This study compares the intrarenal expression of TGF-beta and profibrogenic genes in renal transplant recipients treated with Tac and CsA. The results show that patients diagnosed with Tac nephrotoxicity exhibit increased expression of profibrogenic genes compared to CsA nephrotoxicity.

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

Cellular proliferation determines the events leading to the initiation and development of inflammation, immune activation, cancer, atherogenesis, and other disorders associated with aberrant cell proliferation. Cyclin inhibitor p21 plays a unique role in limiting cell cycle progression. However, its effectiveness can only be demonstrated with direct in vitro and in vivo delivery to control aberrant proliferation. We demonstrate that using a protein-transducing domain p21 protein a) localizes within the nuclear compartments of cells, b) interacts with transcription factors, NF-κB, and NFATs (NFATc and NFATp), and c) inhibits lymphocyte proliferation and expression of proinflammatory cytokines. This study using lymphocyte proliferation as a model suggests that the recombinant p21 protein can directly be delivered as a therapeutic protein to provide a novel, viable, and powerful strategy to limit proliferation, inflammation, alloimmune activation, cancer, and vascular proliferative disorders such as atherosclerosis.

Posttransplantation nephrotoxicity in cardiac transplant recipients treated with CsA for a long term is related to increased expression of TGF-beta and other fibrogenic genes. Therapies designed to inhibit expression of TGF-beta could ameliorate CsA-associated nephrotoxicity in cardiac transplant recipients.

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