IMMUNE-ACTIVATION GENE EXPRESSION IN CLINICALLY STABLE RENAL ALLOGRAFT BIOPSIES: MOLECULAR EVIDENCE FOR SUBCLINICAL REJECTION1,2

Abstract

A significant percentage of biopsies from stable, well-functioning renal allografts have histologic findings consistent with acute rejection or borderline rejection. The implication of this finding is not yet fully understood. We analyzed immune-activation gene transcripts in stable protocol biopsies to determine the extent of immunologic activity of graft-infiltrating cells in this setting. Histologic classification of the biopsies was based on the Banff criteria. To emphasize that the tissue samples were procured from grafts with no clinical evidence of impaired function, we interjected the term "subclinical" into the Banff terminology. This produced three histologic categories: normal, borderline subclinical rejection, and acute subclinical rejection. We used competitive template polymerase chain reaction techniques to quantify transcript amounts for the constant region of the T-cell receptor β chain; the cytokines, tumor necrosis factor α, interleukin (IL)-1β, transforming growth factor β, interferon γ, IL-2, IL-4, IL-10, and IL-15; and the cytotoxic T lymphocyte effector molecules, granzyme B, perforin, and Fas ligand. We found that histologically normal biopsies were typically devoid of gene transcripts or had very low amounts. Conversely, biopsies with acute subclinical rejection by histologic examination had heightened amounts of transcripts for many of the genes assayed. Borderline subclinical rejection samples showed an intermediate amount of expression. These results demonstrate that histologic features of rejection are often accompanied by enhanced expression of pro-inflammatory gene transcripts, despite the absence of clinically overt graft dysfunction. As this state of subclinical rejection could prove detrimental to long-term graft function, a role for surveillance biopsies of stable grafts with intent to treat subclinical rejection should be considered.