TRANSFORMING GROWTH FACTOR (TGF)-?? MIMICS AND ANTI-TGF-?? ANTIBODY ABROGATES THE IN VIVO EFFECTS OF CYCLOSPORINE

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Abstract
Background. Cyclosporine (CsA) has been shown to induce the expression of transforming growth factor (TGF)-β both in vitro and in vivo. It is hypothesized that the efficacy as well as the side effects of CsA are mediated by TGF-β. This study was planned to investigate whether anti-TGF-β mitigated and TGF-β reproduced the in vivo effects of CsA to directly prove this hypothesis. Methods. B6AF1 (H2b/k.d) mice were divided into groups and received the following: CsA, vehicle (olive oil), CsA + anti-TGF-β1 antibody, TGF-β1, 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-β experiments, which were performed 5 days after exogenous TGF-β administration. The efficacy was studied by the anti-CD3-induced ex vivo proliferation of splenocytes measured by [3H]thymidine uptake; TGF-β protein levels were quantified by ELISA. TGF-β, collagen, and fibronectin gene expression was studied using reverse transcriptase-polymerase chain reaction, and histopathological analysis was made on periodic acid-Schiff- and trichrome C-stained thin kidney sections. Results. CsA treatment resulted in decreased ex vivo proliferation of splenocytes, an increase in TGF-β protein in the sera, and renal histopathological changes including tubular swelling, vacuolization, thrombotic microangiopathy, and increased expression of TGF-β, collagen and fibronectin genes. All of these findings were blocked by anti-TGF-β antibody. Conclusion. The study demonstrates the in vivo modulation of the effects of CsA by manipulating TGF-β levels and suggests that TGF-β at least in part mediates CsA's beneficial and detrimental effects.

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