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Non-invasive Imaging of Acute Allograft Rejection after Rat Renal Transplantation Using 18F-FDG PET
Published on: April 28, 2013
The effect of FK778 on acute rat renal allograft rejection and expression of platelet-derived growth factor and
J M Rintala1, J Savikko, S E Rintala
1Transplantation Laboratory, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland. jukka.m.rintala@helsinki.fi
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.
Insights
FK778, a novel immunosuppressant, reduces acute kidney transplant rejection by decreasing platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) early post-transplant. This suggests FK778 may prevent chronic allograft nephropathy (CAN).
Area of Science:
- Immunology
- Nephrology
- Pharmacology
Background:
- Acute rejection is a primary driver of chronic allograft nephropathy (CAN).
- Platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are implicated in CAN development.
- FK778 is a novel immunosuppressant inhibiting pyrimidine biosynthesis.
Purpose of the Study:
- To investigate FK778's effect on acute kidney transplant rejection.
- To evaluate FK778's impact on PDGF and TGF-beta expression.
- To assess FK778's efficacy alone and with calcineurin inhibitors (cyclosporine [CsA] or tacrolimus [Tac]).
Main Methods:
- Rat kidney transplantation models (syngeneic and allogeneic).
- Immunosuppression with FK778, CsA, or Tac.
- Histological and immunohistochemical analysis of graft tissues for growth factors and receptors.
Main Results:
- FK778 dose-dependently reduced inflammatory responses and expression of PDGF and TGF-beta.
- FK778 demonstrated synergistic effects with CsA and Tac, with stronger synergy with Tac.
- Early reduction in PDGF and TGF-beta was observed.
Conclusions:
- FK778 effectively decreases PDGF and TGF-beta expression during acute kidney transplant rejection.
- FK778 shows promise as a therapeutic agent to prevent chronic allograft nephropathy (CAN).
- Synergistic effects with calcineurin inhibitors warrant further investigation.
