Extracellular Vesicles as Biomarkers of Acute Graft-vs.-Host Disease After Haploidentical Stem Cell Transplantation and Post-Transplant Cyclophosphamide

Abstract

Even with high-dose post-transplant cyclophosphamide (PT-Cy) which was initially introduced for graft-versus-host disease (GvHD) prevention in the setting of HLA-haploidentical transplantation, both acute and chronic GvHDs remain a major clinical challenge. Despite improvements in the understanding of the pathogenesis of both acute and chronic GvHDs, reliable biomarkers that predict their onset have yet to be identified. We recently studied the potential correlation between extracellular vesicles (EVs) and the onset of acute (a)GvHD in transplant recipients from related and unrelated donors. In the present study, we further investigated the role of the expression profile of membrane proteins and their microRNA (miRNA) cargo (miRNA100, miRNA155, and miRNA194) in predicting the onset of aGvHD in haploidentical transplant recipients with PT-Cy. Thirty-two consecutive patients were included. We evaluated the expression profile of EVs, by flow cytometry, and their miRNA cargo, by real-time PCR, at baseline, prior, and at different time points following transplant. Using logistic regression and Cox proportional hazard models, a significant association between expression profiles of antigens such as CD146, CD31, CD140a, CD120a, CD26, CD144, and CD30 on EVs, and their miRNA cargo with the onset of aGvHD was observed. Moreover, we also investigated a potential correlation between EV expression profile and cargo with plasma biomarkers (e.g., ST2, sTNFR1, and REG3a) that had been associated with aGVHD previously. This analysis showed that the combination of CD146, sTNFR1, and miR100 or miR194 strongly correlated with the onset of aGvHD (AUROC >0.975). A large prospective multicenter study is currently in progress to validate our findings.

Complex interactions of cellular players in chronic Graft-versus-Host Disease

“…EVs play a role in both innate (4) and adaptive immunity where they can have both pro-and antiinflammatory capabilities, depending on their contents. They can serve as disease biomarkers for aGVHD, as recently shown by Lia et al (5), but are likely involved in several GVHD promoting mechanisms by facilitating cell-cell communication. EVs in GVHD have so far mostly been studied in the context of mesenchymal stem cell (MSC)-based therapy.…”

Global trend in exosome isolation and application: an update concept in management of diseases

“…These include binding of phosphatidylserine to lymphocyte: T cell immunoglobulin domain and mucin domain protein 1 (TIM1) or TIM4, intercellular adhesion molecule 1 (ICAM1) to lymphocyte function-associated antigen 1 (LFA1), and possibly milk fat globule EGF factor 8 protein (MFGE8) to avβ3 or avβ5 integrins. After interaction with molecules on the recipient cell, the exosome could fuse directly to the membrane [ 14 ].…”