A cross-organ tissue gene expression immune signature predates chronicity

Purpose Meta-analysis of 796 microarrays led to the discovery of 11 over-expressed genes (BASP1, CD6, CXCL9, CXCL10, INPP5D, ISG20, LCK, NKG7, PSMB9, RUNX3, and TAP1) in kidney, heart, lung and liver transplant rejection. Herein we developed a quantitative Common Response Module (CRM) score by tissue QPCR to distinguish acute rejection (AR). We also evaluated the impact of this score in 6 month, histologically normal protocol biopsies from patients who either developed (P) or did not develop (nP) progressive chronic injury over the first 24 months post-transplantation. Methods 146 renal allograft biopsies were collected between 1 month-10 years post-transplant as protocol or indicated from patients +/-AR or +/-IFTA. QPCR for the 11 genes was conducted with 18S as control. Significant differences were determined by unpaired two-tailed t tests or ANOVA. Gene expression, CRM scores & clinical variables were examined by multivariate analysis to determine predictive value. Results The 11 gene QPCR-CRM score was significantly increased in AR (mean = 6.202±0.81) when compared to STA (mean=1.716 ± 0.23; p<0.0001) as well as in 6 month protocol biopsies of patients who developed accelerated chronic injury at 24 months (P) (mean=3.22 ± 1.10 & 7.94 ± 2.28) when compared to nP (mean =1.45± 0.33 & 1.92 ± 0.40) at 6 (p = 0.041) & 24 months (p = 0.0003), respectively. The genes with the most significant difference in AR over STA were CXCL9 and CXCL10 (p <0.0001). The most significant changes in chronic injury were seen in CD6 (p<0.001), CXCL9 (p<0.01), and LCK (p<0.01). The 11 gene score was the most significant predictor of AR (p < 0.001) with an AUC of 0.804 (p<0.001, 95% CI = 0.705-0.903) & >75% sensitivity & specificity at a score of >2.24. By multivariate analysis a 5-gene (BASP1, ISG20, NKG7, TAP1, and CXCL9) CRM score at 6 months was significantly (p = 0.0031) predictive of IFTA. Conclusions A highly selected gene set delineates AR from STA, and distinguishes patients destined for rapidly progressive chronicity. Molecular mapping of immune activation is more sensitive than the serum cretainine or tissue histology for predicting patients at high risk of chronic graft injury.