Expression of protective genies in human renal allografts: A regulatory response to injury associated with graft rejection

Background. Long-term survival of a graft requires inhibition of host immune effectors, but protective responses emanating from the graft might be equally important. Expression of the "protective" genes A20, heme-oxygenase-1 (HO-1), and Bcl-x(L) in rodent allo and xenografts correlates with long-term survival. Little is known of the pattern of expression of such protective genes and the implication thereof in clinical transplantation. Methods. We analyzed, by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry, expression of A20, HO-1, and Bel-x, in 31 renal allograft biopsies from patients with suspected rejection. Results. A20 is not expressed in nonrejecting (NR) grafts. Its expression is increased in grafts undergoing acute and chronic rejection (AR and CR) but is weaker in CR. HO-1 is not expressed in NR grafts; it is upregulated in AR but not CR. Bcl-xL is detected in all biopsies with decreased levels in CR. Expression of A20, HO-1, and Bel-x, localizes mainly to endothelial, smooth muscle, and infiltrating mononuclear cells. Conclusions. This data demonstrate that A20 and HO-1 are up-regulated in response to immune injury inferred by AR. Given the antiapoptotic and anti-inflammatory functions of these genes, we hypothesize that their expression survives to limit graft injury by maintaining cell viability and controlling inflammation. Their reduced expression in CR as compared with AR represents either inadequate response to injury or a sequelae of prior injury that jeopardizes further tissue response to immune attack.