Dynamic Inflammatory Gene Expression Profiles Among Patients With and Without Acute Cellular Rejection (ACR) During the First Post-Transplant Year.

Abstract

Early acute cellular rejection (ACR) often occurs within 90 days of liver transplantation. Diagnosis of ACR requires a liver biopsy with associated risk and expenses. We hypothesized that the longitudinal inflammatory gene expression profiles in blood may serve as proxy of the graft status and have utility as a non-invasive diagnostic measure of ACR. Methods: A prospective observational cohort study involving 87 recipients was performed in the CTOT03 Study (NIAID Clinical Trials in Organ Transplantation), collecting blood samples at defined intervals post transplant: within 2 hours of reperfusion, at 1 and 6 weeks, 3, 6, and 12 months. Expression of 102 genes involving in inflammatory and immune responses was profiled in all samples. Samples and genes meeting quality control measures (82 genes in 443 samples) were subjected to: 1) mixed models to examine their association with ACR and interactions with time since transplant; 2) general linear models to test their associations with ACR using a nested case-control study design; and 3) qualitatively profile their changes during the 1st year post-transplant. Results: Widely ranging dynamic changes were observed in inflammatory genes surveyed during the first year. During the study period, 9 patients developed biopsy proven ACR. Mixed model analyses revealed nominally significant associations of inflammatory gene expression with ACR status, time since transplant, and interactions of ACR and time since transplant. In a nested case-control study that included 7 samples collected at ACR diagnosis and 21 non-ACR samples frequency-matched to ACR samples on early allograft dysfunction, age, and time since transplant, TNF, CD40LG, FOSB, and MSRA were found to be nominally significant. Prediction analyses identified a multi-marker model consisting of CAT, CTSB, and GPX4 that may potentially serve as a predictive signature for ACR. Conclusion: Dynamic changes in inflammatory gene profiles during the first year may be the reflection of changes in immunosuppressant dosage, as well as a process during which the grafts were adopted by the recipients. With the precaution of small sample size, our results suggest that multi-marker signature has the potential for the diagnosis/prediction of ACR.