RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection.

Acute cellular rejection (ACR) is the adverse response of the recipient's immune system against the allogeneic graft. Using human surveillance endomyocardial biopsies (EMBs) manifesting ACR and murine allogeneic grafts, we profiled implicated microRNAs (miRs) and mRNAs. MiR profiling showed that miR-21, -142-3p, -142-5p, -146a, -146b, -155, -222, -223, and -494 increased during ACR in humans and mice, whereas miR-149-5p decreased. mRNA profiling revealed 70 common differentially regulated transcripts, all involved in immune signaling and immune-related diseases. Interestingly, 33 of 70 transcripts function downstream of IL-6 and its transcription factor spleen focus forming virus proviral integration oncogene (SPI1), an established target of miR-155, the most upregulated miR in human EMBs manifesting rejection. In a mouse model of cardiac transplantation, miR-155 absence and pharmacological inhibition attenuated ACR, demonstrating the causal involvement and therapeutic potential of miRs. Finally, we corroborated our miR signature in acute cellular renal allograft rejection, suggesting a nonorgan specific signature of acute rejection. We concluded that miR and mRNA profiling in human and murine ACR revealed the shared significant dysregulation of immune genes. Inflammatory miRs, for example miR-155, and transcripts, in particular those related to the IL-6 pathway, are promising therapeutic targets to prevent acute allograft rejection.

Chronic histological damage in early indication biopsies is an independent risk factor for late renal allograft failure.

The impact of early histological lesions of renal allografts on long-term graft survival remains unclear. We included all renal allograft recipients transplanted at a single center from 1991 to 2001 (N = 1197). All indication biopsies performed within the first year after transplantation were rescored according to the current Banff classification. Mean follow-up time was 14.8 ± 2.80 years. In multivariate Cox proportional hazards analysis, arteriolar hyalinosis and transplant glomerulopathy were independently associated with death-censored graft survival, adjusted for baseline demographic covariates. Arteriolar hyalinosis correlated with interstitial fibrosis, tubular atrophy, mesangial matrix increase, vascular intimal thickening and glomerulosclerosis. Clustering of the patients according to these chronic lesions, reflecting the global burden of chronic injury, associated better with long-term graft survival than each of the chronic lesions separately. Early chronic histological damage was an independent risk factor for late graft loss, irrespective whether a specific, progressive disease was diagnosed or not, while T cell-mediated rejection did not. We conclude that individual chronic lesions like arteriolar hyalinosis, tubular atrophy, interstitial fibrosis, glomerulosclerosis, mesangial matrix increase and vascular intimal thickening cannot be seen as individual entities. The global burden of early chronic histological damage within the first year after transplantation importantly affects the fate of the allografts.