AND THERAPEUTIC MEDICINE 19: 2588-2596, 2020 CD5L‑induced activation of autophagy is associated with hepatoprotection in ischemic reperfusion injury via the CD36/ATG7 axis JUNJIAN LI1, WEI LIN2,3 and LEI ZHUANG1 1Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University; 2Science and Technology Information Center, Wenzhou Medical University Library; 3Department of Geriatrics, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China Received August 14, 2018; Accepted July 24, 2019 DOI: 10.3892/etm.2020.8497 Abstract. Hepatic ischemia/reperfusion (I/R) injury is a side the present study identifies CD5L as a novel therapeutic agent effect of major liver surgery that is difficult to prevent. I/R for hepatic I/R injury. injury induces metabolic strain on hepatocytes and limits the tolerable ischemia during liver resection, as well as preserva- Introduction tion times during transplantation. Additionally, I/R injury induces apoptosis in hepatocytes. CD5‑like (CD5L), an inducer For patients with hepatic malignancy, liver resection may often of autophagy, is a soluble scavenger cysteine-rich protein that be the only treatment option (1). Excessive blood loss during modulates hepatocyte apoptosis. The aim of the present study surgery is associated with poor postoperative outcomes (2); to was to determine if pharmacologic CD5L was protective avoid this, vascular inflow occlusion (VIO) is often performed against hepatic ischemia‑reperfusion injury. Hepatocytes were during liver transaction (3). Although VIO effectively subjected to I/R culture conditions, and apoptosis and caspase reduces blood loss, hepatic oxygen supply is interrupted, family activity were measured after I/R to model hepatic which results in metabolic disruption that subjects the liver injury.
    [Show full text]
  • Anti-CD5L (C-Terminal) Polyclonal Antibody (CPBT- 65327RC) This Product Is for Research Use Only and Is Not Intended for Diagnostic Use
    Anti-CD5L (C-terminal) polyclonal antibody (CPBT- 65327RC) This product is for research use only and is not intended for diagnostic use. PRODUCT INFORMATION Product Overview This product detects an epitope within the C-terminal (CT) region of human CD5L, also known as Apoptosis Inhibitor expressed by Macrophages (AIM), and SP alpha. CD5L is a soluble 38kD glycoprotein which is specifically produced by mature macrophages, and has been shown to support their survival and enhance phagocytic function. CD5L expression is upregulated in response to LXR/RXR heterodimer activation. CD5L has been shown to mediate the survival of macrophages in atherosclerotic plaques. Western Blotting detects a band of approximately 38kDa in Raji cell lysates. Specificity CD5L Immunogen 13 amino acid peptide sequence near the carboxy terminus of human CD5L. Isotype IgG Source/Host Rabbit Species Reactivity Human, Mouse Conjugate Unconjugated Applications IHC-P; WB Format Purified IgG - liquid Size 100 μg Preservative 0.02% Sodium Azide Storage in frost-free freezers is not recommended. This product should be stored undiluted. Avoid repeated freezing and thawing as this may denature the antibody. Should this product contain a precipitate we recommend microcentrifugation before use. Warnings For research purposes only GENE INFORMATION 45-1 Ramsey Road, Shirley, NY 11967, USA Email: [email protected] Tel: 1-631-624-4882 Fax: 1-631-938-8221 1 © Creative Diagnostics All Rights Reserved Gene Name CD5L CD5 molecule-like [ Homo sapiens (human) ] Official Symbol CD5L Synonyms CD5L; CD5 molecule-like; AIM; API6; PRO229; Spalpha; SP-ALPHA; CD5 antigen-like; CT-2; apoptosis inhibitor 6; igM-associated peptide; CD5 antigen-like (scavenger receptor cysteine rich family); CD5L; Entrez Gene ID 922 Protein Refseq NP_005885 UniProt ID O43866 Chromosome Location 1q21-q23 Function scavenger receptor activity; 45-1 Ramsey Road, Shirley, NY 11967, USA Email: [email protected] Tel: 1-631-624-4882 Fax: 1-631-938-8221 2 © Creative Diagnostics All Rights Reserved.
    [Show full text]