Down-Regulation of TGF-β and VCAM-1 Is Associated With Successful Treatment of Chronic Rejection in Rats

Abstract

We measured the expression levels of transforming growth factor-beta (TGF-β) and vascular cell adhesion molecule (VCAM-1) in rat kidney grafts undergoing chronic rejection and treated the rats with six different regimens in order to determine correlation between their expression levels and severity of chronic rejection. F344 or Lewis kidneys were transplanted into Lewis recipients to generate allograft or isograft groups, respectively. Graft recipients were treated with one of the following regimens: (1) untreated isograft, (2) untreated allograft, (3) tacrolimus (FK506), 1 mg/kg/d for 10 days, (4) triptolide (PG490-88), 0.5 mg/kg/d for 10 days, and (5) leflunomide analogue (FK778), 10 mg/kg/d for 10 days. Kidneys were harvested on day 90 after transplantation and subjected to histological analysis and gene expression analysis by real-time reverse transcriptase polymerase chain reaction (RT-PCR) for TGF-β and VCAM-1. Gene expression values were compared to measurements of chronic rejection by linear regression analysis. Modified Banff score for transplant pathology show that chronic rejection was mild in the FK778 group, moderate in the PG490-88 group, and severe in the FK506 and allograft control groups. Overall, the expression levels of TGF-β and VCAM-1 show high correlations with histological changes of chronic rejection. Suppression of the expression levels of TGF-β and VCAM-1 is associated with the amelioration of chronic rejection by various drugs, suggesting that these molecules are important key molecules in chronic rejection.