Alterations of miRNA expression regulate the post-transcriptional expression of many target genes in allografts and thus likely help regulate alloreactive processes. We carried out a miRNA expression study (384 human miRNAs) in kidney transplants to identify and assess genetic subtype variations of tissue with morphologically similar histological patterns, as well as discrimination between types of rejection and other processes. We analyzed 95 renal allograft FFPE biopsies by RT-PCR and identified 58 miRNAs (34 upregulated and 24 downregulated) with statistically significant differential expression in biopsies of acute cellular rejection (ACR) (all Banff types) compared to biopsies with no rejection (NR). We found nine miRNAs showing strong correlation with a number of immune and inflammatory mRNAs (seven positive and two negative). Based on this discovery analyses we selected 15 miRNAs (10 upregulated and 5 downregulated) for validation including mir-142-3p, mir-142-5p, mir-155 and mir-223; the latter miRNAs are specifically expressed in immune cells involved in renal graft infiltration. Several of the 15 miRNAs showed strong positive (miR-142-3p, miR-150, miR-223, miR-511, miR-642) or negative correlation (mir-184, mir-204) with immune and inflammatory genes involved in alloimmunity. We verified the expression profiles of the 15 selected miRNAs on 95 new renal FFPE biopsies grouped as NR, ACR, and Borderline/suspicious of ACR (ACR S). We found that the expression level of the miRNAs correlated well with the inflammatory status of the grafts; Banff “Borderline” category biopsies showed the lowest significantly different gene upregulation but also genetic subtypes. Significant differences were found between the relative expression of miRNAs in NR and ACR S (p<0.05), and NR and ACR (p<0.001). Our results indicate that the miRNAs studied in this report are involved in regulation of graft ACR and that there is heterogeneity in morphologically similar cases. Our initial data suggests there is likely involvement of these and other miRNAs in other forms of acute rejection and non-rejection inflammatory conditions.

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