Clinical Applications of

For other titles published in this series, go to www.springer.com/series/7528 Immunonomics Reviews An Official Publication of the International Immunomics Society

Series Editors: Vladimir Brusic, Dana-Farber Institute, Boston, Massachusetts Andras Falus, Semmelweis University, Budapest, Hungary

Editorial Board: Anne S. De Groot, Brown University, Providence, Rhode Island Darren Flower, Edward Jenner Institute for Research, Berkshire, UK Christian Schonbach, Nanyang Technological University, Singapore Shoba Ranganathan, Macquarie University, Australia Marie-Paule Lefranc Universite Montpellier II, Montpellier, France

This peer-reviewed book series offers insight on for 21st century. The technological revolution has borne advances in high-throughput instrumentation and information technology, initiating a renaissance for biomathematics, and biostatistics. Cross-fertilization between and immunology has led to a new field called immunomics, transforming the way in which theoretical, clinical and applied immunology are practiced. Immunomics Reviews will cover integrative approaches and applications to the theory and practice of immunology and explore synergistic effects resulting from a combination of technological advances and the latest analytical tools with the traditional fields of basic and clinical immunology. Andras Falus Editor

Clinical Applications of Immunomics

13 Editor Andras Falus Semmelweis University Budapest, Hungary [email protected]

ISBN: 978-0-387-79207-1 e-ISBN: 978-0-387-79208-8 DOI: 10.1007/978-0-387-79208-8

Library of Congress Control Number: 2008934033

# Springer ScienceþBusiness Media, LLC 2009 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer ScienceþBusiness Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

Printed on acid-free paper springer.com Contents

Integrative Systems Approaches to Study Innate ...... 1 Timothy Ravasi

Immunomics: At the Forefront of Innate Immunity Research ...... 15 Hongtao Guan, Steven K Dower, and Endre Kiss-Toth

Epitope-Based -Derived : A Strategy for Improved Design and Safety ...... 39 Anne S. De Groot, Leonard Moise, Julie A. McMurry, and William Martin

Immunodeficiencies and Immunome: Diseases and Information Services .. 71 Mauno Vihinen

Immunomics of Immune Rejection ...... 87 Ena Wang, Marianna Sabatino, and Francesco M Marincola

Spectrum, Function, and Value of Targets Expressed in Neoplastic Mast Cells ...... 107 Peter Valent

Structure, Allergenicity, and Cross-Reactivity of Plant Allergens ...... 127 Christian Radauer and Heimo Breiteneder

The Live Basophil Allergen Array (LBAA): A Pilot Study ...... 153 Franco H. Falcone, Jing Lin, Neil Renault, Helmut Haas, Gabi Schramm, Bernhard F. Gibbs, and Marcos J.C. Alcocer

Emerging Therapies for the Treatment of Autoimmune Myasthenia Gravis...... 171 Kalliopi Kostelidou, Anastasia Sideri, Konstantinos Lazaridis, Efrosini Fostieri, and Socrates J. Tzartos

v vi Contents

New Diagnostic and Therapeutic Options for the Treatment of ...... 205 Paolo Riccio, Heinrich Haas, Grazia Maria Liuzzi, and Rocco Rossano

Glycoimmunomics of Cancer: Relevance to Monitoring Biomarkers of Early Detection and Therapeutic Response ...... 227 Mepur H. Ravindranath

Translational Immunomics of Cancer Immunoprevention ...... 253 Pier-Luigi Lollini

Index ...... 269 Contributors

Marcos J.C. Alcocer Division of Nutritional Sciences, University of Nottingham, Loughborough, UK Agnese Antognoli Section of Cancer Research, Department of Experimental Pathology, Univer- sity of Bologna, Bologna, Italy Heimo Breiteneder Department of Pathophysiology, Center of Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria Vladimir Brusic Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA, [email protected] Stefania Croci Section of Cancer Research, Department of Experimental Pathology, Univer- sity of Bologna, Bologna, Italy Steven K. Dower Cardiovascular Research Unit, University of Sheffield, Sheffield, UK Franco H. Falcone Division of Molecular and Cellular Science, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK, [email protected] Andras Falus Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary, Nagyva´rad te´r 4, 1089 Budapest, [email protected] Efrosini Fostieri Hellenic Pasteur Institute, Department of Biochemistry, Athens, Greece, [email protected] Bernhard F. Gibbs Medway School of Pharmacy, Universities of Kent and Greenwich, Kent ME4 4TB, UK

vii viii Contributors

Anne S. De Groot Director, Immunology and Informatics Institute, Center for Vaccine Research and Design, Brown University, CEO, EpiVax, Inc., Providence, RI, USA, [email protected] Hongtao Guan Cardiovascular Research Unit, University of Sheffield, Sheffield, UK Heinrich Haas Medigene AG, Martinsried, Germany, [email protected] Helmut Haas Division of Cellular Allergology, Research Centre Borstel, Leibniz Centre for Medicine and Biosciences, D-23845 Borstel, Germany Endre Kiss-Toth Cardiovascular Research Unit, University of Sheffield, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK, [email protected] Kalliopi Kostelidou Hellenic Pasteur Institute, Department of Biochemistry, Athens, Greece, [email protected] Konstantinos Lazaridis Hellenic Pasteur Institute, Department of Biochemistry, Athens, Greece, [email protected] Jing Lin Division of Nutritional Sciences, University of Nottingham, Loughborough, LE12 5RD, UK Grazia Maria Liuzzi University of Bari, Department of Biochemistry and Molecular Biology, 70126 Bari, Italy, [email protected] Pier-Luigi Lollini Section of Cancer Research, Department of Experimental Pathology, Univer- sity of Bologna, I-40126 Bologna, Italy, [email protected] Francesco M. Marincola Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA, [email protected] William Martin EpiVax, Inc., Providence, RI, USA Julie A. McMurry EpiVax, Inc., Providence, RI, USA Contributors ix

Leonard Moise EpiVax, Inc., Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA Santo Motta Department of Mathematics and Computer Science, University of Catania, Italy Annalisa Murgo Section of Cancer Research, Department of Experimental Pathology, Univer- sity of Bologna, Bologna, Italy Sakunthala Muthugounder Childrens Hospital, Los Angeles, CA 90027, USA, [email protected] Giordano Nicoletti Laboratory of Oncologic Research, Rizzoli Orthopaedic Institutes, Bologna, Italy Arianna Palladini Section of Cancer Research, Department of Experimental Pathology, University of Bologna, Bologna, Italy Francesco Pappalardo Department of Mathematics and Computer Science, University of Catania, Catania, Italy Christian Radauer Department of Pathophysiology, Center of Physiology and Pathophysiology, Med- ical University of Vienna, Vienna, Austria, [email protected] Timothy Ravasi Department of Bioengineering, Jacobs School of Engineering, University of California-San Diego, La Jolla, CA 92093,USA, [email protected] Mepur H. Ravindranath Pacific Clinical Research, Santa Monica, CA 90404, USA, [email protected] Neil Renault Division of Nutritional Sciences, University of Nottingham, Loughborough LE12 5RD, UK Paolo Riccio University of Basilicata, Department of Biology D.B.A.F., 85100 Potenza, Italy, [email protected] Rocco Rossano University of Basilicata, Department of Biology D.B.A.F., 85100 Potenza, Italy, [email protected] x Contributors

Marianna Sabatino Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA Gabi Schramm Division of Cellular Allergology, Research Centre Borstel, Leibniz Centre for Medicine and Biosciences, D-23845 Borstel, Germany Senthamil R. Selvan Hoag Cancer Center, Newport Beach, CA 92663, USA, senthamil.selvan@ hoaghospital.org Anastasia Sideri Hellenic Pasteur Institute, Department of Biochemistry, Athens, Greece, [email protected] Socrates J. Tzartos Hellenic Pasteur Institute, Department of Biochemistry; University of Patras, Department of Pharmacy, Athens, Greece, [email protected] Peter Valent Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, A-1090Vienna, Austria, peter.valent@meduniwien. ac.at Mauno Vihinen Institute of Medical Technology, University of Tampere; Tampere University Hospital, FI-33520 Tampere, Finland, [email protected] Ena Wang Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA, [email protected] Introduction: Clinical Immunomics; A New Paradigm for Translational Research

V. Brusic and A. Falus

Rapid improvement in accessibility to molecular databases as well as availability of high-throughput genomic, proteomic, and other ‘’ meth- odologies are forcing a considerable shift in research and development strate- gies for biomedicine. The recent change in research paradigm focusing on biology as system science is still difficult to grasp. , a systematic study of complex interactions in biological systems, is currently closely related to the development and application of and biostatistics tools to genomic and proteomic data. Clinical immunology translates achievements of immunological research to medically relevant applications, that is, diagnosis, prevention, and therapy. It covers a broad area including complex disorders of the (, autoimmune diseases, , and lymphoproliferative disorders), immune responses (to , , transfusion, and transplantation), and immunotherapies (Be´ne´et al. 2000). The complexity of the human immune system has several sources: combinator- ial variability, plasticity, degeneracy and adaptivity of the immune system; interactions of the immune system and other self cells, tissues, and organs; the variability of pathogens, self, and environmental ; and the presence of multiple regulatory pathways. This complexity ensures that huge amounts of data must be produced and analyzed for deciphering the workings of the immune system. To effectively use these huge databanks, we need increasingly sophisticated tools of biostatics, bioinformatics, and mathematical modeling. The integrative approaches combining multiple tools are particularly important in clinical research comprising large cohorts of usually non-homogenous groups where disease phenotype, clinical progression, molecular profiles, and patient characteristics show huge variation. Clinical immunology is not clearly differentiated as a clinical specialty because it involves a number of medical disciplines. Nevertheless,

V. Brusic Cancer Vaccine Center, Dana-Farber Cancer Institute, 77 Avenue Louis Pasteur, HIM 401, Boston, MA 02115, USA, e-mail: [email protected]

xi xii Contributors immunological approaches are increasingly being used as means of medical intervention (Be´ne´et al. 2000). Clinical immunology has a long history. Early writings date back to ancient Greece as far as 2400 years ago when Thucydides described the concept of acquired immunity to an infectious disease: ‘‘... for the same man was never attacked twice – never at least fatally’’ and the use of animal models for medical research: ‘‘But of course the effects which I have mentioned could best be studied in a domestic animal like the dog’’ (Thucydides 1982). The first text recognized (by the WHO) as scientific treatise on infectious disease is a 1100 years old essay by Rhazes, a Persian physician, describing discoveries about smallpox and measles (The Islamic Medical Manuscript Collection 2003). The later stages of the European scientific revolution of late 17th through 19th century brought both the advanced technologies (such as microscope) and the transformation of scientific ideas in chemistry and biology to provide the foundation of modern western medicine. The 19th century saw the development of successful vaccines, while 20th century produced large quantities of knowledge of fine details describing the cellular, molecular, and genetic basis of immunity. A major driver for the advancement of immunology is the expansion of knowledge of structural and functional elements of the immune system at the cellular, organ, organism, and population level. This knowledge is accu- mulated, thanks to scientific and technological progress, which continues unabated; the volume of scientific information is estimated to double every 15 years (Lukasiewicz 1994). The key enabling technologies of genomics (Falus 2005), (Purcell and Gorman 2004; Brusic et al. 2007), and bioinfor- matics (Schonbach¨ et al. 2007), and systems biology (including such genomic pathway analysis) (Tegne´r et al. 2006) provide large quantities of data describing molecular profiles of various physiological and pathological states. Advanced methods for quantification of immune responses provide means for detailed study of human immune pathology and complex host– interactions. enables measurement and characterization of individual cells and molecules representing various experimental states, for example, measure- ment of -specific immune responses (Li Pira et al. 2007). Improvement of assays for immune monitoring (e.g., multiparametric flow cytometry, nanotech- nology for quantitation of production, ELISPOT, intra-cytoplasmic cytokine staining, and mRNA as well as micro-RNA based assays) continuously expands our ability to measure profiles of and other molecules that direct and modulate immune responses (Sachdeva and Asthana 2007). Latest developments in laser scanning cytometry allow the measurement and analysis of effector function of individual cells in situ thus representing molecular and cellular events in physiological and pathological states (Harnett 2007). This volume brings together examples of various topics in clinical immunol- ogy, and various tools of immunomics. This collection of articles is not a complete collection of works in this field. Rather, it is a starting point where examples of various immunomics approaches are studied for advancement of knowledge and translation of these results into new products, methods, and Introduction: Clinical Immunomics; A New Paradigm for Translational Research xiii therapies. Translating basic immunology advances into medical applications increasingly requires multidisciplinary approach and teams comprising clini- cians at the bedside, basic immunologists at the laboratory bench, engineers who develop advanced instrumentation, along with biostatisticians and bioin- formaticians who perform data analyses and interpretations. Immunomics, therefore, is a powerful new technology that combines basic and clinical immu- nology with high-throughput instrumentation and bioinformatics for the ana- lysis and interpretation of the data. Immunomics is similar to genomics and proteomics in that a major challenge is the understanding and manipulating and involved in the functioning of the immune system. In addition, immunomics must address factors arising from the complex micro- environment affecting the immune function, as well as external challenges arising from pathogen diversity. Immunomics screening of markers of the immunologic status will in near future be used to determine who should be enrolled in a particular clinical trial and follow-up of these markers throughout the course of therapy (Tremoulet and Albani 2005). The likely major advances of immunomics will be seen first in the fields of vaccines and high-throughput diagnostics. In addition, immunomic approaches herald the development of the new generation of vaccines and immunotherapies to be tailored precisely to both the genetic make-up of the human population and of the disease profile, be it cancer, allergy, or infection (Brusic and August 2004). This volume has 11 chapters covering a range of immunomic topics. In Chapter ‘‘Integrative Systems Approaches to study Innate Immunity’’, Tim Ravasi describes systems approach to the study of cellular aspects of innate immunity, focusing on . He offers an insight into applications of systems biology, in which all main components and their interactions within a biological system are measured and then assembled into modules for further study This approach makes no assumptions about underlying mechanisms – the measurement is direct; the disadvantage is that it the scale of information that can be obtained is enormous. Systems biology uncovers relations between entities in a biological system and their regulation. Macrophages are in our primary line of defense against pathogens, and they also mediate the pathology of infectious, inflammatory, and malignant disease, and therefore understand- ing the control of their function is expected to translate into rational develop- ment of therapies. In Chapter ‘‘Immunomics: At the Forefront of Innate Immunity Research’’, Guan and Kiss-Toth describe the immunomics of innate immunity as a novel viewpoint in immunology research, integrating the approaches of cellular immu- nology, bioinformatics, genomics, proteomics, immuno-informatics, and other related scientific fields, with the aim to derive integrated models of immune modulatory processes. This chapter focuses on the system-based approaches to characterizing in detail the molecular mechanisms of regulatory processes in innate immune responses. The authors have demonstrated the power of inte- grated approach to characterization of master cytokines, their receptors, signal- ing pathways, and identification of novel components of innate immunity. xiv Contributors

In Chapter ‘‘-Based Immunome-Derived Vaccines: A Strategy for Improved Design and Safety’’, De Groot et al. have explored the immunomics applications in vaccine science. They discuss the combination of bioinformatics prediction tools and an array of experimental models (biochemical assays and animal models). Two case studies, including tularemia and human papilloma virus are presented to demonstrate the utility of immunomics for epitope-based subunit vaccine development. In Chapter ‘‘Immunodeficiencies and Immunome: Diseases and Information Services’’, Mauno Vihinen introduces the concept of Essential Human Immu- nome, and informatics resources for storage and computational analysis of genes and proteins of the immunome. This chapter focuses on primary immu- nodeficiencies and the analysis of related immunome entries from some 5000 patients. These resources assist health professionals to select suitable genetic and clinical tests for immunodeficiencies. In Chapter ‘‘Immunomics of Immune Rejection’’, Wang et al. discuss the combination of high-throughput screening of samples representing autologous tumor rejection, clearance of pathogen, acute allograft rejection, and flares of . The use of systems biology helps identify common elements between these pathologies and precise identification of factors that balance host–target interactions. They investigate the interactions of innate and adap- tive arms of human immune system and their effects to different disease scenarios. In Chapter ‘‘Spectrum, Function, and Value of Targets Expressed in Neoplas- tic Mast Cells’’, Valent explores a number of attempts made to identify novel targets and to develop targeted drugs for mast cell leukemia. In the current paper, emerging new molecular targets expressed in neoplastic mast cells are discussed in light of novel therapeutic concepts, availability of drugs, and forthcoming clinical trials. In Chapter ‘‘Structure, Allergenicity and Cross-Reactivity of Plant Allergens’’, Radauer and Breiteneder provided a detailed review of plant allergens, their structure, allergenicity, and allergic cross-reactivity. Grouping of allergens into structural families enables the identification of shared molecular properties of allergens and the basis for the prediction of allergenicity and analysis of cross- reactivity. The authors have made a case for allergy immunomics that combines allergology, , and bioinformatics. In Chapter ‘‘The Live Basophil Allergen Array (LBAA): A Pilot Study’’, Falcone et al. have described a study where microarrays were used to profile activation of basophil cells. The activation of basophils was measured by detecting basophil activation surface marker CD63, as an indirect measurement of basophil degranulation. Combining protein arrays with functional cell-based assays provides a novel method for detection of allergic sensitization. The authors also discussed the limitations and potential pitfalls of the usage of live basophil allergen array in basophil immunobiology studies. In Chapter ‘‘Emerging Therapies for the Treatment of Autoimmune Myasthe- nia Gravis’’, Kostelidou et al. have written about emerging therapies for the Introduction: Clinical Immunomics; A New Paradigm for Translational Research xv treatment of myasthenia gravis, an . They have described various treatment modalities. The range of therapeutic approaches is stunning but because of lack of knowledge of causative agents. This field offers an ideal ground for the employment of various immunomics approaches. In Chapter ‘‘New Diagnostic and Therapeutic Options for the Treatment of Multiple Sclerosis’’, Riccio et al. have reviewed new diagnostic and therapeutic options for multiple sclerosis, a multifactorial inflammatory autoimmune dis- ease. The immunomics approach combines multiple approaches: molecular biology for blocking tissue damage through blocking the activity of matrix metalloproteinases, nanotechnology for formulation and delivery of therapeu- tic agents, combined with healthy and functional foods. This paper illustrates the holistic nature of immunomics where latest technological advances in combination with lifestyle (diet) modification can exert a profound effect on the course of an autoimmune disease. In Chapter ‘‘Glycoimmunomics of Human Cancer: Relevance to Monitoring Biomarkers of Early Detection and Therapeutic Response’’, Ravindranath, Muthugounder and Selvan describe tools applied to clinical cancer immunology. They have reviewed the developments in early detection and therapeutic responses using gangliosides, a class of glycoantigens that are over- expressed on the tumor cells, relative to their expression on normal cells. Gang- liosides are released from tumor cells into both tumor microenvironment and the bloodstream. They act as immunomodulatory agents in the tumor micro- environment, while in the blood they can be used as biomarkers for diagnostics and prognostics in oncology. Because they are recognized as immunogens, gangliosides represent suitable targets for both diagnosis and therapy. In Chapter ‘‘Translational Immunomics of Cancer Immunoprevention’’, Nicoletti et al. introduced the concept of translational immunomics and appli- cations in immunoprevention of cancer. They have combined genomics and mouse models of mammary tumor for efficient identification of oncoantigens, tumor profiling, and immune monitoring. The combination of mathematical modeling and in vivo immunization with the triplex (tre-component) vaccine of mice that spontaneously develop mammary tumors enabled optimization of vaccine scheduling and minimization of the number of vaccine injections. Clinical immunomics covers a broad range of diseases and this volume is an attempt to bring together work representing a spectrum of immunomic applica- tions to showcase key technologies that will shape clinical immunology in the near future. The articles in this issue show examples of immunomics approaches to cancer, autoimmunity, allergy, and primary immunodeficiencies, along with those that address more basic aspects of large-scale studies of immunology. A common theme in this volume and key concepts deal with various combinations of bioinformatics and biostatistics, instrumentation, molecular biology, animal models, and clinical samples for advancement of clinical immunology. The combination of these approaches enables the identification of complex associa- tion networks between immunologic and clinical outcomes. Identification of clinical outcome features and their precise measurement are essential for xvi Contributors decision making on the selection of optimal therapy and modification of therapy by assessment of early responses (Tremoulet and Albani 2005). Trans- lation of technological and scientific advances into actual clinical solutions remains a huge task and immunomics offers means for systematic analysis and speeding-up the selection, discovery, design, and validation of new diag- nostic and therapeutic products for 21st century.

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