"Early Detection of Cardiac Allograft Rejection through Gene Expression Profiling"

Purpose: Cardiac Allograft Vasculopathy (CAV) is the main cause of allograft failure after the first year post cardiac transplantation (Tx). The first interaction between the donor organ and recipient immune system conditioned by the early perioperative events might determine the future immune properties of the donor/host system and lead to the development of CAV. We hypothesized that peripheral blood mononuclear cells (PBMC) carry molecular signatures during the very early period after transplantation that correlate with the future development of CAV.

Methods: The Cardiac Allograft Rejection Gene expression Observational (CARGO) multicenter study included 629 cardiac Tx recipients between Sep, 2001 - Sep, 2003 and collected 285 custom 7370-gene microarray from 98 patients taken at the time of the scheduled surveillance biopsies to develop a molecular classifier to discriminate acute cellular rejection from quiescence using peripheral PBMC's. Columbia University included 121 patients and collected 105 microarrays from 45 patients. Patients were included in this analysis if they had a follow up coronary angiogram between year 2 and 4 post Tx (37 patients, 95 samples). Seventeen patients (53 samples) showed any grade of CAV. Gene expression data as submitted to the GEO database was filtered to retain only normal and marginal spots. Genes were excluded when having more than 30% missing values for each gene across all the samples. Missing values were imputed using the K (10)-nearest neighbors and differentially expressed genes (FDR 10%) were assessed using Significance Analysis of Microarrays showing hundreds of genes differentially expressed. Among them, several genes including IL2RB, HLA related genes, GZMB, PF4, CXCL5 and CXCL2 but also expression sequence tags and genes of unknown function. Using those samples obtained during the first 30 days after transplant we could accurately identify those patients developing CAV.

Conclusion: this study suggest that gene expression profiling during the very early times after transplantation might predict the occurrence of CAV and lead to the development of new diagnostic methods to assess the risk of future development of CAV and identify new target genes and pathways.