Sklavos, Martha Milton
(2009)
REDOX MODULATION PROTECTS FROM ANTIGEN-DEPENDENT AND ANTIGEN-INDEPENDENT INJURY IN ISLET TRANSPLANTATION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The preservation of reactive oxygen species (ROS) throughout evolution is evidence that ROS are critical components in immunity. These constituents ignite a multitude of redox-dependent pathways triggering pro-inflammatory cytokine production, dendritic cell maturation, and subsequent T cell activation in response to pathogen, autoimmune, and alloimmune insults. The aim of this thesis is to test the ability of redox modulation to suppress aberrant immune responses in islet transplantation. Presently, islet transplantation is only used in desperate cases of glucose dysregulation due to the high failure rate of the procedure, which forces the majority of recipients to resume exogenous insulin within a year of islet transplantation. Hurdles in islet transplantation include hypoxia during islet isolation and ischemia-reperfusion injury upon transplantation. These insults result in primary non-function of islets, while harsh immunosuppressive agents yield islet toxicity and a multitude of complications for the recipient. We tested a catalytic antioxidant (CA), FBC-007, in islet transplantation based on previous work demonstrating that CA impairs innate-immune ROS and pro-inflammatory cytokine production by inhibiting NFκB-DNA binding, hinders CD4 T cell activation, and prevents the transfer of diabetes into young NOD.scid mice. First, the effects of redox modulation on CD8 T cell effector function in allogeneic and transgenic responses were examined in vitro. Human islets were also used in vitro and murine experiments were performed in vivo to test the ability of CA to protect from streptozotocin-induced islet cell death. Additionally, murine islets were incubated with CA in in vivo models of ischemia-reperfusion injury (antigen-independent) or allogeneic (antigen-dependent) transplantation and separately, CA was used as a systemic therapy for allograft recipients. Further experiments were performed to elucidate in vivo protective mechanisms of CA-treatment. An additional approach of interest is the induction of antigen-specific hyporesponsiveness to replace nonspecific immunosuppression. A negative vaccination strategy delivering apoptotic donor alloantigen in a non-inflammatory adjuvant prior to allograft transplantation, was also tested. Collectively, this work demonstrates 1) CA is a non-toxic, islet-sparing, cytoprotective, and immunomodulatory agent capable of promoting islet-function, 2) CA impairs the alloimmune response to induce antigen-specific hyporesponsiveness, and 3) the negative vaccination protocol achieves long-term allograft tolerance.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Sklavos, Martha Milton | mjm36@pitt.edu | MJM36 | |
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| ETD Committee: |
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| Date: |
2 September 2009 |
| Date Type: |
Completion |
| Defense Date: |
1 July 2009 |
| Approval Date: |
2 September 2009 |
| Submission Date: |
2 September 2009 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
allograft rejection; catalytic antioxidant; inflammation; Islet transplantation; redox modulation; Type 1 Diabetes |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-09022009-133758/, etd-09022009-133758 |
| Date Deposited: |
10 Nov 2011 20:01 |
| Last Modified: |
19 Dec 2016 14:37 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9319 |
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