Mathews, Lisa R.
(2014)
Pro-inflammatory cytokine increased IL-33 and ST2 indicate pediatric allograft rejection.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
Organ transplantation prolongs thousands of lives each year. While the evolution of post-transplant immunosuppressant therapies and better surgical techniques have improved short-term patient prognosis, these advancements have had little impact on long-term graft attrition and patient survival rates. Over-immunosuppression caused by anti-rejection therapies drugs increases recipient infections and cancer. Onerous, yet imprecise, surveillance procedures impose a burden on patients, but poorly detect nascent rejection. The identification of reliable biomarkers of rejection would enable earlier identification of rejection episodes and allow dynamic adjustment of immunosuppressant drug therapies. Interleukin (IL)-33 is a novel IL-1 family cytokine that is expressed or induced in several cell types (epithelial, endothelial, and myeloid cells, and myofibroblasts) and found in the tissues of commonly transplanted organs, including the heart, lungs, small bowel, and kidney. IL-33 has pleiotropic effects on the leukocytes and stromal cells expressing its receptor, Growth Stimulation Gene-2 (ST2). The effects of IL-33 are negatively regulated by a soluble decoy receptor, soluble ST2 (sST2). Several studies have demonstrated that mechanical stress or inflammatory stimuli, including IL-1β and TNFα, are able to induce both sST2 and IL-33 in cardiac myocytes and endothelial cells. Clinical measurements of circulating sST2 have been found it to be predictive of cardiovascular disease risk and mortality in patients with a history of myocardial infarction (MI). Specifically, following MI, elevated sST2 indicates severe cardiac damage and predicts patient mortality. Increased levels of sST2 and IL-33 are observed in the sera of patients with inflammatory bowel disorders. Based on these reports, we hypothesized that IL-33 and ST2 expression are distinctly modulated in allografts due to pro-inflammatory cytokines secreted by infiltrating immune cells and that these proteins will serve as sensitive biomarkers of rejection. To test this hypothesis in a cohort of pediatric heart and small bowel transplant recipients, we examined levels of ST2/sST2 and IL-33 both locally in the allograft tissue and systemically during periods of rejection and quiescence. In endomyocardial biopsies (EMB) collected from rejecting heart transplant recipients, we found that both ST2 and IL-33 were increased significantly (p=0.0359 and 0.0049 respectively) compared to non-rejecting patients. Likewise, we observed similar increases in IL-33 and ST2 in patient sera (p=0.0006; sST2 and p=0.0010; IL-33). In small bowel patients undergoing rejection, biopsy samples displayed upregulation of ST2 gene expression (3.94-fold increase over non-rejection) and analysis of collected sera revealed an increase in ST2 levels (p=0.0306) in these patients. Our findings provide strong evidence that ST2 and IL-33 could function as tissue- and most importantly, serum-based biomarkers of rejection. This discovery would benefit the overall public health of allograft recipients by enabling earlier transplant rejection diagnosis, alleviate complications due to over-immunosuppression, and decrease reliance on biopsy procedures.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Mathews, Lisa R. | lrm1@pitt.edu | LRM1 | |
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| ETD Committee: |
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| Date: |
29 September 2014 |
| Date Type: |
Publication |
| Defense Date: |
17 June 2014 |
| Approval Date: |
29 September 2014 |
| Submission Date: |
2 June 2014 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
67 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
ACR Acute Cellular Rejection
AMR Antibody Mediated Rejection
IST Immunosuppressant Therapy
DSA Donor Specific Antigen
EMB Endomyocardial Biopsy
HLA Human Leukocyte Antigen
HTx Heart Transplant
IFN-γ Interferon λ
IL Interleukin
IPA Ingenuity Pathway Analysis
IST Immunosuppressant Therapy
LPS Lipopolysaccharide
POD Post-Operative Date
Qdot Quantum Dot Immunolabeling
SBTx Small Bowel Transplant
sST2 Soluble ST2
ST2 Growth Stimulation Gene 2
Th2 T helper 2
TNFα Tumor Necrosis Factor α
WSI Whole Slide Imaging
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| Date Deposited: |
29 Sep 2014 21:26 |
| Last Modified: |
19 Dec 2016 14:41 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/22220 |
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