A Preclinical Model Of Pig Islet Xenotransplantation As Treatment For Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$4,380,000.00
Summary
The object of this multi-disciplinary program grant is to develop a source of pig insulin secreting tissue that will be used to treat type 1 diabetic patients. At present the number of diabetic patients that would benefit from islet transplantation far outnumber any human source of this tissue. Pigs that have been genetically altered to avoid rejection and enhance survival could overcome this donor shortage problem.. It is our belief that with the appropriate genetic modification pig insulin-sec ....The object of this multi-disciplinary program grant is to develop a source of pig insulin secreting tissue that will be used to treat type 1 diabetic patients. At present the number of diabetic patients that would benefit from islet transplantation far outnumber any human source of this tissue. Pigs that have been genetically altered to avoid rejection and enhance survival could overcome this donor shortage problem.. It is our belief that with the appropriate genetic modification pig insulin-secreting tissue can avoid the aggressive rejection response that occurs with xenographs and provide normal blood glucose control without insulin. This project concentrates on the five main issues that need to be overcome before pig insulin-secreting tissue can be used in diabetics. These are: identifying the best source of insulin secreting tissue to use; adult islets, newborn or foetal islet cell clusters; overcoming the strong rejection response to pig tissue; identifying a safe and effective immunosuppressive regime; producing a new types of genetically modified pigs that will provide islets tissue that will work in humans; and demonstrating that pig islet transplantation will not pose undue infective risks for the patient or community. This truly collaborative program grant has brought together a large group of investigators with strong research records in diabetes, islet transplantation, xenotransplantation, pig transgenesis and pig genetics and includes scientists and clinicians who look after diabetic patients. Unique pig resources will be used including genetically manipulated pigs that have been shown to avoid some of the rejection mechanisms associated with transplanting pig tissue. There is a captive-bred baboon colony that provided a unique model of diabetes. A world class pig transgenesis facility has been enlisted to generate new lines of genetically altered pigs as new data is produced within the group. Finally because of the involvement of the National Pancreas Transplant Unit any proven therapeutic strategy can be brought quickly to clinical trials.Read moreRead less
The Regulation Of Monocyte Derived Dendritic Cells (moDCs) During Allograft Rejection
Funder
National Health and Medical Research Council
Funding Amount
$110,218.00
Summary
Islet transplantation can cure type 1 diabetes, but the required drugs for immunosuppressing graft rejection have side effects. Therefore understanding how immune rejection occurs so that we can suppress in a more discreet selective way is our goal. A type of cell that is prominent during graft rejection is the monocyte derived dendritic cell. We propose that this cell is critical for orchestrating immune responses during rejection. Therefore we wish to determine how such cells are controlled.
Understanding the factors that control T cell responses has been a major focus of immunology. Despite this effort the factors that control T cell development, homeostasis and function are still only incompletely understood. Accordingly we have been studying the TNF-family cytokine BAFF (B cell activation factor of the TNF-family) in relation to T cell behaviour and function. Though BAFF was first described as being critical for B cell development and maturation, a number of lines of evidence ind ....Understanding the factors that control T cell responses has been a major focus of immunology. Despite this effort the factors that control T cell development, homeostasis and function are still only incompletely understood. Accordingly we have been studying the TNF-family cytokine BAFF (B cell activation factor of the TNF-family) in relation to T cell behaviour and function. Though BAFF was first described as being critical for B cell development and maturation, a number of lines of evidence indicate that BAFF may be important in T cell biology. Current studies suggest that BAFF exerts a pro-inflammatory effect upon T cell responses. Surprisingly then, when we examined the role of BAFF upon T cell function in vivo in the context of the allo-immune response, we found that ~60% of BAFF transgenic mice failed to reject a fully-mismatched allograft. Intriguingly, BAFF transgenic mice exhibited an increased number of CD4+ CD25+ Foxp3+ cells in the periphery and in vivo depletion of these CD25+ cells restored the ability of BAFF transgenic mice to reject an allograft. We hypothesize that BAFF plays a potentially powerful anti-inflammatory role in regulating certain T cell dependent immune responses. Our data suggests that BAFF can modulate T cell function by effecting T cell regulation.Read moreRead less