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

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 DSA‐negative 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. Using microarray analysis of kidney biopsies along with HLA antibody information at the time of biopsy, NK cell transcripts and CD56+ NK cells in peritubular capillaries are selectively identified in biopsies from DSA‐positive patients, indicating a role for NK cells in antibody‐mediated rejection.