title: Pre-clinical model of composite foetal pig pancreas fragment/renal xenotransplantation to treat renal failure and diabetes.
abstract: BACKGROUND
  Development of a limitless source of β cells for xenotransplantation into patients suffering type 1 diabetes and renal failure that can control their diabetes and provide normal renal function in one procedure would be a major achievement. For the islet tissue to survive transplantation, as an islet-kidney composite graft this would have significant advantages. It would simplify the surgical procedure; remove the complications caused by the exocrine pancreas whilst reversing diabetes and uraemia. It was our hypothesis that a composite foetal porcine pancreas fragment (FPPF)/renal graft could achieve these objectives in a large pre-clinical animal model as a means to establish whether this would be feasible before moving to the clinic.
  
  
  METHODS
  Inbred 'Westran' pig FPPF were transplanted under the kidney capsule of syngeneic Westran pig recipients without immunosuppression. Following maturation of the FPPF under the renal subcapsular space of this recipient, this kidney bearing the composite FPPF piggyback graft was removed and transplanted into another nephrectomized and pancreatectomized recipient to demonstrate function.
  
  
  RESULTS
  Under the kidney capsule of the first transplant group (n = 6), the FPPF-transplanted tissue developed and matured to form islet cell nests. These composite FPPF/renal grafts were then successfully removed and transplanted into the second functional assessment recipient group. This second group of six composite FPPF/renal-grafted pigs had normal renal function for more than 44 days and normal glucose homoeostasis without exogenous insulin as assessed by normal glucose tolerance tests, K values and normal glucagon secretion. Histological analysis showed despite the ischaemic insult during the composite kidney transplant procedure, there was appropriate development of islet-like structures up to and beyond 224 days after the original transplantation under the kidney capsule.
  
  
  CONCLUSIONS
  This study shows that the use of composite FPPF/renal grafts can cure both diabetes and renal failure with a single-transplant procedure. Using such composite grafts for xenotransplantation would simplify the surgical procedure and protect the islet graft from the immediate innate immune response.
authors.affiliation: Centre for Transplant & Renal Research, Westmead Millennium Research Institute, University of Sydney, Westmead, NSW, Australia. wayneh@med.usyd.edu.au
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Hawthorne
authors.forename: Denbigh M
authors.initials: DM
authors.lastname: Simond
authors.forename: Rebecca
authors.initials: R
authors.lastname: Stokes
authors.forename: Anita T
authors.initials: AT
authors.lastname: Patel
authors.forename: Stacey
authors.initials: S
authors.lastname: Walters
authors.forename: Jane
authors.initials: J
authors.lastname: Burgess
authors.forename: Philip J
authors.initials: PJ
authors.lastname: O'Connell
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery*; D016332:Fetal Tissue Transplantation / Q000379:methods*; D005333:Fetus / Q000033:anatomy & histology*; D005951:Glucose Tolerance Test; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D016030:Kidney Transplantation / Q000379:methods*; D010179:Pancreas / Q000033:anatomy & histology*; D051437:Renal Insufficiency / Q000601:surgery*; D013552:Swine