DOCSLIB.ORG

Antiviral and Immunoregulatory Roles of Natural Killer Cells in Chronic Hepatitis B Virus Infection

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Antiviral and Immunoregulatory Roles of Natural Killer Cells in Chronic Hepatitis B Virus Infection Title page Antiviral and immunoregulatory roles of Natural Killer cells in chronic hepatitis B virus infection A THESIS PRESENTED TO UNIVERSITY COLLEGE LONDON FOR THE DEGREE OF DOCTOR OF PHILOSOPHY BY DIMITRA PEPPA APRIL 2013 DEPARTMENT OF IMMUNOLOGY AND MOLECULAR PATHOLOGY, DIVISION OF INFECTION AND IMMUNITY, UNIVERSITY COLLEGE LONDON UNITED KINGDOM 1 Declaration 'I, Dimitra Peppa, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis.' 2 Abstract Persistent infection with hepatitis B virus (HBV) is a global health burden accounting for more than a 1 million deaths worldwide. Much work has focused on the failure of the adaptive immune response in persistent HBV infection. In contrast innate responses remain poorly characterised. Accumulating evidence indicates the involvement of natural killer (NK) cells in the control of viral infections and shaping of adaptive immunity. Here we investigated the antiviral and immunoregulatory potential of NK cells in chronic Hepatitis B virus infection (CHB). We found that the combination of immunosuppressive cytokines seen in CHB suppresses the non-cytolytic antiviral function of NK cells, whilst maintaining TRAIL mediated killing, which has been associated with hepatocyte apoptosis. Our findings also implicate NK cells in the down-regulation of antiviral T cells, which are profoundly diminished and prone to apoptosis in CHB. Our data show that in vitro depletion of NK cells results in recovery of HBV-specific CD8+ T cells, an effect that was not observed for control virus responses. When NK cells were depleted or not in contact with T cells, the degree of caspase activation in HBV-specific T cells was decreased, supporting a direct and contact dependent NK cell effect on virus-specific CD8+ T cell survival involving induction of apoptosis. NK cells, the predominant population of TRAIL expressing cells in the HBV infected liver, were found in intimate contact with T cells within the liver sinusoidal spaces. The observed upregulation of the death receptor, TRAIL-R2 on CD8+ T cells, imposed by the intrahepatic milieu in HBV infection may sensitise them to apoptosis. Our findings illustrate an important and novel mechanism of immune dysregulation contributing to viral persistence in humans. The potential to selectively deviate NK cells from pathogenic roles, whilst augmenting antiviral functions could improve HBV control and enhance the design of future therapeutic strategies. 3 Acknowledgements I am indebted to Ian Weller for his mentorship and for steering me in the direction of Mala Maini. Mala has been an excellent PhD supervisor. I am truly thankful for the confidence she has shown in me, for always being available for informal chats, for her many words of encouragement and for helping me to maintain a clear focus. Her drive and enthusiasm continues to inspire me. I would also like to thank my co-supervisor, John Trowsdale, for his valuable advice and help over the last four years. None of this work would have been possible without the support from all the members, past and present, of the Maini group. Thank you all for creating such a great working environment, your technical advice, day-to-day help, unlimited supply of caffeine, bottles of wine and importantly your friendship. I would also like to extend my gratitude to our collaborators, clinic staff and patients. In particular, Upkar Gill at the Royal London Hospital for his tireless ability to recruit patients for our study, Chiwen Chang at Cambridge for his help, and Gary Reynolds at Birmingham for his expertise in immunohistochemistry. A big thank you goes to Raymond Welsh and Stephen Waggoner for kindly agreeing to host my short visit at UMass, for providing me with a better insight of murine modeIs and for their thought provoking discussions. I am also grateful to the MRC for funding me during the duration of my PhD. Finally I would like to thank my friends and family for always being there for me. My parents for teaching me to persevere in life, my sister Sofia and George for their unconditional love and support even from a distance and my little nephew, Nikolas, who always manages to put a smile on my face even when experiments are not working. Last but not least, thank you Nick for putting up with me, for counterbalancing Mediterranean emotions so effectively and for never failing to inject optimism and a sense of perspective into our lives. I couldn’t have managed through all the ups and downs without you. 4 List of common abbreviations ADCC Antibody-dependent cellular cytotoxicity ALT Alanine aminotransferase APC Antigen presenting cell Bid Bcl2- interacting domain death agonist Bim Bcl2-interacting mediator Breg Regulatory B cell cccDNA Covalently closed circular DNA CCR7 Chemokine (C-C motif) receptor 7 CD Cluster of differentiation CD3z CD3zeta C-FLIP Cellular FLICE inhibitory protein CFSE Carboxyfluorescein diacetate succinimidyl ester CHB Chronic hepatitis B virus infection CMV Cytomegalovirus CpG Cytosine and guanine separated by phosphate CTL Cytotoxic T lymphocyte CTLA-4 Cytotoxic T-lymphocyte antigen 4 CXCR6 CXC-chemokine receptor 6 DAP-10 DNAX activating protein of 10kD DC Dendritic cell DD Death Domain DED Death effector domain DISC Death inducing signalling complex DNA Deoxyribonucleic acid EAE Experimental autoimmune encephalomyelitis E4BP4 E4 Promoter Binding Protein 4 EBV Epstein-Barr virus ELISA Enzyme-Linked ImmunoSorbent Assay EMCV Encephalomyocarditis virus ER Endoplasmic reticulum FACS Fluorescence activated cell sorter FBS Fetal bovine serum FADD Fas associated protein with death domain FLT3 Fms-like Tyrosine Kinase-3 GATA-3 GATA binding protein 3 GM-CSF Granulocyte-macrophage colony-stimulating factor HA Haemagglutinin HBcAg Hepatitis B virus core antigen HBeAg Hepatitis B virus precore-core antigen HBsAg Hepatitis B virus surface/envelope antigen HBV Hepatitis B virus HCC Hepatocellular carcinoma 5 HCV Hepatitis C virus HDV Hepatitis delta virus HIV Human immunodeficiency virus HLA Human leucocyte antigen HSC Hepatic stellate cell HPC Haematopoietic cell HTLV-1 Human T-cell Lymphotropic Virus ID-2 Inhibitor of DNA binding 2 iDC Immature dendritic cell IFN-α Interferon alpha IFN-γ Interferon gamma IFN-λ Interferon-lamda Ig Immunoglobulin ILC Innate lymphoid cell IL-10 Interleukin-10 IL-12 Interleukin-12 IL-15 Interleukin-15 IL-17 Interleukin-17 IL-18 Interleukin-18 IL-2 Interleukin-2 IL-22 Interleukin-22 IL-29 Interleukin-29 IL-6 Interleukin-6 IL-7 Interleukin-7 IL-8 Interleukin-8 INF-A Influenza A iNK Immature Natural Killer ITAM Immunoreceptor tyrosine–based activation motif ITIM Immunoreceptor tyrosine-based inhibitory motif JAK Janus kinase KC Kupffer cell KIR Killer immunoglobulin receptor KLRG-1 Killer cell lectin-like receptor subfamily G, member 1 LCMV Lymphocytic Choriomeningitis Virus LPS Lipopolysaccharide LSEC Liver sinusoidal epithelial cell LTA Lipoteichoic acid LTi Lymphoid tissue inducer MAPK Mitogen activated protein kinase MCMV Mouse cytomegalovirus MDSC Myeloid-derived dendritic cell MFI Mean fluorescence intensity MHC Major histocompatability complex MHV Murine hepatitis virus 6 MIP Macrophage inflammatory protein MTP Microsomal triglyceride transfer protein NCAM Neural cell adhesion molecule NCR Natural cytotoxicity receptor NEMO NF-kappa-B essential modulator NK Natural killer NKG2A Natural-killer group 2, member A NKG2C Natural-killer group 2, member C NKG2D Natural-killer group 2, member D NKp30 Natural killer cell p30-related protein NKp44 Natural killer cell p44-related protein NKp46 Natural killer cell p46-related protein NKP Natural killer precursor NK-R Natural killer receptor NKT Natural killer T NPC Non-parenchymal cells OPG Osteoprotegerin ORF Open reading frame PAMP Pathogen-associated molecular pattern PBMC Peripheral blood mononuclear cells PBS Phosphate buffered saline pDC Plasmacytoid dendritic cell PCR Polymerase chain reaction PD-1 Programmed death-1 Peg-IFN-α Pegylated-Interferon-α PI3K Phosphoinositide 3-kinase PLC-γ Phospholipase C gamma PMA Phorbol 12-Myristate 13-Acetate PMN Polymorphonuclear PRR Pattern recognition receptor RIP1 Receptor Interacting protein 1 RNA Ribonucleic acid RORγt Retinoic acid receptor related orphan receptor gamma SHP-1 Src homology 2 domain-containing phosphatase-1 SIV Simian immunodeficiency virus SLT Secondary lymphoid tissue SNP Single nucleotide polymorphism STAT-1 Signal transducer and activator of transcription 1 Tcm Central memory CD8+ T cells TCR T cell receptor Tem Effector memory CD8+ T cells Temra Revertant CD8+ T cells TGF-β Transforming growth factor beta Tim-3 T cell immunoglobulin mucin-3 7 TLR Toll-like receptor TNF-α Tumour necrosis factor alpha TNFR1 Tumour necrosis factor receptor 1 TRADD TNF-receptor associated death domain TRAF-2 TNF-receptor associated protein TRAIL TNF-related apoptosis inducing ligand TRAIL-R TNF-related apoptosis inducing ligand receptor Treg Natural regulatory T cell uPa/SCID Urokinase-type plasminogen activator-severe combined immunodeficiency VV Vaccinia virus WHV Woodchuck hepatitis virus ZAP-70 Zeta-chain-associated protein kinase 70 8 Table of Contents Title page ............................................................................................................... 1 Declaration ............................................................................................................ 2 Abstract ................................................................................................................
Load more

Recommended publications
  • Complete Response to PD-1 Blockade Following EBV-Specific T-Cell Therapy in Metastatic Nasopharyngeal Carcinoma
    www.nature.com/npjprecisiononcology CASE REPORT OPEN Complete response to PD-1 blockade following EBV-specific T-cell therapy in metastatic nasopharyngeal carcinoma Corey Smith1, Margaret McGrath2, Michelle A. Neller1, Katherine K. Matthews1, Pauline Crooks1, Laetitia Le Texier1, Benedict Panizza2, ✉ Sandro Porceddu2 and Rajiv Khanna 1 Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated heterogeneous disease and is characterized by peritumoral immune infiltrate. Adoptive T-cell therapy (ACT) has emerged as a potential therapeutic strategy for NPC. However, the tumor microenvironment remains a major roadblock for the successful implementation of ACT in clinical settings. Expression of checkpoint molecules by malignant cells can inhibit the effector function of adoptively transferred EBV-specific T cells. Here we present a novel case report of a patient with metastatic NPC who was successfully treated with a combination of EBV-specific ACT and programmed cell death-1 blockade therapy. Following combination immunotherapy, the patient showed complete resolution of metastatic disease with no evidence of disease relapse for 22 months. Follow-up immunological analysis revealed dramatic restructuring of the global T-cell repertoire that was coincident with the clinical response. This case report provides an important platform for translating these findings to a larger cohort of NPC patients. npj Precision Oncology (2021) 5:24 ; https://doi.org/10.1038/s41698-021-00162-7 1234567890():,; INTRODUCTION disease recurrence by PET/CT for 22 months following complete Nasopharyngeal carcinoma (NPC) remains a significant burden in response. regions of South-East Asia, with incidences as high as 20 per 100,000 in regions of Southern China1. Rates of diagnosis worldwide exceed 70,000 cases annually2.
    [Show full text]
  • Evaluation of Antigen-Specific T-Cell Immunity at the Single Cell Level Using Large Panels of DNA Barcoded MHC Multimers
    Evaluation of antigen-specific T-cell immunity at the single cell level using large panels of DNA barcoded MHC multimers Kivin Jacobsen1, PhD; Dagmar Walter2; Michael Stubbington2; Katherine Pfeiffer2; Charlotte Halgreen1, Stephane Boutet2, Liselotte Brix1 1Immudex, Copenhagen, Denmark, 210x Genomics, CA, US P186 1) Introduction: 3) NGS Data analysis: 4) Antigen-specific T-cell populations detected 6) Phenotyping the bisected ASTC populations: Identification of disease-specific T-cell epitopes is key to the development of Analysis of the sequencing data were performed using Cell Ranger, by Each of the 44 MHC dCODE reagent data were analyzed for identification of many novel vaccines and immunotherapies. Profiling disease-specific T cells, dimensional reduction, clustering, and t-SNE calculation. Loupe Cell Browser, positive cells using a threshold=4 and visualized by t-SNE plot The found ASTC populations were further phenotyped using TotalSeq™C emerging during a cellular immune response e.g. in tumor development or and Loupe V(D)J Browser were used for visual analysis (10x Genomics software antibody data. destruction, is an important aspect of personalized immunotherapy. package). WB2161 A*0201/GILGFVFTL (Flu MP, Influenza) Two markers, HLADR, and CCR7 (Fig 3), was shown to stain one of each of the We have developed dCODE™ Dextramer® technology, for detection of antigen WD2175 A*1101/IVTDFSVIK (EBNA 3B, EBV) bisected ASTC clusters. specific T-cells through DNA barcode using next generation sequencing. In Analysis method: WD2149 A*1101/AVFDRKSDAK (EBNA 3B, EBV) combination with 10x Genomics feature Barcode protocol the technology allows The following stringent rules were set up for the targeted analysis: WB2162 A*0201/ELAGIGILTV (MART-1) Fig.3.
    [Show full text]
  • Expansions of Adaptive-Like NK Cells with a Tissue-Resident Phenotype in Human Lung and Blood
    Expansions of adaptive-like NK cells with a tissue-resident phenotype in human lung and blood Demi Brownliea,1, Marlena Scharenberga,1, Jeff E. Moldb, Joanna Hårdb, Eliisa Kekäläinenc,d,e, Marcus Buggerta, Son Nguyenf,g, Jennifer N. Wilsona, Mamdoh Al-Amerih, Hans-Gustaf Ljunggrena, Nicole Marquardta,2,3, and Jakob Michaëlssona,2 aCenter for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14152 Stockholm, Sweden; bDepartment of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; cTranslational Immunology Research Program, University of Helsinki, 00014 Helsinki, Finland; dDepartment of Bacteriology and Immunology, University of Helsinki, 00014 Helsinki, Finland; eHelsinki University Central Hospital Laboratory, Division of Clinical Microbiology, Helsinki University Hospital, 00290 Helsinki, Finland; fDepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; gInstitute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and hThoracic Surgery, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, 171 76 Stockholm, Sweden Edited by Marco Colonna, Washington University in St. Louis School of Medicine, St. Louis, MO, and approved January 27, 2021 (received for review August 18, 2020) Human adaptive-like “memory” CD56dimCD16+ natural killer (NK) We and others recently identified a subset of tissue-resident − cells in peripheral blood from cytomegalovirus-seropositive indi- CD49a+CD56brightCD16 NK cells in the human lung (14, 15). viduals have been extensively investigated in recent years and are The human lung is a frequent site of infection with viruses such currently explored as a treatment strategy for hematological can- as influenza virus and HCMV, as well as a reservoir for latent cers.
    [Show full text]
  • Early KLRG1+ but Not CD57+CD8+ T Cells in Primary Cytomegalovirus Infection Predict Effector Function and Viral Control
    Early KLRG1+ but Not CD57+CD8+ T Cells in Primary Cytomegalovirus Infection Predict Effector Function and Viral Control This information is current as Aki Hoji, Iulia D. Popescu, Matthew R. Pipeling, Pali D. of September 24, 2021. Shah, Spencer A. Winters and John F. McDyer J Immunol published online 25 September 2019 http://www.jimmunol.org/content/early/2019/09/19/jimmun ol.1900399 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/09/20/jimmunol.190039 Material 9.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published September 25, 2019, doi:10.4049/jimmunol.1900399 The Journal of Immunology Early KLRG1+ but Not CD57+CD8+ T Cells in Primary Cytomegalovirus Infection Predict Effector Function and Viral Control Aki Hoji,*,1 Iulia D. Popescu,*,1 Matthew R. Pipeling,* Pali D. Shah,† Spencer A.
    [Show full text]
  • The Microrna Mir-31 Inhibits CD8+ T Cell Function in Chronic Viral Infection
    ARTICLES The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection Howell F Moffett1, Adam N R Cartwright1, Hye-Jung Kim1, Jernej Godec2, Jason Pyrdol1, Tarmo Äijö3, Gustavo J Martinez4,6, Anjana Rao4, Jun Lu5, Todd R Golub5, Harvey Cantor1, Arlene H Sharpe2, Carl D Novina1 & Kai W Wucherpfennig1,2 During infection, antigen-specific T cells undergo tightly regulated developmental transitions controlled by transcriptional and post-transcriptional regulation of gene expression. We found that the microRNA miR-31 was strongly induced by activation of the T cell antigen receptor (TCR) in a pathway involving calcium and activation of the transcription factor NFAT. During chronic infection with lymphocytic choriomeningitis virus (LCMV) clone 13, miR-31-deficent mice recovered from clinical disease, while wild-type mice continued to show signs of disease. This disease phenotype was explained by the presence of larger numbers of cytokine-secreting LCMV-specific CD8+ T cells in miR-31-deficent mice than in wild-type mice. Mechanistically, miR-31 increased the sensitivity of T cells to type I interferons, which interfered with effector T cell function and increased the expression of several proteins related to T cell dysfunction during chronic infection. These studies identify miR-31 as an important regulator of T cell exhaustion in chronic infection. The control of pathogens and cancers requires proper functioning of pro-inflammatory cytokine signaling by repressing the signaling inhib- the adaptive immune system. CD8+ T cells are a crucial component of itor SOCS1 and promotes the population expansion of anti-viral CD8+ such immune responses; they are able to undergo massive population T cells by blocking the anti-proliferative effect of type I interferons8,9.
    [Show full text]
  • KLICKMER Flyer
    KLICKMER T CELL IMMUNE MONITORING AND BEYOND! YOUR DEXTRAMER® WILL BE READY TO GO IN JUST ONE KLICK Add biotinylated protein to the fluorescent Klickmer and create your personalized Dextramer® reagent. Push the power of Dextramer® beyond the detection of epitope specific T cells. KLICKMER – DESIGN YOUR OWN DEXTRAMER® MOLECULE WHAT IS KLICKMER? KLICKMER A Klickmer is a Dextramer® backbone carrying multiple streptavidins, enabling binding of a high number of biotinylated molecules. Due to the biotin-streptavidin affinity, biotinylated molecules can be loaded onto the Klickmer generating a high avidity multimer displaying your biomolecule. Klickmer reagents carry PE/FITC/APC label, and an unlabeled version is also available. GET INSPIRED BY KLICKMER… Klickmer represent the scaffold to which potentially any biotinylated molecule can be attached. This multipurpose tool serves a range of applications and can help you address your scientific questions. APPLICATIONS Highly sensitive detection of antigen-specific T cell populations. Simulation of antigen presentation to B or T cells. Investigation of the interaction ligand-receptor- expressing cells and identification of ligands for low-affinity interactions or orphan receptors. Amplification of the signal on your cell populations by flow cytometry, or other fluorescence assays. STREPTAVIDIN BIOTINYLATED MOLECULE Isolation of specific antigen-presenting cells. FLUOROPHORE DEXTRAN Only your scientific field will set the limit! REFERENCE 1) Dolton, G, et al. Comparison of peptide-major histocompatibility complex 7) Chancellor, A, et al. CD1b-restricted GEM T cell responses are tetramers and dextramers for the identification of antigen-specific T cells. modulated by Mycobacterium tuberculosis mycolic acid meromycolate Clin Exp Immunol. 2014; 177(1):47-63.
    [Show full text]
  • Predicting Immunogenic Tumour Mutations by Combining Mass Spectrometry and Exome Sequencing
    LETTER doi:10.1038/nature14001 Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing Mahesh Yadav1*, Suchit Jhunjhunwala1*, Qui T. Phung1, Patrick Lupardus1, Joshua Tanguay1, Stephanie Bumbaca1, Christian Franci1, Tommy K. Cheung1, Jens Fritsche2, Toni Weinschenk2, Zora Modrusan1, Ira Mellman1, Jennie R. Lill11 &Le´lia Delamarre11 Human tumours typically harbour a remarkable number of somatic identify 4,285 and 949 non-synonymous variants in MC-38 and TRAMP- mutations1. If presented on major histocompatibility complex class C1, respectively (Fig. 1b). To select for high-confidence mutations and I molecules (MHCI), peptides containing these mutations could po- focus on the mutations likely to be expressed in the majority of the tu- tentially be immunogenic as they should be recognized as ‘non-self’ mour cells, we subsequently selected RNA-seq-based variants that were neo-antigens by the adaptive immune system. Recent work has con- present at a minimum of 20% allelic frequency and overlapped with the firmed that mutant peptides can serve as T-cell epitopes2–9.However, exome-based variants. This resulted in 1,290 and 67 expressed mutations few mutant epitopes have been described because their discovery in MC-38 and TRAMP-C1, respectively. Next we identified 170 predicted required the laborious screening of patient tumour-infiltrating lym- neo-epitopes in MC-38 and 6 predicted neo-epitopes in TRAMP-C1 phocytes for their ability to recognize antigen libraries constructed using the NETMHC-3.4 algorithm11 (Fig. 1b, Supplementary Tables 1 following tumour exome sequencing. We sought to simplify the dis- and 2). Despite high density exome reads, only a small number of non- covery of immunogenic mutant peptides by characterizing their gen- synonymous variants and predicted neo-epitopes in TRAMP-C1 were eral properties.
    [Show full text]
  • Elispot Proficiency Panel 2015
    ELISPOT PROFICIENCY PANEL 2015 March 2016 CONTACT — Charlotte Halgreen FOR MORE INFORMATION [email protected] www.proficiencypanel.com IMMUDEX.COM ELISPOT PROFICIENCY PANEL 2015 This report summarizes the results of the Elispot Proficiency 42 laboratories from 13 Panel 2015. The report provides individual test results for each countries participated in participating laboratory that participated in the Elispot the Elispot Proficiency proficiency panel 2015, as well as an anonymized overview of Panel the other participants’ test results. 42 laboratories from 13 countries participated in the Elispot Participants are active in Proficiency Panel. Participants included researchers and such diverse fields as clinicians active in such diverse fields as Cancer, HIV, Hepatitis, Cancer, HIV, Hepatitis, and Diabetes. and Diabetes Immudex has taken over the MHC Multimer and Elispot proficiency panels from the CIC (Cancer Immunotherapy Consortium of the Cancer Research Institute, USA) and the CIMT (Association for Cancer Immunotherapy, Europe). The proficiency panel services offered by Immudex are open to any laboratory, independent on geographic location or field of interest, with a need to perform accurate and reproducible quantification of antigen-specific T cells. The report is provided using the European numeration. The proficiency panels conducted by Immudex are non-profit Next MHC Multimer and services offered with the intent of testing and ensuring a high Elispot proficiency panels level of proficiency and reliability among the researchers and to be held in the fall clinicians that perform the immune monitoring assays. It is the 2016 and spring 2017, hope and expectation that better immune monitoring assays respectively will lead to better and more efficient immunotherapies.
    [Show full text]
  • Immudex Takes on International Proficiency Panels
    IMMUDEX BECOMES THE PROVIDER OF MHC MULTIMER AND ELISPOT PROFICIENCY PANEL SERVICES IMMUDEX TAKES ON INTERNATIONAL PROFICIENCY PANELS Copenhagen, Denmark, Mainz, Germany, and New York, USA – April 2013 Immudex has entered into a strategic agreement with the US Cancer Immu- notherapy Consortium (CIC) of the Cancer Research Institute, and the Euro- pean Association for Cancer Immunotherapy (CIMT), under which Immudex will provide MHC-peptide multimer and Elispot proficiency panel services world- wide. CIC and CIMT originally established proficiency panel programs to offer an external validation of assay performance and to enhance assay harmonization. Over the years, more than one hundred laboratories have participated not only from the cancer field, but also from other immunological fields utilizing immune monitoring. As a result, two frequently used immune monitoring methods, the MHC-peptide multimer and Elispot assays, have now reached a high degree of harmonization. Immudex, specialized in the detection of antigen-specific T cells, has been an active participant in the proficiency panel process and is globally recognized for its expertise in immune monitoring. Thus Immudex was the logical choice as partner for pro- ficiency panels. Starting in fall of 2013, Immudex will be providing proficiency panels for MHC multimer and Elispot assays to laboratories worldwide, independently of their background and association. Immudex will continue the external validation program established by CIC and CIMT under the successfully implemented harmonization guidelines and will promote a more widespread use of these technologies in the development of new cancer immunotherapies and vaccines against other diseases such as HIV, TB, diabetes and others. Sylvia Janetzki, coordinator of the CIC panel program, explains the rationale for handing the proficiency panels over to Immudex: “Immudex has been an activate partner and valued col- laborator in our panel activities.
    [Show full text]
  • CD8 T Cell Differentiation During Immune Responses
    UNIVERSITÉ PARIS DESCARTES FACULTÉ DE MEDECINE-site Necker INSERM U1020 (ex U591) _______________________________________________________________________ THÈSE Pour obtenir le grade de DOCTEUR Sciences de la Vie et de la Santé Discipline: Immunologie École Doctoral: Gc2iD Présentée et soutenue publiquement par Sara Sofia de Campos Pereira Lemos Le 23 Mai 2014 CD8 T cell differentiation during immune responses Jury: Dr. Jacqueline MARVEL Rapporteur Dr. Sylvie GUERDER Rapporteur Dr. Jérôme DELON Examinateur Dr. Nicolas BLANCHARD Examinateur Dr. Benedita ROCHA Directeur de these 1 To a wonderful person, an extraordinary woman and an amazing mother... my mother, Arlete Pereira “The first precept was never to accept a thing as true until I knew it as such without a single doubt.” René Descartes (French philosopher and scientist) “We live where no one knows the answer and the struggle is to figure out the question” Joshua Schimel (in “Writing Science” book). “ To be great, be whole; Exclude nothing, exaggerate nothing that is not you. Be whole in everything. Put all you are Into the smallest thing you do. So, in each lake, the moon shines with splendor Because it blooms up above.” Fernando Pessoa (Portuguese poet) “The beauty of life is not about finding something big enough, but rather on finding something deep enough! Sara Lemos (a dreamer!) 2 Acknowledgments My very first and respectful acknowledgment I owe to an extraordinary scientist and remarkable person: my supervisor Benedita ROCHA. Thank you for accepting me in your lab, for supervising this work, for all the opportunities given to grow as a PhD student and as a person, for all the freedom at the bench, and yet for always pushing me forward.
    [Show full text]
  • Resistance to Tgfβ Suppression and Improved Anti-Tumor Responses In
    ARTICLE DOI: 10.1038/s41467-017-01427-1 OPEN Resistance to TGFβ suppression and improved anti- tumor responses in CD8+ T cells lacking PTPN22 Rebecca J. Brownlie 1,2, Celine Garcia1, Mate Ravasz1, Dietmar Zehn3, Robert J. Salmond 1,2 & Rose Zamoyska 1 Transforming growth factor β (TGFβ) is important in maintaining self-tolerance and inhibits T cell reactivity. We show that CD8+ T cells that lack the tyrosine phosphatase Ptpn22, a major 1234567890 predisposing gene for autoimmune disease, are resistant to the suppressive effects of TGFβ. Resistance to TGFβ suppression, while disadvantageous in autoimmunity, helps Ptpn22−/− T cells to be intrinsically superior at clearing established tumors that secrete TGFβ. Mechanistically, loss of Ptpn22 increases the capacity of T cells to produce IL-2, which overcomes TGFβ-mediated suppression. These data suggest that a viable strategy to improve anti-tumor adoptive cell therapy may be to engineer tumor-restricted T cells with mutations identified as risk factors for autoimmunity. 1 Institute of Immunology and Infection Research, University of Edinburgh, Ashworth Laboratories, Charlotte Auerbach Road, Edinburgh EH9 3FL, UK. 2 Leeds Institute of Cancer and Pathology, University of Leeds, Wellcome Trust Brenner Building, St James’s University Hospital, Leeds LS9 7TF, UK. 3 School of Life Sciences Weihenstephan, Technical University Munich, Weihenstephaner Berg 3, Freising 85354, Germany. Correspondence and requests for materials should be addressed to R.J.S. (email: [email protected]) or to R.Z.
    [Show full text]
  • Insights Provided by the Α4–Integrin Deficient NOD Mouse
    cells Article Adaptive Immunity and Pathogenesis of Diabetes: Insights Provided by the α4–Integrin Deficient NOD Mouse 1, 1 2 2 2 Salim Oulghazi y , Sarah K. Wegner , Gabriele Spohn , Nina Müller , Sabine Harenkamp , Albrecht Stenzinger 3, Thalia Papayannopoulou 4 and Halvard Bonig 1,2,4,* 1 Institute for Transfusion Medicine and Immunohematology, School of Medicine, Goethe University, Sandhofstraße 1, 60528 Frankfurt, Germany; [email protected] or [email protected] (S.O.); [email protected] (S.K.W.) 2 Institute Frankfurt, German Red Cross Blood Service BaWüHe, Sandhofstraße 1, 60528 Frankfurt, Germany; [email protected] (G.S.); [email protected] (N.M.); [email protected] (S.H.) 3 Institute for Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 672, 69120 Heidelberg, Germany; [email protected] 4 Department of Medicine/Division of Hematology, University of Washington, 1959 NE Pacific St., Seattle, WA 98195, USA; [email protected] * Correspondence: [email protected]; Tel.: +49-69-6782177 Current address: Department of Internal Medicine V (Hematology/Oncology/Rheumatology), y University Hospital Heidelberg, Im Neuenheimer Feld 672, 69120 Heidelberg, Germany. Received: 11 November 2020; Accepted: 2 December 2020; Published: 4 December 2020 Abstract: Background: The spontaneously diabetic “non-obese diabetic” (NOD) mouse is a faithful model of human type-1 diabetes (T1D). Methods: Given the pivotal role of α4 integrin (CD49d) in other autoimmune diseases, we generated NOD mice with α4-deficient hematopoiesis (NOD.α4-/-) to study the role of α4 integrin in T1D. Results: NOD.α4-/- mice developed islet-specific T-cells and antibodies, albeit quantitatively less than α4+ counterparts.
    [Show full text]