Similar gene transcript paterns in chronic rejections of kidney allografts

Petra Hribova¹, Irena Brabcova¹, Janka Slatinska², Eva Honsova³, Roman Zachoval⁴, Ondrej Viklicky^1,2.

¹Transplant Laboratory, Departments of ²Nephrology, and ³Transplant Pathology, Institute for Clinical and Experimental Medicine; ⁴Department of Urology, Thomayer University Hospital with Polyclinic; Prague, Czech Republic.

Chronic rejections are the main reason of late kidney allograft loss. Transcriptome differences in chronic T-cell mediated rejection (CTCMR) and chronic antibody mediated rejection (CAMR) have not been described yet.

Late case biopsies (>3M) were performed in 2007-2009 in CNI/MMF treated patients. Histological diagnosis was made according to Banff’09 classification. Biopsy specimens from patients with CTCMR (n=9), CAMR (n=13) and from patients with stable kidney graft function and normal histological findings in protocol biopsies (n=10) was stabilized in the RNA-later. Using the Taqman Low Density Array, the intrarenal expressions of 378 genes relating to immune response (T-cell activation, B-cell activation, cytokines, chemokines, growth factors, immune regulators and apoptosis) were analyzed with respect to the graft outcome.

Patients with CTCMR and CAMR did not differ significantly in renal function (eGFR, proteinuria) at the time of biopsy. Three patients with CTCMR and four with CAMR lost their grafts during the follow-up.

Both types of chronic rejection were associated with up-regulation of many genes as compared with control group: chemokines (CCL4, CCL5 , CXCL9, CXCL10, CXCL11), growth factor TGFB1, MHC class II (HLA-DMA, HLA-DMB, HLA-DRA), genes of humoral immune response (ADA, CD53, C4A, C4B, HLA-DRA, UBD), T-cell associated transcripts (CD3D, CD86, LAG3) including cytotoxic (CCL4, CCL5, GBP1,GZMK). In hierarchical clustering CTCMR and CAMR gene expression profiles were found to be similar. Patients whose graft failed during the follow-up because of CAMR had higher expression of AGR2, AGR3, BFAR, CD59, CD9 and IFNGR2, but lower expression of CCL19 and TRADD than patients, whose graft survived. This indicates upper regulation of cell migration and adhesion and lowering of apoptotic signals in failing grafts.

In this study, the similar mechanisms that involved T-cells and B-cells mediated immunity in both chronic antibody- and T-cell mediated rejections were found out.