Kidney failure is a major health disorder in Australia and with more diabetes the number of patients waiting for transplant on dialysis is increasing. Current treatments give good initial survival of the kidney transplant but most kidneys are lost due to chronic damage . We propose a number of tolerance strategies in a model of kidney transplantation that will allow transplantation without longterm immunosuppression.
The goal of our work is to improve outcomes for patients who are blind or seriously visually impaired as a result of corneal disease. Such patients can regain vision through a corneal transplant, but many such transplants fail. A corneal graft may fail because of an unwanted immune response, because blood vessels grow into the graft, or because some corneal cells die. We plan to transfer genes to the donor cornea in the laboratory, prior to corneal transplantation, to avoid such failure.
Basic Mechanism Of Spontaneous Tolerance Of Liver Allografts In A Rat Model.
Funder
National Health and Medical Research Council
Funding Amount
$374,625.00
Summary
Many thousands of Australians have a failing liver and the only treatment for this is a liver transplant. Liver transplantation is a major life-saving strategy and hundreds of Australians are rescued each year who would otherwise have died. Rejection of the transplant is the major problem affecting these patients. This project investigates an animal model where a transplanted rat liver is not rejected, even though the recipient receives no treatment. Previous studies from our group have shown th ....Many thousands of Australians have a failing liver and the only treatment for this is a liver transplant. Liver transplantation is a major life-saving strategy and hundreds of Australians are rescued each year who would otherwise have died. Rejection of the transplant is the major problem affecting these patients. This project investigates an animal model where a transplanted rat liver is not rejected, even though the recipient receives no treatment. Previous studies from our group have shown that acceptance is due to donor white blood cells transferred with the liver and based on this finding we are developing treatments that can be used in transplant patients. The current application for funding tests another breakthrough that we have recently made, that treatment of the recipient with a substance called interleukin 4 prevents liver acceptance. This finding shows that interleukin 4, which was previously thought to be involved in preventing transplant rejection, is actually involved in stimulating rejection of the liver. It might therefore be possible to prevent rejection by altering the pattern of its expression, for example, by using an antibody to remove it. This application also aims to examine the overall expression of a very large number of genes in liver transplant acceptance compared with rejection. This will use a new technology called gene array analysis to examine expression of at least 5,000 genes to identify those that are increased during liver acceptance. In addition, gene therapy will be used to increase expression of a single gene called IDO that we and others have found to be associated with transplant acceptance. This gene will be expressed in white blood cells of the liver donor after transplantation to promote liver acceptance and prevent rejection. Ultimately it is intended that these findings will be used to prolong the survival of liver transplant patients by revealing new ways to prevent rejection of liver transplants.Read moreRead less
DEVELOPMENT OF CLINICALLY APPLICABLE STRATEGIES TO INDUCE AND MONITOR LONG TERM ACCEPTANCE OF LIVER ALLOGRAFTS
Funder
National Health and Medical Research Council
Funding Amount
$287,036.00
Summary
Liver transplantation is the only therapy for end-stage liver disease and thousands of Australian lives have been saved with this treatment. The major complication of liver transplantation is rejection which leads to loss of about half of the transplanted livers by ten years. Liver transplants in many animal models are not rejected and function normally for the life of the animal. Using one such animal model we have shown that white cells from the donor are responsible for the absence of rejecti ....Liver transplantation is the only therapy for end-stage liver disease and thousands of Australian lives have been saved with this treatment. The major complication of liver transplantation is rejection which leads to loss of about half of the transplanted livers by ten years. Liver transplants in many animal models are not rejected and function normally for the life of the animal. Using one such animal model we have shown that white cells from the donor are responsible for the absence of rejection. Of interest, these cells appear to stimulate a rapid and extreme immune response, which closely resembles rejection. The main difference is that it is quicker and more marked than rejection and then exhausts itself. This observation is unexpected and suggests possibilities for new treatments. Furthermore it questions the effectiveness of our present treatment for rejection of transplanted livers. We have already shown that some kinds of drugs given to prevent rejection in humans actually have the opposite effect in the animal model and prevent long-term acceptance of liver transplants. The aim of this work is to develop in our animal model a better way of treating human liver transplant patients. This will incorporate injection of donor white cells and treatment with drugs which promote the beneficial effects of these cells. We will also develop ways of testing the blood or the liver of the human liver transplant patients early after transplantation to find out whether the patient is accepting the liver or not. This means that we should be able to try this new treatment method in liver transplant patients once it has been optimised in the animal model.Read moreRead less
Targeting Innate Immunity To Prevent Chronic Dysfunction Of The Transplanted Kidney
Funder
National Health and Medical Research Council
Funding Amount
$497,057.00
Summary
Kidney transplantation is the optimal treatment for patients suffering from end-stage kidney disease. Chronic transplant dysfunction is the major barrier to long-term health after transplantation, and is the subject of this application. Our studies suggest a signaling system activates immunity and leads to chronic transplant dysfunction. We aim to block this signaling system in mouse models to identify clinically applicable treatments to prevent kidney transplant failure.
Antibody-mediated Dendritic Cell Depletion To Attenuate GVHD
Funder
National Health and Medical Research Council
Funding Amount
$434,510.00
Summary
Not all patients with leukemia will be cured by chemotherapy. Stem cell transplantation improves their chances of survival. Stem cell transplantation requires intensive chemotherapy and radiotherapy to eradicate the underlying disease and infusion of healthy stem cells to provide an anti-leukemic effect and normal blood cells. Recovery from transplantation is not straightforward. Recovery can be hampered by the immunological reaction of the donor cells against the patient (Graft versus Host Dise ....Not all patients with leukemia will be cured by chemotherapy. Stem cell transplantation improves their chances of survival. Stem cell transplantation requires intensive chemotherapy and radiotherapy to eradicate the underlying disease and infusion of healthy stem cells to provide an anti-leukemic effect and normal blood cells. Recovery from transplantation is not straightforward. Recovery can be hampered by the immunological reaction of the donor cells against the patient (Graft versus Host Disease [GVHD]), despite immunosuppression. GVHD produces serious damage to the internal organs and lining of the mouth and gut. Recovery can also be circumvented by leukemic relapse. GVHD is associated with an increased risk of death and dying after transplantation. To date therapy for GVHD has relied on eliminating the T cells that cause the disease. However for T cells to cause damage they must first be primed with antigen presented on activated dendritic cells. The intensive conditioning therapy required to eradicate the underlying disease before transplantation also activates dendritic cells. Our project seeks to investigate the effects of lethal and non-lethal conditioning on dendritic cells with the aim of validating the use of antibodies designed to deplete activated dendritic cells as therapy for graft versus host disease.Read moreRead less
The transplantation of healthy stem cells from a donor into a recipient with blood cancer (stem cell transplantation) is the most effective curative therapy for the majority of patients. Unfortunately this process results in unwanted, often fatal, side effects including infection, a rejection process known as graft-versus-host disease and in some patients, the leukaemia still recurs. This research will refine new treatments focused on overcoming these limitations and improving transplant outcome