Profiling Tissue and Biofluid miR-155-5p, miR-155*, and miR-146a-5p Expression in Graft vs. Host Disease

Abstract

Introduction: Acute graft vs. host disease (aGvHD) is a frequent complication following allogeneic haematopoeitic transplantation (HSCT). Despite recent advances, there are no universally accepted biomarkers to determine development of aGvHD. MicroRNAs miR-146a and miR-155 have been previously associated with aGvHD and show promise as clinically translatable biomarkers. In this study, we performed comprehensive expression profiling of miR-146a, miR-155, and miR-155* expression in aGvHD target tissue and biofluids and relate expression to post-HSCT outcomes.Materials and Methods: MicroRNA expression was assessed by qRT-PCR in gastrointestinal (n = 31) and skin (n = 31) biopsies as well as serum (exploratory cohort n = 34, verification cohort n = 81, diagnostic cohort n = 65) and urine (exploratory cohort n = 30, verification cohort n = 56, diagnostic cohort n = 20) biofluids, including extracellular vesicle (EV) cohorts (serum EV n = 15, urine EV n = 30). Expression was related to aGvHD incidence, severity and overall survival.Results: In GI samples, expression of miR-155 (p = 0.03) and miR-146a (p = 0.03) was higher at aGvHD onset compared to patients with no GvHD. In skin biopsies, expression of miR-155 (p = 0.004) was upregulated in aGvHD patients compared to normal control skin. Expression of miR-146a was higher in aGvHD compared to no aGvHD biopsies (p = 0.002). In serum, miR-155 (p = 0.03) and miR-146a (p = 0.02) expression was higher at day 14 (D14), while in urine expression was elevated at D7 post-HSCT in patients who developed aGvHD compared to those disease-free. This was verified in an independent serum (miR-155 p = 0.005, miR-146a p = 0.003) and urine (miR-155 p = 0.02, miR-146a p = 0.04) cohort, where both microRNAs were also associated with aGvHD by ROC analysis. In serum and urine samples taken at the time of aGvHD symptoms, expression of miR-155 and miR-146a was also elevated (serum miR-155 p = 0.03, miR-146a p < 0.001; urine miR-155 p = 0.02, miR-146a p = 0.02). In contrast, miR-146a and miR-155 were downregulated at D14 in serum EVs and at D7 in urine EVs in patients who developed aGvHD compared to those that remained disease-free, in both an exploratory (serum miR-155 p = 0.02, miR-146a p = 0.06; urine miR-155 p = 0.02, miR-146a p = 0.07) and an independent cohort (serum miR-155 p = 0.01, miR-146a p = 0.02).Conclusions: These results further support a role for miR-155 and miR-146a as non-invasive, clinically relevant biomarkers for aGvHD. However, the link between their involvement in generalized inflammation and in specific pathophysiology requires further investigation at a systemic level.

Dynamic interplay of microRNA in diseases and therapeutic

“… 49 Crossland et al demonstrated miR‐155 and miR‐146a as non‐invasive biomarkers for acute GvHD. 50 A similar study also reported that miR‐155 strongly affects the expression of alloreactive T cells in acute GvHD. 51 miR‐181a affects the function of T lymphocytes by downregulating the target cytokine IFN‐γ, thereby attenuating the severity of acute GvHD.…”

“…Liu et al showed that miR‐223 can inhibit the clinical syndrome of aGvHD in mice by suppressing the migration of donor T cells 49 . Crossland et al demonstrated miR‐155 and miR‐146a as non‐invasive biomarkers for acute GvHD 50 . A similar study also reported that miR‐155 strongly affects the expression of alloreactive T cells in acute GvHD 51 .…”

Clinical Significance of microRNAs in Hematologic Malignancies and Hematopoietic Stem Cell Transplantation

“…In addition, the upregulation of miR-146a and miR-155 in the 14-day period after HSCT was found in serum samples of patients who later developed aGvHD. Nevertheless, expression results of both miR-146a and miR-155 supported their potential to be biomarkers for GvHD development [164].…”

Biomarkers for early complications post hematopoietic cell transplantation: Insights and challenges

“…A risk score developed using metabolite and transcriptome analysis incorporating 5 metabolite markers from glycerophospholipid metabolism was predictive of acute GVHD ( 55 ). miR-155 and miR-146a measured in target tissues at the time of GVHD onset and measured in extracellular vesicles in serum and urine in the early post-transplant period before GVHD onset have been predictive of acute GVHD ( 56 ).…”