Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.796211
Title: Immunohistological observations on foetal pancreas and isolated pancreatic islet transplantation in rats
Author: Brown, Malcolm Wilson
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1989
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Abstract:
Although it is now rare for a patient to succumb to the acute metabolic derangements of diabetes mellitus, diabetic patients still have a reduced life expectancy and many develop disabling complications. The balance of the available evidence suggests that near-physiological control of glucose metabolism at an early stage in the disease would prevent many of the microangiopathic and neuropathic changes otherwise seen. At present, whole organ or segmental pancreatic transplantation offers the most physiological system of insulin administration available, but the hope for the future is that isolated islet or foetal pancreas transplantation will become a clinical reality. As well as requiring only a relatively minor procedure for effective transplantation, an advantage that isolated islets and foetal pancreas have over whole organ or segmental pancreas grafts is the ability to survive in vitro allowing storage and a potential opportunity for immunomodulation. Immunomodulation prior to transplantation aims to reduce immunogenicity by altering the antigen content of a graft. Following the realisation of the particular importance of MHC class II positive cells in antigen presentation, much attention has been focussed on methods of removing these cells. Although foetal tissues generally express much lower levels of MHC antigens than adult organs, rat foetal pancreas allografts are rapidly rejected and immunomodulation of this tissue has been particularly difficult to achieve. Experiments described in this thesis confirm the low levels of MHC antigen expression in the freshly isolated rat foetal pancreas. However, removal from the foetal environment resulted in an increased antigen expression in foetal pancreas maintained in tissue culture and stimulation with interferon-gamma (IFN-gamma) demonstrated the ability of the foetal pancreas to synthesise and express MHC antigens. DA foetal pancreas, which is rapidly rejected when transplanted to the renal subcapsular site of PVG recipients, responded to allografting by demonstrating a marked increase in MHC class I antigen expression on all cell types. This increased class I expression included exocrine cells which had been shown to remain negative in isografts. In allografts, MHC class II antigens were expressed de novo on duct epithelium and exocrine cells whilst endocrine cells remained resistant to the induction of class II expression. Isograft class II expression was unchanged. Class II expression on exocrine cells and duct epithelium (which are absent in purified islet preparations) would be of importance if these cells were then able to function as antigen presenting cells and this could provide one possible explanation for the comparative resistance of foetal pancreas to immunomodulation. The function of foetal pancreas transplants can be affected by factors other than graft rejection and serial immunohistological examination offers an alternative method of graft assessment. Using this technique, Cyclosporin A treatment was found to prolong the survival of DA allografts in PVG and Lewis recipients, although subsequent discontinuation of Cyclosporin A was followed by rapid rejection. Cyclosporin A was also found to have a profound effect on the antigen expression of foetal pancreas allografts with the pattern of expression coming to resemble that of the isograft. In addition, both the magnitude and phenotype of the cellular infiltrate was also affected. Induction of antigen expression on the cells of rejecting allografts is probably a consequence of the local release of lymphokines and may precede any evidence of cellular damage by several days. Supportive evidence for a local release of lymphokine was provided by the observed increase in antigen expression on the allograft recipient's renal tubular cells adjacent to the transplanted foetal pancreas. This induced expression on renal tubular cells occurred only when rejection was present and although some evidence of a very limited graft-versus-host reaction was seen in parent strain to F1 transplant experiments, renal tubular-antigen induction appeared to be a consequence of the local release of lymphokine rather than as a result of graft-versus-host-mediated damage to the recipient's renal tubules. Evidence that IFN-gamma represented a possible candidate as a lymphokine of particular importance in the induction of antigen expression was provided by observing a pattern of changes in the pancreas glands of adult rats given systemic IFN-gamma which was similar to that seen in allografted foetal pancreas.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.796211  DOI: Not available
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