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Investigation of Penicillamine-Induced Autoimmunity

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Investigation of Penicillamine-Induced Autoimmunity Mechanistic Investigation of Penicillamine-Induced Autoimmunity: Covalent Binding of Penicillamine to Macrophages, Involvement of Th17 cells, and Its Relation to Idiosyncratic Drug-induced Liver Injury By Jinze Li A thesis submitted in conformity with the requirements for the degree of DOCTOR OF PHILOSOPHY Graduate Department of Pharmaceutical Sciences University of Toronto ©Copyright by Jinze Li 2009 Library and Archives Bibliothèque et Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l’édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre référence ISBN: 978-0-494-61128-9 Our file Notre référence ISBN: 978-0-494-61128-9 NOTICE: AVIS: The author has granted a non- L’auteur a accordé une licence non exclusive exclusive license allowing Library and permettant à la Bibliothèque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l’Internet, prêter, telecommunication or on the Internet, distribuer et vendre des thèses partout dans le loan, distribute and sell theses monde, à des fins commerciales ou autres, sur worldwide, for commercial or non- support microforme, papier, électronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L’auteur conserve la propriété du droit d’auteur ownership and moral rights in this et des droits moraux qui protège cette thèse. Ni thesis. Neither the thesis nor la thèse ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent être imprimés ou autrement printed or otherwise reproduced reproduits sans son autorisation. without the author’s permission. In compliance with the Canadian Conformément à la loi canadienne sur la Privacy Act some supporting forms protection de la vie privée, quelques may have been removed from this formulaires secondaires ont été enlevés de thesis. cette thèse. While these forms may be included Bien que ces formulaires aient inclus dans in the document page count, their la pagination, il n’y aura aucun contenu removal does not represent any loss manquant. of content from the thesis. ABSTRACT Mechanistic Investigation of Penicillamine-Induced Autoimmunity: Covalent Binding of Penicillamine to Macrophages, Involvement of Th17 cells, and Its Relation to Idiosyncratic Drug-induced Liver Injury By Jinze Li Faculty of Pharmacy, University of Toronto 2009 The mechanisms of idiosyncratic drug reactions (IDRs) are unknown; however, most appear to be immune-mediated. Their idiosyncratic nature and the paucity of animal models make mechanistic studies very difficult. One of the few animal models is penicillamine- induced autoimmunity in Brown Norway rats. The major focus of this thesis was the use of this model to study the interaction between penicillamine and macrophages, the involvement of Th17 cells, and extension of this model to idiosyncratic drug-induced liver injury. One of the costimulatory signals leading to T cell activation appears to be reversible Schiff-base formation between an amine on T cells and an aldehyde on macrophages. We hypothesized that penicillamine binds to these aldehydes leading to macrophage activation and autoimmunity. By using biotinylated aldehyde-reactive agents such as ARP, we demonstrated the existence of aldehydes on the surface of macrophages. We synthesized biotinylated-penicillamine and it also binds to macrophages. Several proteins to which ARP binds were identified providing clues to the signal transduction pathways leading to macrophage activation. Biological consequences of this binding were investigated with a microarray study. ARP binding was also observed in the macrophage cell line, RAW264.7, and incubation with penicillamine stimulated the production of TNF-α, IL-6, and IL-23. II Hydralazine and isoniazid, which are known to cause a lupus-like syndrome in humans and irreversibly bind to aldehyde groups, were also found to activate RAW264.7 cells. Th17 cells are prominent in autoimmune syndromes and Th17-associated cytokines such as IL-17 were elevated in the penicillamine-treated animals that developed autoimmunity. We have hypothesized that some drug-induced liver injury has an autoimmune component. A pilot study quantified serum concentrations of 26 cytokines/chemokines in patients with various forms of acute liver failure (ALF): idiosyncratic drug-induced ALF, acetaminophen-induced ALF, and viral hepatitis. IL-17 was elevated in 60% of patients with idiosyncratic drug-induced ALF, which supports an autoimmune component in these patients; however, it was also elevated in many cases of acetaminophen-induced ALF, presumably released by the innate immune system. These studies provide important insights into the mechanism of penicillamine-, hydralazine-, and isoniazid-induced autoimmunity and also provide clues to other IDRs that may have an autoimmune component. III ACKNOWLEDGEMENT It still feels like yesterday when Jack interviewed me in his office, his face beaming while making the remark “learning science in graduate school is fun!”. Four years have already passed by and I am writing this concluding note with a very mixed feeling. This four-year graduate school in Jack’s lab is a truly exciting adventure and one of the most important steps in my career. I would regret my doctoral education if I did not join Jack’s lab in which I benefited from the generous help of many friends and colleagues to whom I want to express my sincere gratitude. First of all, I would like to whole-heartedly thank my supervisor, Dr. Jack Uetrecht for his great mentorship and friendship throughout this program. Being a mentor, he gives trust, encouragement, and guidance that have allowed me to complete this challenging work in a timely fashion. It is really a great honor and pleasure to work with him. Being a friend, he cares about my well-being and shares with me his thoughts and experience that makes me feel belong. To quote what Jack said at his conference of adverse drug reactions a couple of years ago, “the students do become in a sense like your family and like a family, you see them develop and go off and succeed”, to me this four-year experience does feel more like a family journey that I would cherish forever. I would also like to thank my advisory committee, Dr. Allan Okey, Dr. Micheline Piquette-Miller, Dr. Robert Inman, the internal examiner, Dr. Robert Macgregor, and the external examiner of my thesis, Dr. Dan Wierda from the Lilly Research Labs. I very much value the opinions and time taken by them throughout my research program and thesis preparation. Very importantly, I give my regards and blessings to all my lab buddies in Jack’s group, particularly Wei Lu, Julia Ip, Jie Chen, Baskar Mannargudi, Tharsika Tharmanathan, Xu Zhu, Feng Liu, Xin Chen, Ping Cai, Xiaochu Zhang, Stephanie Pacitto, and Jacintha Shenton for their intellectual inputs, friendship, and the happy hours of gossiping together, which is certainly one of major sources of fun during my PhD education. Meanwhile, I IV want to give my special thanks to Hong Gou as a great friend who has been supporting and inspiring me in many respects. Finally, I would like to take this opportunity to thank my wife, Yanmei Chen whose constant encouragement and love I have relied on throughout my PhD program. Also, I am indebted to my daughter, mom, and dad for their care, understanding, and love. This work would not have been possible without my family. It is to them that I dedicate this dissertation. V TABLE OF CONTENTS ABSTRACT........................................................................................................................................................II ACKNOWLEDGEMENT............................................................................................................................... IV TABLE OF CONTENTS................................................................................................................................. VI LIST OF THESIS PUBLICATIONS AND ABSTRACTS............................................................................ IX LIST OF ABBREVIATIONS ............................................................................................................................X LIST OF FIGURES ...................................................................................................................................... XIV LIST OF TABLES......................................................................................................................................... XVI CHAPTER 1........................................................................................................................................................1 GENERAL INTRODUCTION ..........................................................................................................................1 1.1. ADVERSE DRUG REACTIONS................................................................................................................2 1.2. IDIOSYNCRATIC DRUG REACTIONS..................................................................................................5 1.2.1. CLINICAL MANIFESTATIONS OF IDRS............................................................................................6 1.2.2. RISK FACTORS FOR IDRS...................................................................................................................6
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