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Effects of GM-CSF on Dendritic Cells and Regulatory T Cells in Parkinson’S Disease Patients and Models of Parkinson’S Disease

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Effects of GM-CSF on Dendritic Cells and Regulatory T Cells in Parkinson’S Disease Patients and Models of Parkinson’S Disease University of Nebraska Medical Center DigitalCommons@UNMC Theses & Dissertations Graduate Studies Fall 12-15-2017 Effects of GM-CSF on Dendritic Cells and Regulatory T cells in Parkinson’s Disease Patients and Models of Parkinson’s Disease Charles Schutt University of Nebraska Medical Center Follow this and additional works at: https://digitalcommons.unmc.edu/etd Part of the Immunopathology Commons, and the Other Neuroscience and Neurobiology Commons Recommended Citation Schutt, Charles, "Effects of GM-CSF on Dendritic Cells and Regulatory T cells in Parkinson’s Disease Patients and Models of Parkinson’s Disease" (2017). Theses & Dissertations. 236. https://digitalcommons.unmc.edu/etd/236 This Dissertation is brought to you for free and open access by the Graduate Studies at DigitalCommons@UNMC. It has been accepted for inclusion in Theses & Dissertations by an authorized administrator of DigitalCommons@UNMC. For more information, please contact [email protected]. Effects of GM-CSF on Dendritic Cells and Regulatory T cells in Parkinson’s Disease Patients and Models of Parkinson’s Disease By Charles Schutt A Dissertation Presented to the Faculty of the Graduate College in the University of Nebraska in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Department of Pharmacology and Experimental Neuroscience Under the Supervision of Professor R. Lee Mosley University of Nebraska Medical Center Omaha, Nebraska November, 2017 Supervisory Committee: Howard E. Gendelman M.D. Larisa Y. Poluektova, M.D., Ph.D. Tammy L Kielian Ph. D. Joyce C. Solheim Ph. D. ii ACKNOWLEDGMENTS There are too many people who have contributed to my graduate studies to acknowledge all of them, but several people need to be named. First, I would like to thank my advisor Dr. R. Lee Mosley for giving me the opportunity to pursue my careers goals. I am grateful for his time, patience, support, and guidance over the years spent in his laboratory. Through his efforts, I think I have become a better student, scientist, and person. I would also like to acknowledge my committee members, Drs. Howard, Gendelman, Tammy Kielian, Larisa Poluektova, and Joyce Solheim for their time, attention, and guidance. I am grateful for their comments, criticisms, encouragement, and support. This support is instrumental for my development as a student and a scientist. Especially, I would like to thank Dr. Gendelman for his continued financial support for these projects, especially for allowing me to play a role in the clinical trial. I would like to acknowledge all the past and current members of the Drs. Mosley and Gendelman laboratories. I would like to thank Dr. Kristi Anderson, Bhagya Dyavar Shetty, Dr. Katherine Estes, Dr. Lisa Kosloski, Dr. Elizabeth Kosmacek, Max Kuenstling, Yamen Lu, Dr. Jatin Machhi, Krista Namminga, Katherine Olson, Adam Szlachetka DDS, Rebecca Wilshusen, and Dr. Yuning Zhang for all their help planning, executing and analyzing experiments. I was grateful for the opportunity to learn from and work with each of you. I would also like to thank summer students Anna Miller, Katie Schueth, Katie Zheng, Sarah Whitmire, Chaoran Ji, Keith Prive, and X. Isabel Heifetz Ament for all their hard work and help generating some of the included data and for the opportunity I was given to teach them and improve my ability to instruct trainees. I would also like to acknowledge Dr. Shilpa Buch’s laboratory for their help performing luminex assays, Dr. Steven Bonesera’s laboratory for the use of their thermocycler for all PCR array iii experiments, the University of Nebraska Medical Center Flow Cytometry Research Core Facility, and graduate students Sam Johnson, Johnathan Herskovitz, and Nathan Smith for their help characterizing bone marrow dendritic cells. I would also like to thank the faculty and staff in the Pharmacology and Experimental Neuroscience Department. I am grateful for their help in navigating my time at the Nebraska Medical Center and for delivering lectures and facilitating my research projects. There are a great number of people who played a role in my development as a student and a scientist that I would like to acknowledge. I would like to thank Mr. Mark Stallman and Mr. Jerry Van Dyck, two high school science teachers who were instrumental turning an interest in science into a career path. I would like to thank Dr. Donald Stratton and Dr. Dean Hoganson, my two advisors at Drake University who guided me toward my goal of going to graduate school. I would like to thank the members of the Forage Additives Research Group at Pioneer Hi-Bred International who gave me my first research experiences which still shape how I plan and execute experiments. I would like to thank Dr. Jason Bartz, my advisor at Creighton University during my Master’s thesis work as well as Dr. Anthony Kincaid, Dr. Ron Shikiya, Dr. Jacob Ayers, Michelle Kramer, Dr. Sam Saunders, Dr. Qi Yuan, Dr. Katie Langenfeld, Melissa Clouse, Tom Eckland, and Maria Christensen for their guidance, patience, and support during my time at Creighton University and beyond. The lessons learned at Creighton University have shaped me as a person and as a scientist. Lastly, I would like to acknowledge the Institute for Environmental Health for giving me a chance to develop as a leader and a manager. Lastly, I would like to thank my parents, Robert and Kathi Schutt, my sister, Rebecca Jackson, my brother-in-law, Joshua Jackson, my nephew, Thomas Jackson, iv my nieces, Tabitha Jackson and Miriam Jackson, and countless other family members and friends for their encouragement, support and prayers. They have meant the world to me. This dissertation is dedicated to Sue Schutt and Steve Russo. Your love and support has been missed. v ABSTRACT Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Pathologically, loss of nigrostriatal neurons and dopamine released by these neurons are responsible for PD motor symptoms. During PD, activation of resident microglia and infiltrating lymphocytes leads to progressive neuroinflammation and reduction in the number and function of regulatory immune cells. Neuroinflammation contributes to progressive neurodegeneration and declining motor function. Reducing neuroinflammation is the target for novel PD therapeutics. Our goal is to increase the number and function of regulatory T cells (Tregs) in PD patients to decrease neuroinflammation and reduce PD symptoms. One potential therapy is granulocyte- macrophage colony stimulating factor (GM-CSF) which induces Tregs, decreases neuroinflammation, and protects dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) model of PD. In a Phase 1 trial, recombinant human GM-CSF (sargramostim) was well- tolerated in PD patients, increased Treg frequency and function, and improved motor function. Expression of helper T cell-related genes in CD4+CD25- cells in blood was determined by PCR array. Sargramostim increased expression of both pro- and anti- inflammatory cytokine genes supporting the notion that sargramostim alters the immune response by increasing the expression of immune mediators, including anti-inflammatory genes. As T cells do not express GM-CSF receptors and to explore myeloid-mediated Treg induction, GM-CSF-induced bone marrow-derived dendritic cells were further cultured with GM-CSF and/or stimulated with nitrated α-synuclein. Continued culture with GM-CSF yielded little change in dendritic cells as determined by surface co-stimulatory molecule expression, and proinflammatory cytokine expression and release; however, vi their ability to induce Tregs was diminished. In contrast, stimulation with nitrated α- synuclein, regardless of continued culture in GM-CSF, increases proinflammatory gene expression by dendritic cells, but showed variable effects on Treg induction. In the MPTP model, adoptive transfer of GM-CSF-induced tolerogenic dendritic cells protect dopaminergic neurons in the substantia nigra, decrease neuroinflammation, and increase splenic Tregs in a fashion similar to direct administration of GM-CSF. In conclusion, GM-CSF induces Tregs in part by acting on dendritic cells to change their response to stimulation. The data suggest that GM-CSF may not suppress neuroinflammation directly, but rather alters the immune response with increased expression of anti-inflammatory mediators and induction of Tregs. Moreover, the introduction of nitrated α-synuclein and possibly other misfolded proteins diminishes homeostasis and Treg induction. vii TABLE OF CONTENTS ACKNOWLEDGMENTS ............................................................................................... ii ABSTRACT .................................................................................................................. v LIST OF FIGURES ..................................................................................................... ix LIST OF TABLES ........................................................................................................ xi LIST OF ABBREVIATIONS ........................................................................................ xii CHAPTER 1 ................................................................................................................... 1 INTRODUCTION ........................................................................................................ 1 PARKSINSON’S DISEASE ..................................................................................... 1 NEUROINFLAMATION AND PARKINSON’S DISEASE
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