Abstract
Immune responses to HLA and development of anti-donor HLA (DSA) have been shown to play a role in chronic rejection following transplantation. We hypothesized that Abs to MHC changes microRNAs (miRNAs) leading to chronic lung allograft rejection. Microarray analysis was performed in a murine model of anti-MHC induced obliterative airway disease (OAD), a correlate of obliterative bronchiolitis. A unique profile of dysregulated miRNAs was detected in OAD mice on day 7 and 15 after Ab administration compared to control. Sixty-seven miRNAs were increased and 42 miRNAs were decreased in OAD mice on day 7. In addition, 15 miRNAs were over expressed and 16 miRNAs were under expressed in OAD mice on day 15. The expression of miR-16 and miR-195 were significantly decreased in lungs of OAD mice by qPCR and in situ hybridization with increases of H-2 Aa and H-2 Dma mRNA levels. Significant reduction of miR-16 and miR-195 levels were also noted in lung transplant (LTx) patients with DSA compared to LTx without DSA. Bioinformatic TargetScan and Reporter Assays identified the binding of miR-16 and miR-195 to the 3’UTR of Regulatory Factor X 5. qPCR and immunohistochemistry indicated post-transcriptional increases of Regulatory Factor X 5 mRNA and protein expression not only in OAD mice and but also in LTxR with DSA which was associated with increased expression of HLA-DPA1, HLA-DQA1, and HLA-DRA mRNA. Therefore, our results demonstrated that miRNAs induced by alloimmunity may play important roles in chronic rejection after LTx.