Regulation Of Inflammation And Thrombosis By Endothelial Protein C Receptor And Thrombomodulin In Xenograft Rejection
Funder
National Health and Medical Research Council
Funding Amount
$35,085.00
Summary
Pig-to-human organ transplantation may be the solution to the human organ shortage crisis. However, cross-species organ transplantation invariably results in graft destruction and rejection. Genetically modified mice expressing anti-rejection proteins will be tested to assess their effects and benefits on grafts. If such genes improve graft outcome, pigs with similar genetic modifications will be generated for the purposes of pig-to-primate organ transplantation studies.
The Role And Function Of Macrophages In Cellular Xenograft Rejection
Funder
National Health and Medical Research Council
Funding Amount
$323,250.00
Summary
The long term objective of this project is to develop pig insulin secreting tissue as a treatment for type 1 diabetes. At present the main barrier to this is rejection. In paricular a type of white blood cell called macophages has an important role in causing the rejection seen in xenotransplantation (the transplantation of pig tissue into humans). Our reseach group has made novel observations which show that the way macrophages respond to a xenotransplant is different to the way it behaves to t ....The long term objective of this project is to develop pig insulin secreting tissue as a treatment for type 1 diabetes. At present the main barrier to this is rejection. In paricular a type of white blood cell called macophages has an important role in causing the rejection seen in xenotransplantation (the transplantation of pig tissue into humans). Our reseach group has made novel observations which show that the way macrophages respond to a xenotransplant is different to the way it behaves to the transplant of an organ from the same species. In the rejection of pig insulin secreting tissue, macrophages are able to respond in the absence of ongoing signals from T cells. This project aims to identify the receptors on macrophages that are responsible for this response. In particular those receptors that are important for facilitating the migration of macrophages to the transplant site and the receptors that allow macrophages to distinguish self from non-self will be analysed. Hopefully these receptors will be used as targets for new therapeutic agents that could be used to prevent the strong rejection response that occurs when pig insulin secreting tissue is transplanted into humans.Read moreRead less
The successful treatment of many conditions in which the relevant organ has failed completely and irreversibly is to replace the organ with a new one i.e. to perform a transplant. It is well known that there are far fewer organs available for transplantation than the number needed. This means that for those conditions where a supportive treatment is available, eg. the artificial kidney, patients must be maintained by that method, however for other organs such as hearts, lungs and livers, there i ....The successful treatment of many conditions in which the relevant organ has failed completely and irreversibly is to replace the organ with a new one i.e. to perform a transplant. It is well known that there are far fewer organs available for transplantation than the number needed. This means that for those conditions where a supportive treatment is available, eg. the artificial kidney, patients must be maintained by that method, however for other organs such as hearts, lungs and livers, there is no mechanical substitute. If these patients do not receive a transplant, they die. A solution to this problem is to use organs from animals. This is called xenotransplantation. The pig is the most suitable donor, however despite the many similarities to humans which make pigs suitable, there are many differences which are still to be overcome before we can use pig xenotransplants clinically. These differences are at a very fine molecular level and prevent the normal integration of the pig organ into the human recipient. It is well established that the single most important difference which causes this rejection is a sugar molecule like a blood group which pigs have but humans do not. This is called Gal. This is also present in most animal species and we have completely removed it from a strain of mice by genetic modification. Unfortunately it has not been possible to make this change in pigs. However, the genetically modified mice give us a test model to determine precisely how much and by what mechanisms the Gal antigen is responsible for the rejection process.Read moreRead less
Immunobiology Of Carbohydrate Antigens In Xenotransplantation
Funder
National Health and Medical Research Council
Funding Amount
$563,554.00
Summary
Xenotransplantation, the transplanting of organs from other species, is now seen as a viable solution to the problem of lack of supply of suitable human donors. The recent production of genetically engineered pigs represented a critical step towards clinical xenotransplantation. However, other sugars still remain that cause rejection. This project examines the consequences of these sugars.
Intravascular Coagulopathy In Discordant Xenotransplantation
Funder
National Health and Medical Research Council
Funding Amount
$447,750.00
Summary
The successful treatment of many conditions in which the relevant organ has failed completely and irreversibly is to replace that organ with a new one ie. to perform a transplant. It is well known that there are far fewer organs available for transplantation than the number needed. This means that for those conditions where a supportive treatment is available, eg. the artificial kidney, patients must be maintained by that method, however for other organs such as hearts, lungs and livers, there i ....The successful treatment of many conditions in which the relevant organ has failed completely and irreversibly is to replace that organ with a new one ie. to perform a transplant. It is well known that there are far fewer organs available for transplantation than the number needed. This means that for those conditions where a supportive treatment is available, eg. the artificial kidney, patients must be maintained by that method, however for other organs such as hearts, lungs and livers, there is no mechanical substitute. If these patients do not receive a transplant, they die. A solution to this problem is to use organs from animals. This is called xenotransplantation. The pig is the most suitable donor, however despite many similarities to humans which make it suitable, there are many differences which are still to be overcome before clinical application is possible. These differences are at a very fine molecular level and prevent the normal integration of the organ into the new recipient. The result is that the new organ is rejected within minutes. This process is called hyperacute rejection and by research into its mechanism it was found to be due to just a few differences. We and others have genetically modified pigs so that they have the human components and this has completely prevented this form of rejection. However,we have found a second barrier which causes a rejection response after a few days. It is now known that a major component of the cause of this second barrier is a few differences in the clotting system. We propose to make further genetic modifications which we think will prevent this rejection. This project proposes to examine various genetic modifications and test their effect in small animal models before going on to make and test pigs in which human anti-clotting genes have been inserted. . If we are successful, the possibility of replacing failed human organs with animal organs will be a step closer.Read moreRead less
Intravascular Coagulopathy In Discordant Xenotransplantation
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The successful treatment of many conditions in which the relevant organ has failed completely and irreversibly, is to replace that organ with a new one ie. to perform a transplant. It is well known that there are far fewer organs available for transplantation than the number needed. This means that for those conditions where a supportive treatment is available, eg. the artificial kidney, patients must be maintained by that method, however for other organs such as hearts, lungs and livers, there ....The successful treatment of many conditions in which the relevant organ has failed completely and irreversibly, is to replace that organ with a new one ie. to perform a transplant. It is well known that there are far fewer organs available for transplantation than the number needed. This means that for those conditions where a supportive treatment is available, eg. the artificial kidney, patients must be maintained by that method, however for other organs such as hearts, lungs and livers, there is no mechanical substitute. If these patients do not receive a transplant, they die. A solution to this problem is to use organs from animals. This is called xenotransplantation. The pig is the most suitable donor, however despite many similarities to humans which make it suitable, there are many differences which are still to be overcome before we can use xenotransplants clinically. These differences are at a very fine molecular level and prevent the normal integration of the organ into the new recipient. The result is that the new organ is rejected within minutes. This process is called hyperacute rejection and by research into its mechanism it was found to be due to just a few differences. We and others have genetically modified pigs so that they have the human genes and this has completely prevented this form of rejection. However,we have found a second barrier which causes a rejection response after a few days. It is now known that a major component of the cause of this second barrier is a few differences in the clotting system. We propose to make further genetic modifications which we think will prevent this rejection. This project proposes to examine various genetic modifications and test their effect in small animal models before going on to make and test pigs into which human genes have been inserted. If we are successful, the possibility of replacing failed human organs with animal organs will be a step closer.Read moreRead less
Many people with organ failure need a transplant to survive. Unfortunately most patients who would benefit from a transplant are unable to receive one because of the shortage of living or deceased donors. A possible solution to this shortage is to use animal organs. Pigs are the most suitable animal donor. This project aims to produce and test genetically modified pigs which can provide organs that will be resistant to rejection when transplanted into human recipients.