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(Circulation. 2004;110:3822-3829.)
© 2004 American Heart Association, Inc.

Transplantation

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

Ashwani K. Khanna, PhD; Matthew S. Plummer, BS; Gail Hilton, BS; Galen M. Pieper, PhD; Steven Ledbetter, PhD

From the Division of Nephrology (A.K.K., M.S.P.), and Division of Transplant Surgery (G.H., G.M.P.), Medical College of Wisconsin, Milwaukee, and Genzyme Corporation, Boston, Mass (S.L.).

Correspondence to Ashwani K. Khanna, PhD, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail akkhanna{at}mcw.edu

Received June 9, 2004; revision received July 29, 2004; accepted August 11, 2004.

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-ß (TGF-ß) 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-ß in part mediates both the immunosuppressive and nephrotoxic effects of cyclosporine, recipients were treated with cyclosporine with and without anti–TGF-ß antibody to determine whether anti–TGF-ß antibody could reduce the nephrotoxic effects of cyclosporine. Intrarenal expression of TGF-ß, 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-ß protein was studied by immunohistochemistry and with the use of ELISA to quantify circulating levels of TGF-ß protein in plasma. Cyclosporine-induced graft survival (immunosuppressive effect) was abrogated with a higher concentration (2.5 mg/kg) of anti–TGF-ß 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-ß 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-ß antibody to ameliorate cyclosporine-associated nephrotoxicity in cardiac transplant recipients.

Key Words: transplantation • coronary disease • kidney • transforming growth factors

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