This project studies the mechanisms involved in rejection of skin and heart grafts using a novel model to track the behaviour of individual graft-reactive white blood cells. We will test two promising new techniques to limit graft rejection: using drugs to inhibit the entry of graft-reactive cells into the graft, and administering cells with the ability to suppress the function of graft-reactive cells. This work will help us to design new therapies to prevent heart graft rejection.
Towards A New Normokalemic Arrest Paradigm For Orthotopic Heart Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$489,634.00
Summary
Innovations from Nature to Heart Transplantation:a Real Heart Stopper Heart preservation is limited to 4-6 hours of cold-ischaemic storage (0 to 4 C). The risk of post-transplant death doubles if the donor heart is stored from 1 to 5 hours, and triples with 7 hrs storage times. We have developed a new preservation solution borrowing from natural hibernators that will permit organs to be safely stored for up to 15 hours, and offering new opportunities to organ donors and recipients worldwide.
Pharmacological Preconditioning And Sodium/hydrogen Exchange Inhibition To Optimise Preservation Of The Donor Pig Heart
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Heart transplantation has become established as an extremely beneficial treatment for patients with end-stage heart failure, however its success is limited by the restricted availability of donor hearts. Many hearts that could be considered for heart transplantation cannot be used because of damage that can occur to potential donor hearts after the death of the donor. This damage is caused in part by deterioration in heart function after death and in part by the process of removal and cold stora ....Heart transplantation has become established as an extremely beneficial treatment for patients with end-stage heart failure, however its success is limited by the restricted availability of donor hearts. Many hearts that could be considered for heart transplantation cannot be used because of damage that can occur to potential donor hearts after the death of the donor. This damage is caused in part by deterioration in heart function after death and in part by the process of removal and cold storage that occur prior to transplantation of the heart. This study will examine two new methods of optimising the quality and preservation of the donor heart for transplantation. The treatments to be investigated in this study are aimed at preventing damage to the donor heart after death and during the process of transplantation. The studies will be conducted in a pig model of heart transplantation that we have developed in our laboratory. The treatments will be administered to the donor pig after induction of brain death and also to the recipient during transplantation of the heart. As the model closely mimics all aspects of human heart transplantation, any positive findings that stem from these studies will be directly applicable to human transplantation. Improved preservation of the donor heart will make the operation safer and will potentially increase the number of hearts that can be used for transplantation. As many donors provide multiple organs for transplantation eg kidneys, liver, lungs and pancreas, the treatments that we are investigating have the potential to improve the recovery of all these organs after transplantation.Read moreRead less
Delayed Phase Of Remote Ischemic Preconditioning: Clinical Application And The Role Of Kallikrein-kinin Pathway.
Funder
National Health and Medical Research Council
Funding Amount
$159,197.00
Summary
Brief episodes of interruption of blood flow to the arm or leg provide strong protection against prolonged interruption of blood flow to a target organ (e.g., heart or lung). This is known as remote ischemic preconditioning (RIPC). The strongest protection occurs 24 hours after blood flow interruption to the limb and may be mediated by a humoral cascade known as kallikrein-kinin. RIPC may provide protection against heart attack and stroke.
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.
Does Galalpha(1,3)Gal Still Play A Role In Xenograft Destruction After The Production Of Gal Knockout Pigs?
Funder
National Health and Medical Research Council
Funding Amount
$706,062.00
Summary
Advances in surgical and immunosuppressive techniques has led to organ transplantation as the method of choice for the treatment of many diseases. However, the number of suitable donors is dwindling, due to many factors, but largely as a result of the reduction in deaths from car accidents. Xenotransplantation, the transplanting of organs from species other than humans, is now seen as a viable solution to the world wide problem of lack of supply of suitable human donors. The pig is the most suit ....Advances in surgical and immunosuppressive techniques has led to organ transplantation as the method of choice for the treatment of many diseases. However, the number of suitable donors is dwindling, due to many factors, but largely as a result of the reduction in deaths from car accidents. Xenotransplantation, the transplanting of organs from species other than humans, is now seen as a viable solution to the world wide problem of lack of supply of suitable human donors. The pig is the most suitable for a variety of reasons. However, the problem is that all humans contain natural antibodies to the pig which would lead to rejection within a few minutes as the antibodies bind to the transplant and reverse its rapid destruction (so called hyperacute rejection). Recent studies from our laboratory have indicated that most, if not all, of the antibodies react with the sugar - galactose present on many molecules on the surface of transplanted pig tissues. Our studies have indicated very large amounts of this material present in pig blood vessels - guaranteeing the early rejection of transplanted organs such as kidney, heart and liver. The production of knockout pigs which do not express the galactose sugar is an important pre-requisite for successful xenotransplantation. Recently knockout pigs which lack an enzyme that makes this sugar have been produced, but not all the sugar was destroyed. We have recently described a second novel enzyme that also makes this sugar. We will examine a role of this enzyme in xenotransplantation. These studies will be the prelude to the production of pigs which could be used for human transplantation.Read moreRead less
Neural Transplantation Of Human Bone Marrow Stromal Cells To Replace Oligodendrocytes Lost In Multiple Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$249,750.00
Summary
Multiple sclerosis is a disease of the central nervous system in which myelin (an insulative coating around the axons of neurons) and oligodendrocytes (the cells that produce myelin) are attacked and damaged by an unknown process. This damage is referred to as demyelination and results in a blocking or weakening of nerve signal conduction. Some of the symptoms of multiple sclerosis are weakness, tingling or numbness of limbs, and double vision or visual loss. One strategy to repair the demyelina ....Multiple sclerosis is a disease of the central nervous system in which myelin (an insulative coating around the axons of neurons) and oligodendrocytes (the cells that produce myelin) are attacked and damaged by an unknown process. This damage is referred to as demyelination and results in a blocking or weakening of nerve signal conduction. Some of the symptoms of multiple sclerosis are weakness, tingling or numbness of limbs, and double vision or visual loss. One strategy to repair the demyelination is to transplant cells into the damaged brain that can replace the damaged oligodendrocytes and remyelinate. Studies have shown that oligodendrocyte progenitor cells and neural stem cells transplanted into the brain can mature into oligodendrocytes and myelinate axons. However these cells are very difficult to obtain, the best source is foetal terminations but the use of such tissue raises ethical and practical problems. Recently cells found in adult bone marrow, called marrow stromal cells, have been shown to differentiate into neural cells when transplanted into the brain. This raises the possibility that sufferers of multiple sclerosis may be able to have marrow stromal cells taken from their bone marrow and then transplanted into their brains to replace their damaged oligodendrocytes. Our study will investigate the differentiation of marrow stromal cells into oligodendrocytes and determine if marrow stromal cells transplanted into demyelinated mouse brain can replace damaged oligodendrocytes and remyelinate areas of damage.Read moreRead less
Tolerogenic Dendritic Cells In Common Marmoset Renal Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$162,756.00
Summary
ORGAN TRANSPLANT PATIENTS currently need life-long immune suppressing drugs to prevent rejection, often using 15 medications a day, costing Australia $52M in 2002. These drugs increase risks of infection and cancer. 90% of patients develop some form of cancer over 30 years. They also cause non-specific side effects including high blood pressure, diabetes and osteoporosis. The average lifespan of a kidney transplant is 8-15 years. Major causes of kidney transplant loss are rejection and drug toxi ....ORGAN TRANSPLANT PATIENTS currently need life-long immune suppressing drugs to prevent rejection, often using 15 medications a day, costing Australia $52M in 2002. These drugs increase risks of infection and cancer. 90% of patients develop some form of cancer over 30 years. They also cause non-specific side effects including high blood pressure, diabetes and osteoporosis. The average lifespan of a kidney transplant is 8-15 years. Major causes of kidney transplant loss are rejection and drug toxicity. TRANSPLANTS ARE REJECTED when a recipient's immune system sees the kidney as foreign. Immune suppressing drugs prevent rejection by stopping the reaction to foreign tissues, but this causes increased infection and cancer risk. IMMUNE TOLERANCE means the recipient's immune system sees a transplant not as foreign but as part of itself, no longer reacting to it. If tolerance could be achieved for transplants, patients wouldn't need to use immune suppressing drugs. Costs of immune suppression would be nil. Tolerance is the best long-term solution for patients needing transplants. Tolerance has been achieved in various ways in mice models. DENDRITIC CELLS can be used to induce tolerance as they can silence a recipient's immune system, preventing it from seeing transplant tissues as foreign. We have shown in mice that a single infusion of a certain type of dendritic cells caused prolonged transplant tolerance without needing immune suppression. This project aims to use dendritic cells to induce tolerance in a marmoset model - a required step before allowing this therapy to be done in humans. PRIMATES like MARMOSETS have close genetic identity to humans and are ideal transplant models as their immune systems react much more like humans than other animals. Marmosets are not an endangered species and are smaller, cheaper and easier to care for than other primates. Ultimately, experiments in other species would need repeating in primates before human trials could be done.Read moreRead less