B Cell-Related Biomarkers of Tolerance Are Up-Regulated in Rejection-Free Kidney Transplant Recipients

Abstract

Background: Recently, several molecular signatures of tolerant patients who were off immunosuppression were identified. In this prospective study we evaluated such biomarkers in kidney transplant recipients treated with CNI based triple immunosuppression. Methods/Materials: Using a quantitative real-time RT-PCR, mRNA expression of 11 genes associated with transplantation tolerance (Sagoo et al. J Clin Invest. 2010) or with rejection was prospectively monitored in the peripheral blood of the cohort of 67 kidney transplant recipients at POD 0, 7, 14, 21, 28, 60, 90 and month 6 and 12. Moreover, these biomarkers were cross-sectionally evaluated in 15 patients with chronic antibody mediated rejection (follow-up median 4.7 years) and patients with long term (>15 yrs) stable kidney graft function (n=31; follow-up median 18.3 years). Expression patterns of tolerant genes were prospectively monitored and compared between kidney transplant recipients with or without acute rejection and also between stable graft function and chronic rejection groups. Generalized linear model with gamma distribution for repeated measures was used for statistical analysis of longitudinal data and Mann-Whitney test for cross-sectional data. Results: In the prospectively monitored group, 37 patients were free of acute rejection at first year while 10 patients experienced acute rejection and 20 patients borderline changes. Three B cell-related genes, CD79B, MS4A1 and TCL1A, showed constantly higher expression levels in rejection-free patients as compared to borderline changes group (P< 0.0001, P< 0.0001; P< 0.05) and rejection group (all P< 0.0001), while on the contrary TMEM176B expression levels where lower (both P< 0.0001). There were no differences among expression patterns of other analyzed genes within the 12-month follow-up. Comparing long-term stable graft function with long-term chronic rejection groups, the observed expressions of FOXP3 and TOAG-1 genes were significantly higher while (P< 0.05) TCL1A significantly lower (P< 0.05) in long-term stable graft function group; in all other analyzed genes no differences were observed. Conclusion: Our study has confirmed the role of several molecular biomarkers of tolerance in real life settings also in patients treated with standard immunosuppression. The question whether the weaning of the immunosuppression is safe according to such biomarkers may be answered by a prospective validation trial. Supported by: IGA MZCR NS 10517-3/2009 and GACR P301/11/1568