Divito, Sherrie Jill
(2009)
Recipient dendritic cells dictate allograft fate.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Organ transplantation is a life-saving and increasingly common procedure, as it often serves as the only treatment available for end-stage organ disease. Although the constant development of new and more effective immunosuppressive drugs has revolutionized the prevention and treatment of acute graft rejection, these drugs have significant toxicity, greatly increase patient susceptibility to neoplasms and infection and exert little impact on chronic rejection.A major obstacle to developing improved therapeutics is a lack of understanding the mechanisms by which the adaptive immune response is initiated, and how cellular therapies impact this response. Previous research has provided a mechanistic scaffold, however numerous gaps, often filled with assumptions rather than data, remain. In this dissertation, I demonstrate that contrary to current dogma, dendritic cell (DC)-based therapies simply serve as a source of alloantigen, and therefore have comparable efficacy to alternative cellular therapies. Further, I show that contradictory to the current paradigm of direct pathway T cell priming, recipient antigen-presenting cells (APC) stimulated via CD40 ligation by indirect pathway CD4+ T cells is requisite for a direct pathway response and allograft rejection. Conversely, I did validate the assumption that donor passenger APC are required for the direct pathway T cell response, but further show that they are also required for the indirect pathway T cell response, indicating that donor APC serve as a source of alloantigen for presentation by recipient APC. Finally, through investigating the role of recipient APC in cardiac allograft rejection, I identified that the recently described population of inflammatory monocyte-derived DC play a crucial role as effector cells that mediate a DTH-like response within cardiac allografts during acute rejection, while at the same time, inhibiting T cell effector responses within the graft and systemically.Overall, our data provide essential puzzle pieces to understanding the processes of acute allograft rejection and insight into the utility of DC-based therapies for transplantation.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Divito, Sherrie Jill | sjd12@pitt.edu | SJD12 | |
|
| ETD Committee: |
| Title | Member | Email Address | Pitt Username | ORCID |
|---|
| Committee Chair | Morelli, Adrian E | morelli@imap.pitt.edu | MORELLI | | | Committee Member | Larregina, Adriana | | | | | Committee Member | Beer-Stolz, Donna | | | | | Committee Member | Lakkis, Fadi | | | | | Committee Member | Salter, Russell | | | |
|
| Date: |
28 July 2009 |
| Date Type: |
Completion |
| Defense Date: |
12 June 2009 |
| Approval Date: |
28 July 2009 |
| Submission Date: |
27 July 2009 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
antigen re-processing; monocytes; negative vaccination; tolerance; transplantation |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-07272009-195433/, etd-07272009-195433 |
| Date Deposited: |
10 Nov 2011 19:54 |
| Last Modified: |
15 Nov 2016 13:47 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/8663 |
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