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Published on: September 7, 2022
Host microRNAs are decreased in pediatric solid-organ transplant recipients during EBV+ Post-transplant
Ayantika Sen1, Jeanna Enriquez1, Mahil Rao1
1Department of Surgery, Stanford University School of Medicine, Stanford, CA, United States.
Insights
Epstein-Barr virus-positive post-transplant lymphoproliferative disorder (PTLD) is linked to reduced levels of specific microRNAs (miRs) in circulation. These circulating miRs, particularly miR-17, miR-19, and miR-106a, may offer diagnostic potential for EBV+ PTLD.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Post-transplant lymphoproliferative disorder (PTLD) is a significant complication following solid organ transplantation, often associated with Epstein-Barr virus (EBV) infection and compromised T cell immunity.
- Previous research indicated that EBV infection alters microRNA (miR) expression in B cells, with miR-194 uniquely suppressed in EBV-positive (EBV+) PTLD cell lines, targeting IL-10.
- The role of circulating miRs in EBV-associated PTLD remains largely uninvestigated.
Purpose of the Study:
- To investigate if altered microRNA expression in circulation is associated with EBV-positive PTLD.
- To quantify levels of specific miRs in plasma and extracellular vesicles (EVs) of pediatric solid organ transplant recipients with and without EBV+ PTLD.
Main Methods:
- Quantified levels of miRs-17, 19, 106a, 155, and 194 in plasma and extracellular vesicles (EVs) from pediatric solid organ transplant recipients.
- Matched EBV+ PTLD+ patients (n=?) with EBV+ PTLD- controls (n=?) from the NIH-sponsored CTOTC-06 study.
- Analyzed EV size (50-70 nm) using nanoparticle tracking analysis.
Main Results:
- Significantly decreased levels of miR-194 were observed in EBV+ PTLD tumors compared to EBV- PTLD.
- Reduced levels of miRs-17, 19, and 106a were found in both plasma and EVs of EBV+ PTLD+ patients compared to controls.
- miR-155 levels were similar across all patient groups; approximately 90% of cell-free miRs were contained within EVs.
Conclusions:
- Circulating miRs, particularly miR-17, miR-19, and miR-106a, are significantly reduced in pediatric solid organ transplant recipients with EBV+ PTLD.
- Extracellular vesicles play a crucial role in transporting these miRs in the circulation.
- These findings suggest that circulating miRs within EVs hold potential for diagnostic and mechanistic insights into EBV+ PTLD, warranting further investigation for therapeutic applications.
Abstract:
Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation. Predisposing factors include primary Epstein-Barr virus (EBV) infection, reactivation of EBV in recipient B cells, and decreased T cell immunity due to immunosuppression. In our previous studies EBV infection was demonstrated to markedly alter the expression of host B cell microRNA (miR). Specifically, miR-194 expression was uniquely suppressed in EBV+ B cell lines from PTLD patients and the 3'untranslated region of IL-10 was determined to be targeted by miR-194. Although EBV has been shown to regulate host miR expression in B cell lymphoma cell lines, the expression of miRs in the circulation of patients with EBV-associated PTLD has not been studied. The objective of this study was to determine if changes in miR expression are associated with EBV+ PTLD. In this study, we have shown that miR-194 is significantly decreased in EBV+PTLD tumors and that additional miRs, including miRs-17, 19 and 106a are also reduced in EBV+PTLD as compared to EBV-PTLD. We quantitated the levels of miRs-17, 19, 106a, 155, and 194 in the plasma and extracellular vesicles (EV; 50-70 nm as determined by nanoparticle tracking analysis) from pediatric recipients of solid organ transplants with EBV+ PTLD+ that were matched 1:2 with EBV+ PTLD- pediatric transplant recipients as part of the NIH-sponsored Clinical Trials in Organ Transplantation in Children, (CTOTC-06) study. Levels of miRs-17, 19, 106a, and 194 were reduced in the plasma and extracellular vesicles (EV) of EBV+ PTLD+ group compared to matched controls, with miRs-17 (p = 0.034; plasma), miRs-19 (p = 0.029; EV) and miR-106a (p = 0.007; plasma and EV) being significantly reduced. Similar levels of miR-155 were detected in the plasma and EV of all pediatric SOT recipients. Importantly, ~90% of the cell-free miR were contained within the EV supporting that EBV+ PTLD tumor miR are detected in the circulation and suggesting that EVs, containing miRs, may have the potential to target and regulate cells of the immune system. Further development of diagnostic, mechanistic and potential therapeutic uses of the miRs in PTLD is warranted.
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