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Overcoming Self-Reactivity Through Immunological and Metabolic Redox Modulation

Delmastro-Greenwood, Meghan/M (2012) Overcoming Self-Reactivity Through Immunological and Metabolic Redox Modulation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Delmastro-Greenwood, Meghan/Mmmd33@pitt.eduMMD33
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorPiganelli, Jon Djdp51@pitt.eduJDP51
Committee MemberKane, Larrylkane@pitt.eduLKANE
Committee MemberMorelli, Adrian E morelli@imap.pitt.eduMORELLI
Committee MemberGiannoukakis, Nickngiann1@pitt.eduNGIANN1
Committee MemberOury, Tim Dtdoury@pitt.eduTDOURY
Date: 17 December 2012
Date Type: Publication
Defense Date: 2 November 2012
Approval Date: 17 December 2012
Submission Date: 6 December 2012
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 251
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: redox modulation, type 1 diabetes, oxidative stress, type 2 diabetes, bioenergetics, TH1 T cells
Date Deposited: 17 Dec 2012 13:52
Last Modified: 15 Nov 2016 14:08


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