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Naiyana Gujral University of Alberta ANTIBODY-BASED DIAGNOSTIC AND THERAPEUTIC APPROACHES ON GLUTEN-SENSITIVE ENTEROPATHY by Naiyana Gujral A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Pharmaceutical Sciences Faculty of Pharmacy and Pharmaceutical Sciences © Naiyana Gujral Fall 2013 Edmonton, Alberta Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission. DEDICATION I dedicate this thesis to my beloved family with all my love respect, and gratitude. ABSTRACT Gluten-sensitive enteropathy, called Celiac disease (CD), is one of the most frequent autoimmune diseases, occurring in 1% people worldwide, upon gliadin ingestion. Currently, the only treatment available for CD individual is a strict life-long gluten-free diet. Chicken egg yolk immunoglobulin Y (IgY) is produced and examined for its efficacy in vitro, ex vivo, and in vivo to prevent enteric absorption of gliadin. This antibody was also used to develop sensitive and rapid detection kits for gluten. The extracted toxic gliadin was immunized into chickens inducing humoral immune response to produced gliadin-specific IgY antibodies. The IgY antibody was separated from non-protein component in egg yolk and was purified by gel chromatography, showing > 95% purity on electrophoresis. One gram of purified IgY antibody contains 79 mg of specific anti-gliadin IgY antibody based on quantitative ELISA technique. Under in vitro simulated gastric and intestinal conditions, competitive ELISA demonstrated that 1.5 mg anti-gliadin IgY completely neutralized 6.6 g gliadin in test tube. Using Caco2 cell culture as ex vivo test, anti-gliadin IgY prevented gliadin absorption (at a ratio of 1:3,000), resulting in no pro-inflammatory response (TNF-α and IL-1β). In-vivo BALB/c mice study showed that 31 μg specific anti-gliadin IgY antibody prevented 100 mg gliadin absorption in the gastrointestinal tract when both antibody and gliadin were orally fed. The developed antibody was used to also develop sensitive double antibody sandwich ELISA (DAS-ELISA) Immunoswab and Immunostrip assay based on anti- gliadin IgY and biotinylated monoclonal antibody (mAb) showing a detection limit of 4 ng/mL, 1.25 µg/mL and 0.25 µg/mL, respectively. Anti-gliadin IgY has potential to be used as an oral passive antibody therapy to treat CD. This CD therapeutic candidate may provide an effective means of preventing CD when co-administered with gliadin contained food. Further clinical studies are warranted to test anti-gliadin IgY formulation in CD subjects exposed to gluten. The combination of anti-gliadin IgY and biotinylated mAb provided reliable, sensitive and inexpensive tools for the detection of gluten in gluten-free and gluten- contained food products. ACKNOWLEDGEMENTS I wish to extend my sincere gratitude to the following people: My former supervisor Dr. Mavanur R. Suresh, whose expertise and knowledge added considerably to my graduate experience. I wish him good health and happiness. Dr. Hoon H. Sunwoo for his guidance and enthusiasm in the pursuit of knowledge seeded the curiosity within me and truly inspired me throughout the program. Dr. Raimar Lobenberg for his generously accepting the responsibility to supervise me after Dr. Suresh. I am deeply indebted to him for their assistance, guidance, and constructive advice. The completion of this thesis would have not been possible without timely support from my supervisors, Drs. Lobenberg and Sunwoo. I would like to extend special thanks to my supervisory committee members, Drs. Michael R. Doschak and Alan BR Thomson for continuous guidance, encouragement and constructive suggestions. I am very thankful to Drs. Sharon Marsh and Miyoung Suh for serving on my defense committee. I wish to acknowledge all members of Dr. Sunwoo’s lab for their continuous support. Special thanks to my parents (Krishna Sony and Varin Gujral) who raised me with love and supported me in all my pursuits. My brother (Amarin Sony) and sister (Keinariin Gujral) for always believing in me and keeping me motivated. Without you I would not be the person I am today. I extend my thanks to my dear friend, Wanwisa Hannok, with whom I have made the journey through graduate school. It would not have been half as enjoyable without her. Finally, I would like to thank to the following institutes: The Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada, for accepting me in the graduate studies program and providing me with the facilities, training, qualification and financial support. Alberta Livestock and Meat Agency (Edmonton, Alberta, Canada), Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada and IGY INC (Edmonton, Alberta, Canada) for financial support. TABLE OF CONTENTS CHAPTER 1: Introduction ............................................................................................ 1 1.1 Definition of celiac disease .................................................................................... 2 1.2 Prevalence .............................................................................................................. 2 1.2.1 Normal at-risk persons ................................................................................... 3 1.2.2 High at-risk persons ........................................................................................ 4 1.3 CD causing factors ................................................................................................. 5 1.3.1 Genetic factors ................................................................................................ 6 1.3.2 Dietary gluten factor ....................................................................................... 8 1.3.3 Other causing factors ...................................................................................... 9 1.3.4 Time of trigger (onset of gluten intolerance) ................................................ 10 1.4 Pathogenesis ......................................................................................................... 11 1.4.1 Site of CD ..................................................................................................... 13 1.4.2 Intestinal permeation of gliadin ..................................................................... 13 1.5 Celiac symptoms .................................................................................................. 16 1.6 Diagnosis .............................................................................................................. 18 1.6.1 Diagnostic tests ............................................................................................. 20 1.7 Treatment ............................................................................................................. 25 1.7.1 Gluten free diet ............................................................................................. 25 1.7.2 Possible pharmaceutical therapies ................................................................ 26 1.7.3 Oral passive antibody therapy ........................................................................... 28 1.8 Antibody ............................................................................................................... 28 1.8.1 Characteristics of IgY ................................................................................... 29 1.9 Production of IgY ................................................................................................. 37 1.9.1 Yield of IgY .................................................................................................. 37 1.9.2 IgY purification ............................................................................................ 39 1.9.3 Egg yolk IgY powder processing ................................................................. 40 1.10 IgY stability ....................................................................................................... 41 1.10.1 Heat .............................................................................................................. 41 1.10.2 Cold .............................................................................................................. 42 1.10.3 pH ................................................................................................................. 42 1.10.4 Heat and pH combination ............................................................................. 42 1.10.5 Proteolytic enzymes...................................................................................... 43 1.11 Protectants and IgY formulation ........................................................................ 44 1.12 Applications of IgY ........................................................................................... 46 1.12.1 Passive immunization ..................................................................................
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