Heightened Expression of the Cytotoxicity Receptor NKG2D Correlates with Acute and Chronic Nephropathy After Kidney Transplantation

Abstract

The activating cytotoxicity receptor NKG2D binds to stress-regulated molecules encoded by the major histocompatibility complex class I chain-related (MIC) and UL-16-binding protein (ULBP)/retinoic acid early transcript (RAET) gene family. To assess whether acute allograft rejection leads to an induction of these inducible ligands and their receptor NKG2D, we examined the mRNA profiles in kidney transplant biopsies. Expression levels were correlated with the incidence of acute rejection (aRx) episodes and chronic allograft nephropathy (CAN) proven by histology. Whereas MICA, ULBP1/3 and RAET1-E did not display heightened gene expression, elevated levels of NKG2D mRNA could be associated with aRx (p < 0.001). Immunohistology of kidney biopsies diagnosed with aRx revealed NKG2D + cells in tubulointerstitial areas positive for CD8 + cells. Most importantly, elevated levels of NKG2D mRNA were associated with restricted long-term graft function assessed by the glomerular filtration rate at 6, 12 and 18 months posttransplantation. Induced NKG2D mRNA expression was still observable in biopsies diagnosed with CAN (p < 0.001), demonstrating a higher sensitivity and specificity compared to CD3, granzyme B and granulysin mRNA measurement. Significant elevated levels of NKG2D mRNA M. Seiler and I. Brabcova contributed equally to the manuscript. could be further detected in urine sediment prior to aRx, suggesting this receptor as a new candidate marker for the diagnosis of acute and chronic allograft rejection.

The Activating Immunoreceptor NKG2D and Its Ligands Are Involved in Allograft Transplant Rejection

“…The expression of NKG2D ligand mRNA has been described in human transplant samples under circumstances of acute allograft rejection, chronic allograft nephropathy, and renal acute tubular necrosis (22,23), making it likely that the NKG2D ligand upregulation demonstrated in our study is relevant to human transplantation. Notably, although we detected up-regulation of NKG2D ligand transcripts in skin allografts, anti-NKG2D mAb did not prolong survival of BALB/c skin grafts in C57BL/6 Cd28 Ϫ/Ϫ recipients (not shown).…”

Tribbles-1 as a Novel Biomarker of Chronic Antibody-Mediated Rejection

“…31 Moreover, this study focused on chronic injury, but TRIB1 could also be increased in acute rejection. TRIB1 differs from the other minimally invasive biomarkers of transplant rejection described to date that are of T/NK cell origin, [7][8][9]32 in that it is expressed primarily by APC as well as EC. As such, our findings point toward a possible but as yet unconfirmed role for APC in this pathology.…”

“…RNA was reversetranscribed into cDNA using polydT oligonucleotide and Maloney leukemia virus reverse transcription (Invitrogen). RNA was extracted from human urine samples as described previously 32 and reversetranscribed into cDNA using an RT-Omniscript kit (QIAGEN) according to the manufacturer's instructions.…”

Effector Mechanisms of Rejection

“…Two ligands of NKG2D, namely RAEL1 and RRLT, were found to be expressed in rat liver allograft and to be linked to acute rejection (Zhuo et al 2010). Moreover, in human kidney transplant biopsies, an elevated level of NKG2D mRNAwas also associated with acute rejection (Seiler et al 2007). NK cells produce a variety of cytokines, including IFN-g, TNF-a, and TGF-b, as well as colony-stimulating factors (Cuturi et al 1987(Cuturi et al , 1989Anegon et al 1988).…”