Serum Mir-29a Is Up-Regulated In Acute Graft Versus Host Disease (aGVHD) After Allogeneic Hematopoietic Stem Cell Transplantation (allo HSCT) and Activates Dendritic Cells (DCs)

Autor: Yvonne A Efebera, Parvathi Ranganathan, Xueyan Yu, Jessica Hofstetter, Sabrina L Garman, Laura Gibson, William Petros, Michael Craig, Cecelia Fernandez-Cymering, Mehdi Hamadani, Guido Marcucci, Steven M. Devine, Muller Fabbri, Ramiro Garzon
Rok vydání: 2013
Předmět:
Zdroj: Blood. 122:4471-4471
ISSN: 1528-0020
0006-4971
Popis: Background aGVHD is one of the most frequent and lethal complications after allo HSCT, underscoring the need to develop novel therapies. To achieve this goal, aGVHD mechanisms needs to be further elucidated. Recently it was reported that miRNAs are modulating aGVHD. In addition miRNAs are also present in the human serum and regulate immune responses. Here, we hypothesize that serum miRNAs expression is deregulated in aGVHD and could play a role in aGVHD pathogenesis. Methods To identify miRNAs associated with aGVHD we performed serum miRNA expression analysis using deep-sequencing from allo HSCT recipients samples at the time of clinical suspicion of aGVHD. Peripheral blood (PB) samples were collected weekly until day 100+ and at the time of clinical diagnosis of aGVHD from allo HSCT patients enrolled into OSU11002. After serum separation, total RNA was extracted using Trizol. Libraries were constructed using the small RNA profiling kit and sequenced on the Solid analyzer. A mouse model of aGVHD (B6 mice donor splenocytes and BM cells transplanted to lethally irradiated F1 recipients) was used to assess serum miRNA expression in animals with aGVHD. Results In this study we included 10 patients with aGVHD (bowel n=2; skin (n=5) and both skin and bowel aGVHD (n=3). Median age was 51.9, conditioning regimens were mainly non-myeloablative (n=9), with unrelated donors (n=9). PB samples from allo HSCT patients with no aGVHD and matched for age, disease, conditioning regimen, donor and timing of sample collection were obtained and used as controls. Sequence alignment was performed using miRBase. Normalization as reads per million was followed by quantiles. We compared miRNA expression between all patients with aGVHD (n=10) and controls (n=7) using class comparison (BRB). We found 7 miRNAs up-regulated (miR-146a, miR-323-b, miR-34c, miR-363, miR-4245, miR-29a, miR-181a* ) and 3 miRNAs down-regulated (miR-3168, miR-662, miR-550a) (Fold change (FC) >2, p50-fold). This binding leads to the activation of NFkB as measured by a NF-κB assay in TLR8–HEK-293 cells treated only with Dotap-miR-29a. Validation of these results using murine and human DCs are undergoing. Summary Altogether, our results indicate that serum miR-29a is up-regulated during aGVHD and activates DCs, likely by direct binding to TLR8 and inducing NFkB activation Disclosures: No relevant conflicts of interest to declare.
Databáze: OpenAIRE
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