Transforming growth factor (TGF)-beta mimics and anti-TGF-beta antibody abrogates the in vivo effects of cyclosporine - Demonstration of a direct role of TGF-beta in immunosuppression and nephrotoxicity of cyclosporine

Background. Cyclosporine (CsA) has been shown to induce the expression of t ransforming growth factor (TGF)-beta both in vitro and in vivo. It is hypot hesized that the efficacy as well as the side effects of CsA are mediated b y TGF-P. This study was planned to investigate whether anti-TGF-p mitigated and TGF-P reproduced the in vivo effects of CsA to directly prove this hyp othesis, Methods. B6AF(1), (H2(b/k.d)) mice were divided into groups and received th e following: CsA, vehicle (olive oil), CsA + anti-TGF-pl antibody, TGF-beta 1, or vehicle phosphate-buffered saline/bovine serum albumin. All studies were carried out at 10 and 28 days after the last day of CsA administration with the exception of the exogenous TGF-P experiments, which were performe d 5 days after exogenous TGF-P administration. The efficacy was studied by the anti-CD3-induced ex vivo proliferation of splenocytes measured by [H-3] thymidine uptake; TGF-P protein levels were quantified by ELISA, TG;F-P, co llagen, and fibronectin gene expression was studied using reverse transcrip tasepolymerase chain reaction, and histopathological analysis was made on p eriodic acid-Schiff- and trichrome C-stained thin kidney sections. Results. CsA treatment resulted in decreased ex vivo proliferation of splen ocytes, an increase in TGF-P protein in the sera, and renal histopathologic al changes including tubular swelling, vacuolization, thrombotic microangio pathy, and increased expression of TGF-P, collagen and fibronectin genes. A ll of these findings were blocked by anti-TGF-p antibody. Conclusion. The study demonstrates the in vivo modulation of the effects of CsA by manipulating TGF-P levels and suggests that TGF-P at least in part mediates CsA's beneficial and detrimental effects.