FK778 ameliorates post-transplant expression of fibrogenic growth factors and development of chronic rejection changes in rat kidney allografts.
BACKGROUND
Acute rejection is the major risk factor for the development of subsequent chronic allograft nephropathy (CAN), which is the primary reason for late allograft loss in kidney transplantation. Platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are the main mitogens mediating mesenchymal cell proliferation. Their early post-transplant induction may start cascades leading to the development of CAN. An immunosuppressive drug, FK778, inhibits de novo pyrimidine biosynthesis and several receptor tyrosine kinases (RTKs). Here we investigated its effects on acute and chronic rejection as well as post-transplant PDGF and TGF-beta expression in combination therapy with calcineurin inhibitors (CNIs).


METHODS
Kidney transplantations were performed from DA to WF rats. Syngenic DA-DA grafts were used as controls. Allografts were immunosuppressed with a combination of FK778 (10 mg/kg/day p.o.) and CsA (1.5 mg/kg/day s.c.) or tacrolimus (Tac) (1.5 mg/kg/day p.o.). Grafts were harvested 5 and 90 days after transplantation for histology and immunohistochemistry (PDGF-A, PDGF-B, PDGFR-alpha, PDGFR-beta, TGF-beta, TGF-betaR). The dose response of FK778 on acute rejection was studied with monotherapy of 5, 10 and 20 mg/kg/day. Chronic changes were scored according to the Chronic Allograft Damage Index (CADI).


RESULTS
FK778 ameliorated the early post-transplant inflammatory response dose dependently. Additive effects were seen with FK778 and CNIs. Significantly lower CADI scores were seen in combination therapy of FK778 and CNIs compared with CNI monotherapies. FK778 also significantly reduced both early and late PDGF and TGF-beta expression when combined with CNIs.


CONCLUSIONS
These results indicate that FK778 could prevent the development of CAN and be a promising therapy also in clinical kidney transplantation.
Rintala
Jukka M
JM
Transplantation Laboratory, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland. jukka.m.rintala@helsinki.fi
Savikko
Johanna
J
Rintala
Sini E
SE
von Willebrand
Eva
E
D000480:Alkynes / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016030:Kidney Transplantation / Q000473:pathology*; D008297:Male; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051381:Rats; D011920:Rats, Inbred WF; D012307:Risk Factors; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014184:Transplantation, Homologous
D000480:Alkynes; D065095:Calcineurin Inhibitors; 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