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 transforming growth factor (TGF)-beta both in vitro and in vivo. It is hypothesized that the efficacy as well as the side effects of CsA are mediated by TGF-beta. This study was planned to investigate whether anti-TGF-beta mitigated and TGF-beta 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-beta1 antibody, TGF-beta1, 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-beta experiments, which were performed 5 days after exogenous TGF-beta administration. The efficacy was studied by the anti-CD3-induced ex vivo proliferation of splenocytes measured by [3H]thymidine uptake; TGF-beta protein levels were quantified by ELISA. TGF-beta, 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-beta protein in the sera, and renal histopathological changes including tubular swelling, vacuolization, thrombotic microangiopathy, and increased expression of TGF-beta, collagen and fibronectin genes. All of these findings were blocked by anti-TGF-beta antibody.


CONCLUSIONS
The study demonstrates the in vivo modulation of the effects of CsA by manipulating TGF-beta levels and suggests that TGF-beta at least in part mediates CsA's beneficial and detrimental effects.
Khanna
A K
AK
The Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee 53226, USA. akkhanna@mcw.edu
Cairns
V R
VR
Becker
C G
CG
Hosenpud
J D
JD
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology* / Q000633:toxicity; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D016572:Cyclosporine