title: Epidermal growth factor inhibition, a novel pathway to prevent chronic allograft injury.
abstract: BACKGROUND
  Chronic allograft injury remains a major problem in clinical kidney transplantation and different growth factors participate in its development. Epidermal growth factor (EGF) affects cell proliferation and mitogenesis through its tyrosine kinase receptor. Erlotinib is an orally administered tyrosine kinase inhibitor used in clinical oncology to inhibit EGF signaling. We investigated its effect on the development of chronic allograft injury in an experimental kidney transplantation model.
  
  
  METHODS
  Kidney transplantations were performed between Dark Agouti and Wistar Furth rats. Recipients were immunosuppressed either with cyclosporine A (CsA, 1.5 mg/kg/day subcutaneously) or with CsA and erlotinib (10 mg/kg/day orally). Kidney grafts were harvested after 5 and 90 days for histology and immunohistochemistry. Aorta denudation model was used for the erlotinib dose response study to define the optimal dose for the transplantation study.
  
  
  RESULTS
  Epidermal growth factor expression was increased in CsA-treated allografts which developed intense chronic changes on day 90. Erlotinib ameliorated neointimal formation in the dose response study. In addition, erlotinib decreased chronic rejection changes and maintained better graft function in kidney transplantation model. Late posttransplant EGF and EGF receptor levels were reduced with erlotinib.
  
  
  CONCLUSIONS
  Based on these findings, EGF mediates in part the development of chronic allograft injury. Its inhibition with erlotinib prevents chronic rejection and maintains better allograft function. Therefore, EGF blocking by erlotinib provides a novel pathway to prevent chronic allograft injury.
authors: 1 Transplantation Laboratory, University of Helsinki, Helsinki, Finland. 2 Helsinki University Central Hospital, Transplantation and Liver Surgery Unit, Helsinki, Finland. 3 Helsinki University Central Hospital, Department of Medicine, Division of Nephrology, Helsinki, Finland. 4 Address correspondence to: Jukka M. Rintala, M.D., Transplantation Laboratory, PO Box 400 (Haartmaninkatu 3) 00029, Hospital District of Helsinki and Uusimaa (HUS), Finland.
authors: Jukka M
authors: JM
authors: Rintala
authors: Johanna
authors: J
authors: Savikko
authors: Niina
authors: N
authors: Palin
authors: Sini E
authors: SE
authors: Rintala
authors: Petri K
authors: PK
authors: Koskinen
authors: Eva
authors: E
authors: von Willebrand
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D002908:Chronic Disease; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D000069347:Erlotinib Hydrochloride; D006084:Graft Rejection / Q000517:prevention & control*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D011799:Quinazolines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D014184:Transplantation, Homologous
chemical_list: D011799:Quinazolines; D004815:Epidermal Growth Factor; D000069347:Erlotinib Hydrochloride