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

• Published in: Circulation (New York, N.Y.) N.Y.), 2004-12, Vol.110 (25), p.3822-3829
• Main Authors: KHANNA, Ashwani K, PLUMMER, Matthew S, HILTON, Gail, PIEPER, Galen M, LEDBETTER, Steven
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Blood. Blood coagulation. Reticuloendothelial system; Cardiology. Vascular system; Collagen - biosynthesis; Collagen - genetics; Cyclosporine - therapeutic use; Cyclosporine - toxicity; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Drug Evaluation, Preclinical; Fibronectins - biosynthesis; Fibronectins - genetics; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Heart Transplantation - adverse effects; Heart Transplantation - immunology; Immunosuppressive Agents - therapeutic use; Immunosuppressive Agents - toxicity; Immunotherapy; Kidney - drug effects; Kidney - metabolism; Kidney Diseases - chemically induced; Kidney Diseases - genetics; Kidney Diseases - metabolism; Kidney Diseases - prevention & control; Kidney Function Tests; Matrix Metalloproteinase 1 - biosynthesis; Matrix Metalloproteinase 1 - genetics; Medical sciences; Pharmacology. Drug treatments; Rats; Rats, Inbred Lew; Rats, Inbred WF; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Tissue Inhibitor of Metalloproteinase-2 - biosynthesis; Tissue Inhibitor of Metalloproteinase-2 - genetics; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - biosynthesis; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - immunology; Transplantation, Heterotopic; Transplantation, Homologous - adverse effects; Transplantation, Homologous - immunology; Vertebrates: cardiovascular system
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000150400.15354.7D

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-beta (TGF-beta) is one of the most potent mediators of the fibrogenic effects of cyclosporine. With the use of an experimental rodent model, heterotopic heart transplantation was performed, creating histocompatibility-disparate allografts. Because TGF-beta in part mediates both the immunosuppressive and nephrotoxic effects of cyclosporine, recipients were treated with cyclosporine with and without anti-TGF-beta antibody to determine whether anti-TGF-beta antibody could reduce the nephrotoxic effects of cyclosporine. Intrarenal expression of TGF-beta, 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-beta protein was studied by immunohistochemistry and with the use of ELISA to quantify circulating levels of TGF-beta protein in plasma. Cyclosporine-induced graft survival (immunosuppressive effect) was abrogated with a higher concentration (2.5 mg/kg) of anti-TGF-beta antibody, whereas a lower concentration (1 mg/kg) inhibited both cyclosporine-induced expression of fibrogenic molecules and renal toxicity. These results provide credence to the pivotal role of TGF-beta 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-beta antibody to ameliorate cyclosporine-associated nephrotoxicity in cardiac transplant recipients.