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Pro-inflammatory cytokine increased IL-33 and ST2 indicate pediatric allograft rejection

Mathews, Lisa R. (2014) Pro-inflammatory cytokine increased IL-33 and ST2 indicate pediatric allograft rejection. Master's Thesis, University of Pittsburgh. (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Mathews, Lisa R.lrm1@pitt.eduLRM1
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorTurnquist, HethHet5@pitt.eduHET5
Committee MemberReinhart, Todd reinhar@pitt.eduREINHAR
Committee MemberMetes, Dianametesdm@upmc.eduDIM4
Committee MemberMalliard, Robbierbm19@pitt.eduRBM19
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
Date Deposited: 29 Sep 2014 21:26
Last Modified: 19 Dec 2016 14:41


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