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.
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-beta (TGF-beta) is one of the most potent mediators of the fibrogenic effects of cyclosporine.


RESULTS
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.


CONCLUSIONS
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.
Khanna
Ashwani K
AK
Division of Nephrology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA. akkhanna@mcw.edu
Plummer
Matthew S
MS
Hilton
Gail
G
Pieper
Galen M
GM
Ledbetter
Steven
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D016572:Cyclosporine / Q000627:therapeutic use / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D005353:Fibronectins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D016027:Heart Transplantation / Q000009:adverse effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use / Q000633:toxicity*; D007167:Immunotherapy; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D007677:Kidney Function Tests; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous / Q000009:adverse effects* / Q000276:immunology
D000911:Antibodies, Monoclonal; D005353:Fibronectins; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D019716:Tissue Inhibitor of Metalloproteinase-2; D016572:Cyclosporine; D003094:Collagen; D020781:Matrix Metalloproteinase 1