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Interleukin-15-Mediated Immunotoxicity and Exacerbation of Sepsis

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INTERLEUKIN-15-MEDIATED IMMUNOTOXICITY AND EXACERBATION OF SEPSIS: ROLE OF NATURAL KILLER CELLS AND INTERFERON γ By Yin Guo Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Microbiology and Immunology December 2016 Nashville, Tennessee Approved Luc Van Kaer, Ph.D. Stokes Peebles, M.D. Lorraine Ware, M.D. Daniel Moore, M.D., Ph.D. Edward Sherwood, M.D, Ph.D. i Copyright © 2016 by Yin Guo All Rights Reserved ii ACKNOWLEDGEMENTS I would like to thank my thesis mentor, Dr. Edward Sherwood for his tremendous instruction and support during my entire Ph.D. training course. I joined Dr. Sherwood’s lab in the department of Microbiology and Immunology of University of Texas Medical Branch (UTMB) at Galveston in 2011. I appreciated the offer Dr. Sherwood provided to move to Vanderbilt University together. During the new lab setup period, he gave me a lot of encouragement about going out to meet students and professors at the Pathology, Microbiology and Immunology Department. From making new friends in our department, I started to know a lot of useful information and resources about how to adapt to new life in Nashville and how to prepare for the qualifying exam. Dr. Sherwood is a highly responsible and enthusiastic mentor although he has busy medical practice in the operating room and needs to write many grants. I have to say, he is the most diligent person I have seen in the world. It is amazing to me that he never seems to be exhausted or desensitized with reviewing our papers, reading papers, writing grants, and discussing data and new ideas. But at the same time, he never passes his stress to us and allows us to work in our hours at our own pace. He is also open-minded as he allows us to explore new ideas, techniques or models in our research. I feel very fortunate to have great colleagues in Dr. Sherwood’s lab. Julia Bohannon is a great friend and instructor that extensively contribute to my Ph.D. training. She teaches me many basic lab techniques and offers me good suggestions from being a great scientist to being a great mom. I would like to thank Liming Luan, a wonderful helper with my experiments. With his generous help, I am able to fasten my graduation by generating a lot of data from big iii experiments. I would like to thank Jingbin Wang for helping me breed IL-15 KO mice during my maternity leave and check mice at night sometimes. I thank Naeem Patil and Antonio Hernandez for their great help with my experiments and paper review. I also thank Benjamin Fensterheim as he is the greatest teacher for my academic writing and speaking. He also tells me many interesting things in music, politics, movies and living styles in the USA. Special thanks to my thesis committee who have been continuously supportive throughout my graduate training. I thank Dr. Luc Van Kaer for chairing my committee and providing useful scientific knowledge and suggestions. I felt very grateful when he agreed to chair my committee, even if he never taught me or even knew me, as a transfer student by that time. I thank Dr. Lorraine Ware for providing a detailed review of my proposal for the qualifying exam and supporting my thesis project and new parental life. I thank Dr. Stokes Peebles for lending me his immunology textbook, asking insightful scientific questions and taking the time to meet me out of his busy schedule. Finally, I thank Dr. Daniel Moore for providing great suggestions for my project, offering me IL-15 knockout mice from the colony in his lab and allowing me to work with Blair Stocks, an MSTP student in his lab for human IL-15 superagonist project. I also would like to thank other people in our department. Whitney Rabacal is my great friend in Dr. Eric Sabzda’s lab. She taught me how to isolate leukocytes from livers and how to do immunohistochemistry staining on my slides. We also encourage and support each other when we meet with difficulties for our research or life. I thank Dr. Lan Wu for providing a lot of good suggestions about my science career and the balance between work and family. I also iv want to thank Pavlo Gilchuk for his generous offer of flow antibodies for my experiments. Special thanks to my classmates and professors at UTMB who have offered great help during my first year in the USA. At last, I would like to thank my family. My parents and parents in law have always been supportive of my graduate training. They helped me take care of Amy, my daughter so I can have sufficient time to devote myself to scientific research. I also thank my husband, Xiang Zhang, for conferring endless support and care and encouraging me to take exercise after work. Finally, I would like to thank my daughter Amy, who is the best thing that ever happened to me. She gave me a lot of inspirations for everyday life and makes me a stronger and a greater person. Overall, I would like to thank Vanderbilt University for providing a friendly and multi- cultural environment for international students. I feel grateful to meet friends from other countries, which introduces me to a broader world and become open-minded. v TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ................................................................................................................................ iii LIST OF FIGURES ............................................................................................................................................ x LIST OF TABLES ............................................................................................................................................xiii LIST OF ABBREVIATIONS ............................................................................................................................. xiv CHAPTER I.................................................................................................................................................. - 1 - INTRODUCTION ..................................................................................................................................... - 1 - Thesis overview ................................................................................................................................. - 1 - Immunotherapy background ............................................................................................................ - 2 - IL-15 discovery, trans-presentation and expression ......................................................................... - 5 - IL-15 signaling ................................................................................................................................... - 7 - IL-15 superagonist (IL-15 SA) ............................................................................................................ - 8 - Impact of IL-15 on innate immune cells ............................................................................................ - 8 - Natural Killer (NK) Cells ................................................................................................................. - 8 - Natural Killer T (NKT) Cells and Intraepithelial Lymphocytes (IEL) ............................................. - 11 - Impact of IL-15 on adaptive immune cells ...................................................................................... - 11 - CD8+ T lymphocytes .................................................................................................................... - 11 - CD4+ T lymphocytes .................................................................................................................... - 12 - B lymphocytes ............................................................................................................................. - 13 - IL-15 knockout (IL-15 KO) mice ....................................................................................................... - 13 - IL-15 toxicity .................................................................................................................................... - 14 - The role of IL-15 in autoimmune and chronic inflammatory diseases ........................................... - 15 - Sepsis............................................................................................................................................... - 15 - Definition of sepsis ...................................................................................................................... - 15 - Epidemiology of sepsis ................................................................................................................ - 18 - Etiology of sepsis ......................................................................................................................... - 19 - Treatments of sepsis ................................................................................................................... - 19 - vi Clinical trials of sepsis ................................................................................................................. - 20 - Animal models of sepsis .............................................................................................................. - 21 - Sepsis timeline ............................................................................................................................ - 24 - Pathophysiology of sepsis ........................................................................................................... - 25 - Inflammation
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