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Characterization of T Lymphocytes from Pediatric Heart Transplant Patients who Carry EBV Loads in their Peripheral Blood

Nelson, Emily (2014) Characterization of T Lymphocytes from Pediatric Heart Transplant Patients who Carry EBV Loads in their Peripheral Blood. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Hypothesis: The Epstein-Barr (EBV) virus causes a harmless, lifelong infection in nearly all adults, but is found in 85% of all cases of post-transplant lymphoproliferative disorders (PTLD). In healthy adults, it is a latent infection, but in some patients who have received a transplant, it is present for months at a time in the peripheral blood. This chronic viral load carrier state is an important risk factor for developing PTLD, although the viral load itself does not predict the disease. A recent hypothesis from our lab identified an inadequate Type 1 T cell response, increased EBV replication and a shift toward T follicular-like (TFh) cells as issues that may contribute to a viral load carrier state. For this thesis, our hypothesis is that pediatric heart transplant patients with EBV loads are those whose CXCR3+ (Type 1) EBV-specific CD8+ T cells are decreased (no adequate anti-EBV surveillance), and whose CXCR5+ (TFh) CD4+ T cells are increased (help to EBV-infected memory B cells).
Objectives: Our objectives were to assess the frequency and phenotype of Type 1 EBV-specific CD8+ T cells and of CD4+ T cells in pediatric heart transplant patients who have viral loads but are otherwise asymptomatic of EBV-related disease.
Methods: We recruited healthy controls and patients under University of Pittsburgh-approved IRB protocols. The patient viral loads were determined with real time PCR in the clinical laboratory, and the frequency and phenotype of different T cell populations were identified using flow cytometry on whole blood.
Results: In CD8+ T cell populations, EBV-specific T cells have a decreased ability to regulate infected cells, but others maintain a high level of activation. These activated cells up-regulate EBV-specific markers that allow them to travel to B cell areas in germinal centers, possibly to control infected B cells. Conversely, in these same patients, CD4+ T cell populations have also gained the ability to migrate to B cell areas, but these cells may up-regulate IL-21 and provide help to infected B cells.
Conclusions: Some pediatric heart transplant patients display populations of both CD8+ T cells and CD4+ T cells that up-regulate CXCR5 and thus can migrate to the B cell area of the tonsils, which are a key area of EBV reactivation. While CXCR5high EBV-lytic specific CD8+ T cells may be able to control lytic reactivation, CXCR5 CD4+ T cells may encourage B cell proliferation and differentiation to plasmablasts, which could lead to the viral load carrier state and therefore increase a patient’s risk for developing PTLD.
Public Health Significance: PTLD is the leading cause of tumors in pediatric patients who have received a transplant, and while PTLD mortality has varied greatly as treatments have improved, recent research has found mortality rates still approach 50%. This research seeks to provide a better understanding of the relationship between EBV loads, EBV reactivation and T cell control. These studies may provide assistance to research that seeks to identify early markers of risk for dangerous EBV loads, as early treatment often results in better outcomes.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Nelson, Emilyemilynelson@gmx.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee MemberMetes, Diana M.metesdm@upmc.eduDIM4
Committee MemberRowe, David T.rowe1@pitt.eduROWE1
Thesis AdvisorKingsley, Lawrence A.kingsley@pitt.eduKINGSLEY
Date: 29 January 2014
Date Type: Publication
Defense Date: 19 November 2013
Approval Date: 29 January 2014
Submission Date: 20 November 2013
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 44
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MPH - Master of Public Health
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: EBV, PTLD, transplant
Date Deposited: 29 Jan 2014 17:18
Last Modified: 19 Dec 2016 14:41
URI: http://d-scholarship.pitt.edu/id/eprint/20055

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