title: The effect of acute rejection and cyclosporin A-treatment on induction of platelet-derived growth factor and its receptors during the development of chronic rat renal allograft rejection.
abstract: BACKGROUND
  In the development of chronic kidney allograft rejection acute rejection (AR) is the single most important risk factor. Although Cyclosporin A (CsA) medication has decreased the incidence of AR, chronic rejection (CR) is still the major reason for late allograft loss. Platelet-derived growth factor (PDGF) is a major mitogen mediating mesenchymal cell proliferation in CR. We have investigated the impact of AR and different doses of CsA on the expression of PDGF ligands and receptors in the development of CR.
  
  
  METHODS
  Kidney transplantations were performed from DA to WF rats and syngenic controls were done from DA to DA rats. Two groups of allografts were treated daily with CsA either at low dose (1.5 mg/kg) or high dose (5 mg/kg). Third group of allografts was treated with CsA 5 mg/kg/day for 1 week and then left untreated until the development of AR. AR episodes were treated with CsA 5 mg/kg/day. Grafts were harvested 3 months after transplantation for histology and immunohistochemistry (PDGF-AA, -BB and PDGFR-alpha, -beta).
  
  
  RESULTS
  In syngenic grafts no histological signs of CR were seen and the expression of PDGF ligands and receptors remained almost nonexistent. AR episodes increased the chronic rejection changes. High-dose CsA-treatment ameliorated inflammation compared to low-dose CsA-treatment, although it failed to inhibit the development of chronic changes. More fibrosis was even seen in high-dose than in low-dose CsA-treated grafts. CR in each allograft group was associated with induction of all PDGF ligands and receptors (P<0.05 compared with syngenic controls) in interstitial inflammatory cells, capillary endothelium, and arterial smooth muscle cells. In the group with AR episodes the expression was further increased.
  
  
  CONCLUSIONS
  Our results demonstrate that CsA treatment cannot inhibit the expression of PDGF ligands and receptors in the development of chronic kidney allograft rejection and that AR episodes induce even more PDGF and its receptors in the graft indicating a link between AR and subsequent development of CR.
authors.affiliation: Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, P.O. Box 21 (Haartmaninkatu 3), FIN-00014 University of Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Savikko
authors.forename: Erkki A
authors.initials: EA
authors.lastname: Kallio
authors.forename: Eero
authors.initials: E
authors.lastname: Taskinen
authors.forename: Eva
authors.initials: E
authors.lastname: von Willebrand
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002908:Chronic Disease; D016572:Cyclosporine / Q000627:therapeutic use*; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis*; D013997:Time Factors; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
chemical_list: D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D016572:Cyclosporine; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor