Anti-transforming growth factor antibody at low but not high doses limits cyclosporine-mediated nephrotoxicity without altering rat cardiac allograft survival: Potential of therapeutic applications

Abstract

Background-Long-term treatment of cardiac transplant recipients with cyclosporine results in a progressive decline in kidney function in a large number of patients. This complication is one of the most important prognostic parameters that determine the outcome of cardiac transplantation. Transforming growth factor-β (TGF-β) is one of the most potent mediators of the fibrogenic effects of cyclosporine. Methods and Results-With the use of an experimental rodent model, heterotopic heart transplantation was performed, creating histocompatibility-disparate allografts. Because TGF-β in part mediates both the immunosuppressive and nephrotoxic effects of cyclosporine, recipients were treated with cyclosporine with and without anti-TGF-β antibody to determine whether anti-TGF-β antibody could reduce the nephrotoxic effects of cyclosporine. Intrarenal expression of TGF-β, collagen, fibronectin, matrix metalloproteinase-2, and tissue inhibitor of metalloproteinase-2 was studied with the use of reverse transcription-polymerase chain reaction. Intrarenal expression of TGF-β protein was studied by immunohistochemistry and with the use of ELISA to quantify circulating levels of TGF-β protein in plasma. Cyclosporine-induced graft survival (immunosuppressive effect) was abrogated with a higher concentration (2.5 mg/kg) of anti-TGF-β antibody, whereas a lower concentration (1 mg/kg) inhibited both cyclosporine-induced expression of fibrogenic molecules and renal toxicity. Conclusions-These results provide credence to the pivotal role of TGF-β in immunosuppression-associated renal toxicity in recipients of cardiac transplantation. Furthermore, these findings support a potentially significant therapeutic use of optimal concentration of anti-TGF-β antibody to ameliorate cyclosporine-associated nephrotoxicity in cardiac transplant recipients.