The importance of reactive oxygen species (ROS) is illustrated by their crucial roles in immunology and disease pathologies. ROS can activate redox-dependent transcription factors, promoting a host of proinflammatory immune responses that are exacerbated during oxidative stress. The aim of this thesis is to determine how redox modulation impairs self-reactivity and aberrant inflammation in diabetes. Prevention of CD4+ TH1 T cell activation is critical for restricting autoreactive immune responses and maintaining pancreatic β cell integrity in type 1 diabetes. Moreover, decreasing the inflammatory milieu and subsequent complications is necessary for restoring insulin sensitivity in type 2 diabetes. Although current immunosuppressive therapies are invaluable for transplantations, small molecule inhibitors with low toxicity are necessary for stopping autoreactivity and treating inflammatory-driven metabolic diseases. We utilized a catalytic antioxidant (CA) in diabetogenic models based on previous work demonstrating that redox modulation promotes T cell hyporesponsivness and impairs innate cell cytokine secretion by blocking NF-κB activation. Additionally, CA sustains health of isolated islets, delays islet allograft rejection, and inhibits transfer of diabetes into young NOD.scid mice.
First, the mechanisms behind CA-mediated CD4+ TH1 T cell hyporesponsivness were investigated in vitro and in vivo using diabetogenic murine experiments with a focus on the redox-dependent sheddase TACE and one of its substrate, LAG-3, a negative regulator of T cell activation. Ability to track type 1 diabetes progression through a serum biomarker, soluble LAG-3, was also assessed from both murine and human samples. Next, CA-mediated alteration(s) of immune cell metabolism was characterized. Effects on glycolysis and oxidative phosphorylation were assessed to determine additional mechanisms of regulation and where treatment efficiency wanes. Lastly, redox modulation was evaluated in treatment of high-fat diet-induced type 2 diabetes. Markers of inflammation and diabetic complications were measured to ascertain the severity of insulin resistance.
Collectively, this work is a distinct contribution to the knowledge of CA treatment and its ability to 1) inhibit diabetogenic TH1 responses through regulation of a redox-dependent metalloprotease and subsequent cleavage of a negative T cell surface marker; 2) prevent self-reactivity through metabolic regulation; and 3) reduce inflammation and complications in high-fat diet-induced type 2 diabetes.
|Advisor:||Piganelli, Jon P.|
|Commitee:||Giannoukakis, Nick, Kane, Larry, Morelli, Adrian|
|School:||University of Pittsburgh|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 74/07(E), Dissertation Abstracts International|
|Subjects:||Biochemistry, Pathology, Immunology|
|Keywords:||Diabetes, Oxidative stress, Redox modulation, Self-reactivity|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be