FK778, a powerful new immunosuppressant, effectively reduces functional and histologic changes of chronic rejection in rat renal allografts

Abstract

FK778 effectively reduces functional and histologic chronic kidney allograft rejection in the rat.

Mycophenolate Mofetil Is Associated with Altered Expression of Chronic Renal Transplant Histology

“…In a renal allograft model of chronic rejection in Fischer to Lewis rats, MMF substantially reduced chronic tubulointerstitial damage, fibrointimal hyperplasia and glomerulosclerosis (16), although another study failed to see a suppression of chronic histology sum scores unless sirolimus was added, when a synergistic effect was observed (33). Interestingly, FK778, the active leflunomide metabolite and de novo pyrimidine synthesis inhibitor, also reduced chronic histological changes including the development of tubular atrophy, fibrointimal hyperplasia, transplant glomerulopathy and glomerulosclerosis in the same experimental chronic rejection model (34). In addition, mononuclear cell infiltration, serum allo-specific antibody production and intragraft TGFb mRNA expression was decreased (34).…”

FK778 Attenuates Cytomegalovirus-Enhanced Vein Graft Intimal Hyperplasia in a Rat Model

“…More precisely, it has been shown that FK778 may inhibit SMC proliferation. In various experimental models it has been demonstrated that FK778 effectively attenuates vascular responses to injury by diminishing neointima formation and fibrointimal hyperplasia, perhaps through inhibition of the receptor tyrosine kinase activity in vascular SMC or their progenitors [14,27,28] . Also in our rat model of epigastric vein-to-common femoral artery interposition grafts a daily regimen of 15 mg/kg FK778 significantly reduced IH resulting in a lower percentage stenosis as compared to the control group.…”

The new malononitrilamide immunosuppressant FK778 prolongs corneal allograft survival in the rat keratoplasty model

“…It has been shown that FK778 inhibits acute rejection in experimental solid organ transplantation. [1][2][3][4][5][6] Furthermore, FK778 shows some mechanisms, which are separate from the blockade of pyrimidine synthesis. FK778 inhibits the DC-derived activation of T-cells via blocking the activation of the transcription factor NF-KB .…”

“…[1][2][3][4][5][6] The substance has been found to be effective and safe in a phase II study in renal transplantation in humans. 7 As the mechanism of graft rejection in solid organ transplantation differs considerably from those in corneal transplantation, it is necessary to evaluate the efficacy of FK778 in preventing corneal graft rejection in an animal model.…”