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.
The current treatment for diabetes involves diet, drugs and insulin treatment. While these are satisfactory for some adult onset diabetes, it is clear that in juvenile diabetes, the disease can progress in the presence of careful insulin dosage. It is apparent that the whole islet as a functional unit is likely to give the best control of diabetes, as when patients are transplanted with whole or segments of pancreas from human donors, as not only is there an improvement in their diabetic status, ....The current treatment for diabetes involves diet, drugs and insulin treatment. While these are satisfactory for some adult onset diabetes, it is clear that in juvenile diabetes, the disease can progress in the presence of careful insulin dosage. It is apparent that the whole islet as a functional unit is likely to give the best control of diabetes, as when patients are transplanted with whole or segments of pancreas from human donors, as not only is there an improvement in their diabetic status, the vessel lesions improve. Transplantation therefore offers a new therapy to diabetic patients for reversal of their disease and improvement in the serious side affects found in the eye, kidney and blood vessels. However, transplantation introduces a problem in that there is simply not sufficient human islets available for organ or islet transplantation, and in this light, animals are being examined as a possible source of islets. This is called xenografting or xenotransplantation. Of all the animal species, the pig is the most suitable donor for a variety of reasons, for example similar control of blood sugar to humans. The ultimate aims of the study are to examine possible genetic modifications that would allow the production of transgenic pig islets for transplantation to humans for the treatment of diabetes. The focus of the proposed studies is to elucidate the optimal combinations using mouse models. Importantly this study will establish the proof of principle and provide information on the genes that will be useful to finally genetically modify pigs for clinical use.Read moreRead less
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