Transcriptional Signals of T-cell and Corticosteroid-sensitive Genes Are Associated With Future Acute Cellular Rejection in Cardiac Allografts

Background: Profiling mRNA levels of 11 informative genes expressed by circulating immune effector cells identifies cardiac allograft recipients at low risk for current moderate-severe acute cellular rejection (ACR). Methods: We conducted a nested case-control study of 104 cardiac allograft recipients to investigate the association of transcriptional profiles of blood samples with either a future rejection episode within 12 weeks of a baseline clinical sample or persistent histologic quiescence for the same time period. Results: The transcription profile yielded a score (0 to 40 scale) of 27.4 ± 6.3 for future rejectors (n = 39) and 23.9 ± 7.1 for controls (n = 65) (p = 0.01). In patients who were ≤180 days post-transplant, the gene expression score was 28.4 ± 4.9 for rejectors (n = 28) and 22.4 ± 7.5 for controls (n = 48) (p < 0.001). In this period, no samples from patients who went on to reject within 12 weeks had gene expression scores of <20. Differential expression of the gene IL1R2 was significantly associated with future events. Of 33 additional genes profiled, 5 supported corticosteroid-sensitive constituents (IL1R2 and FLT3), whereas 6 supported T-cell activation (PDCD1). Conclusions: These data suggest that pathways regulating T-cell homeostasis and corticosteroid sensitivity are associated with future ACR in cardiac allografts and suggest that these signals are evident before histologically detectable rejection.