FK778: new cellular and molecular mechanisms of action

Transplantation Proceedings
Sonja SchrepferHermann Reichenspurner

Abstract

The new malononitrilamide FK778 is currently being evaluated as an immunosuppressant for organ transplantation. Its main mechanism is inhibition of a pivotal enzyme of pyrimidine biosynthesis. This report revealed new mechanisms of action on different cell types involved in acute and chronic allograft rejection. Purified Brown-Norway rat aortic endothelial cell (EC) cultures were pretreated with several concentrations of FK778. Endothelial adhesion molecule expression (ICAM-1/VCAM-1) stimulated with TNF-alpha was quantified by immunofluorescence. Purified Lewis rat lymphocytes (LC) incubated with FK778 were stimulated via TCR/CD28 signals, and CD25 expression was quantified using FACS analysis. Uridine addition was used in all assays to reverse the pyrimidine synthesis blockade. Lymphocyte-EC interaction was assessed by micromanipulator-assisted single-cell adhesion assays. Finally, smooth muscle cell (SMC) proliferation and migration was analyzed. Uridine addition was used in all assays to reverse the pyrimidine synthesis blockade. TNF-alpha stimulation and TCR/CD28 co-stimulation significantly increased EC ICAM-1/VCAM-1-expression and LC CD25 surface expression, respectively. These effects were dose-dependently inhibited by F...Continue Reading

References

Nov 22, 2005·The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation·Tobias DeuseHermann Reichenspurner

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Citations

Aug 24, 2007·Expert Opinion on Investigational Drugs·Cevdet Ozdemir, Cezmi A Akdis
Mar 5, 2013·Journal of Medicinal Chemistry·Hélène Munier-LehmannYves L Janin
Mar 6, 2012·Phytotherapy Research : PTR·Shuli ManChangxiao Liu

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