The effect of FK778 on acute rat renal allograft rejection and expression of platelet-derived growth factor and transforming growth factor-beta.
BACKGROUND
Acute rejection is the single most important risk factor for the development of subsequent chronic allograft nephropathy (CAN). Both platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are major mitogens mediating mesenchymal cell proliferation and epithelial to mesenchymal cell transition. Early posttransplant induction of these growth factors may start molecular mechanisms leading to CAN. A new promising immunosuppressive drug, FK778, is an analogue of the active metabolite of leflunamide, which inhibits de novo pyrimidine biosynthesis. Herein we investigated the effect of FK778 on acute rejection and on the expression of PDGF and TGF-beta both alone and in combination with cyclosporine (CsA) or tacrolimus (Tac).


METHODS
Kidney transplantations were performed from Dark Agouti (DA) to Wistar-Furth (WF) rats with syngeneic controls between DA rats. No immunosuppression was given to syngeneic grafts. Allografts were immunosuppressed with FK778 alone or in combination with CsA or Tac. Grafts were harvested on day 5 for histology and immunohistochemistry (PDGF-A, -B, PDGFR-alpha, -beta, TGF-beta1, and TGF-betaR1).


RESULTS
FK778 ameliorated the inflammatory response and reduced PDGF and TGF-beta expression in a dose-dependent manner. It also showed synergy with calcineurin inhibitors, an effect that was stronger with Tac than with CsA.


CONCLUSIONS
Our results indicated that FK778 decreased PDGF and TGF-beta expression early in acute rejection, suggesting it to be a promising therapy for CAN.
Rintala
J M
JM
Transplantation Laboratory, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland. jukka.m.rintala@helsinki.fi
Savikko
J
J
Rintala
S E
SE
von Willebrand
E
E
D000480:Alkynes / Q000494:pharmacology*; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D006084:Graft Rejection / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology*; D009570:Nitriles / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D051381:Rats; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D016559:Tacrolimus / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics*; D014184:Transplantation, Homologous
D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D016572:Cyclosporine; D016559:Tacrolimus