NK Cell Transcripts and NK Cells in Kidney Biopsies from Patients with Donor-Specific Antibodies: Evidence for NK Cell Involvement in Antibody-Mediated Rejection

Abstract

To explore the mechanisms of antibody-mediated rejection (ABMR) in kidney transplants, we studied the transcripts expressed in clinically indicated biopsies from patients with donor-specific antibody (DSA). Comparison of biopsies from DSA-positive versus DSAnegative patients revealed 132 differentially expressed transcripts: all were associated with class II DSA but none with class I DSA. Many transcripts were expressed in DSA-positive ABMR but were also expressed in T-cell-mediated rejection (TCMR), reflecting shared molecular features. Removal of shared transcripts created 23 DSA selective transcripts (DSASTs). Some DSASTs (6/23) showed selective high expression in NK cells, whereas others (8/23) were expressed in endothelium or in endothelium plus other cell types (7/23). Of 145 biopsies ranked by DSAST expression, the 25 with highest DSAST expression primarily consisted of ABMR (22/25, 88%), either C4d-positive or C4d-negative. By immunostaining, CD56+ and CD68+ cells in peritubular capillaries, but not CD3+ cells, were increased in ABMR compared to TCMR, compatible with a role for NK cells, as well as macrophages, as effectors in endothelial injury during ABMR. Thus, the strategy of using DSASTs in the biopsy to identify mechanism-related transcripts in biopsies from patients with clinical phenotypes indicates the selective involvement of NK cells in ABMR.

The Clinical and Genomic Significance of Donor-Specific Antibody–Positive/C4d-Negative and Donor-Specific Antibody–Negative/C4d-Negative Transplant Glomerulopathy

“…The Edmonton group showed that the biopsy specimens from DSA+ patients displayed three molecular phenotypes: upregulation of ENDAT (24), NKAT (25), and GRIT (26), similar to our findings. IFN-g secreted by T cells and NK cells is essential for induction of class I and II antigens on endothelium and increases antibody binding to the endothelium, which is followed by complement fixation to induce allograft inflammation and injury.…”

“…Hidalgo et al studied the gene expression profiles of biopsy specimens with AMR and identified 23 selective gene transcripts in AMR (DSAST) but not cellular rejection (25). Six of those 23 genes showed selective high expression in NK cells and 8 were primarily expressed in endothelium.…”

The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology

“…A set of transcripts (DSA‐specific transcripts [DSASTs]) was determined to be differentially expressed in renal allograft biopsies from DSA‐positive versus ‐negative patients 29, a finding that was later confirmed independently at a different center 30. Consequently, DSASTs have the potential to identify cases of ABMR in patients with non‐detectable HLA DSA.…”

“…Generating consensus for sets of molecules or classifiers reflecting certain biological or disease processes related to the established histologic Banff lesions would enable us to assess and validate their clinical value. In this regard, the most robust evidence is currently available for the association among antibody‐mediated injury; microcirculation inflammation; and increased expression of endothelial, NK cell, and inflammation‐associated transcripts in the allograft 29, 54, 55.…”

The Cell Biology of Cytomegalovirus: Implications for Transplantation

“…In solid organ transplant patients, acute CMV infection increases the CD57+ NKGDC hi (memory phenotype) pool, which appears to be CMV specific (179). The effects of CMV and NK cells in the setting of MHC-mismatched grafts are linked to coronary vasculopathy and renal graft injury (180)(181)(182)(183)(184)(185)(186)(187)(188). In part, this is mediated by cytokine-mediated stimulation of alloreactive T cells and by direct alloimmune injury (156).…”