Dissertation
The role of myelin-specific regulatory CD8 T cells in relapsing-remitting demyelinating disease
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2019
DOI: 10.17077/etd.005197
Abstract
Multiple Sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) characterized by the infiltration of inflammatory immune cells across the blood-brain barrier, resulting in neurological dysfunction. Our laboratory has shown that CNS-specific CD8 T cells possess a disease suppressive function in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In humans, this suppressive function of CD8 T cells is deficient during MS relapses. Therefore, my studies focus on understanding the therapeutic ability of CD8 T cells in the context of relapsing-remitting disease (RR-EAE).
In my dissertation, I show that that PLP178-191-specific CD8 T cells ameliorate disease severity in an antigen-specific manner. I ascertained that the suppressive subset of CD8 T cells was contained within the CD25+ CD8 T cell compartment post-in vitro activation with PLP178-191. I also probed the role of endogenously generated CNS-specific CD8 T cell responses by using Listeria monocytogenes (LM) encoding CNS antigens to preferentially prime suppressive CD8 T cells in vivo. Infection with LM expressing PLP175-194 endogenously induces disease suppressive CD8 T cells that protect and treat PLP178-191 disease. Importantly, a combination of CD8 T cell adoptive transfer boosted by LM infection also successfully treats ongoing disease induced by a non-cognate peptide (PLP139-151), indicating that this approach could be effective even in the context of epitope spreading. My findings support a potential immunotherapeutic strategy using LM vaccination to enhance disease regulatory CD8 T cells in demyelinating disease.
Details
- Title: Subtitle
- The role of myelin-specific regulatory CD8 T cells in relapsing-remitting demyelinating disease
- Creators
- Ashley A. Brate
- Contributors
- Nitin J. Karandikar (Advisor)Kevin Legge (Advisor)Vladimir Badovinac (Committee Member)John T. Harty (Committee Member)Scott Lieberman (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Immunology
- Date degree season
- Autumn 2019
- DOI
- 10.17077/etd.005197
- Publisher
- University of Iowa
- Number of pages
- ix, 106 pages
- Copyright
- Copyright 2019 Ashley A. Brate
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical refereces (pages 98-106).
- Public Abstract (ETD)
Multiple sclerosis, or MS, is a disease in which the body’s own white blood cells (critical components of the immune system that normally protect us from infection) attack the brain and spinal cord, leading to progressive disability. MS affects ~2.3 million people worldwide, and while there are several treatments that slow disease progression, there is currently no cure, which necessitates new approaches to therapy.
To better understand how to treat MS, we must understand the different components of the immune system that contribute to MS. My research has focused on a type of white blood cell called the CD8 T cell, which is not well studied in the field. I have found that CD8 T cells can suppress and prevent disease in an animal model of MS.
The goal of my dissertation is to characterize suppressive CD8 T cell populations to one day successfully employ them as actual therapies for MS patients. Using various biochemical and immunological methods, I have found that suppressive CD8 T cells have unique surface molecules that can be used to identify, isolate, and employ them in models of disease. Furthermore, the defensive action of these cells can be boosted using a novel vaccination strategy.
My exciting findings have brought us closer to a new therapeutic approach to MS, in which specific populations of CD8 T cells are induced to suppress this debilitating disease.
- Academic Unit
- Immunology Graduate Program
- Record Identifier
- 9983779599402771
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