Immunomics of Renal Allograft Acute T Cell-Mediated Rejection Biopsies of Tacrolimus- and Belatacept-Treated Patients

Background. Belatacept-based therapy in kidney transplant recipient has been shown to increase long-term renal allograft and patient survival compared with calcineurin inhibitor-based therapy, however, with an increased risk of acute T cell-mediated rejection (aTCMR). An improved understanding of costimulation blockade-resistant rejections could lead to a more personalized approach to belatacept therapy. Here, immunomic profiles of aTCMR biopsies of patients treated with either tacrolimus or belatacept were compared. Methods. Formalin-fixed paraffin-embedded renal transplant biopsies were used for immunohistochemistry and gene expression analysis using the innovative NanoString technique. To validate NanoString, transcriptomic profiles of patients with and without biopsy-proven aTCMR were compared. Biopsies from 31 patients were studied: 14 tacrolimus-treated patients with aTCMR, 11 belatacept-treated patients with aTCMR, and 6 controls without rejection. Results. A distinct pattern was seen in biopsies with aTCMR compared to negative controls: 78 genes had a higher expression in the aTCMR group (false discovery rate P value <.05 to 1.42e-05). The most significant were T cell-associated genes (CD3, CD8, and CD4; P < 1.98e-04), gamma-interferon-inducible genes (CCL5, CXCL9, CXCL11, CXCL10, TBX21; P < 1.33e-04) plus effector genes (GNLY, GZMB, ITGAX; P < 2.82e-03). Immunophenotypical analysis of the classic immune markers of the innate and adaptive immune system was comparable between patients treated with either tacrolimus or belatacept. In addition, the transcriptome of both groups was not significantly different. Conclusions. In this small pilot study, no difference was found in immunomics of aTCMR biopsies of tacrolimus- and belatacept-treated patients. This suggests that clinically diagnosed aTCMR reflects a final common pathway of alorecognition which is unaffected by the type of immunosuppressive therapy.