Pancreas Transplantation: Development of Successful Preclinical Models

Sammanfattning: Pancreas transplantation is today a technically successful procedure and provides an alternative to insulin injections for the treatment of Type I diabetes mellitus. This thesis was undertaken while pancreas transplantation was developing and while several fundamental questions were being asked about both endocrine and exocrine drainage of the transplanted pancreas as well as how best to diagnose and prevent rejection. In order to answer some of these questions large animal models were established of: duct-occluded segmental pancreatic autografts; whole pancreatico-duodenal allografts; and simultaneous pancreas and kidney (SPK) allografts. Using these models the thesis investigated; long term endocrine and graft function, histology and physiology of acute and hyperacute rejection; systemic and portal venous drainage; and aspects of immunosuppression. In the long term duct-occluded segmental pancreas autograft, extensive fibrosis and coalescence of islets occurred and though endocrine function was not normal, glycosylated haemoglobin levels were normal and diabetic microvascular disease was averted for at least five years. In the pancreaticoduodenal allograft, rejection could be diagnosed either by cytology using total corrected increment (TCI) scores from fine needle aspiration biopsy (FNAB) and by comparison with urinary amylase levels gave an earlier and more specific diagnosis of rejection diagnosed by conventional pancreas needle core biopsy (NCB) histology. Portal venous drainage was not shown to provide any advantages over systemic drainage in this model. Longitudinal data from pancreas transplant alone (PTA) were compared with kidney transplant alone (KTA) and SPK. Increased immunosuppression was required by SPK recipients than either KTA or PTA and the most sensitive marker of pancreas rejection in SPK was NCB of the simultaneous kidney transplant. The most complex model established was to demonstrate and investigate hyperacute rejection in sensitised recipients, confirming the importance of the lymphocytotoxic crossmatch in clinical practice and laying the ground work for comparison with xenotransplant rejection in the future. Each of these experimental solutions provided a sound basis upon which to take decisions in our clinical pancreas transplant program.