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
Monitoring Of Leucocyte Cytokine-chemokines To Improve Morbidity And Rejection Rates In Lung Transplant Patients
Funder
National Health and Medical Research Council
Funding Amount
$373,973.00
Summary
Lung transplantation has become established therapy for many serious lung diseases. The early success rate is now very good, but at five years after transplant the survival rate is only around 60%. This problem is largely due to chronic graft failue as a result of chronic rejection or bronchiolitis obliterans syndrome. This project will specifically investigate the causes of BOS and thereby provide new information on how we may best treat this problem. An improvement in this area is critical.
HLA-E, a protein expressed by all cells regulates both innate and adaptive immune responses by binding to receptors found on white blood cells. This project will examine different ways that lymphocytes recognise this protein and its role in infection and transplantation.
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
Approaches To Allogeneic Chimerism For The Induction Of Transplantation Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
All patients with organ failure who receive a transplant require lifelong immunosuppressive medications to prevent the body from rejecting the foreign tissue. Indefinite immunosuppressive therapy is associated with significant side-effects which include infections and cancers. In addition, long-term loss of the transplants due to slow rejection (chronic rejection) remains high. Achieving a state of immunological tolerance in which transplanted tissue is regarded as self, but reactivity to all ot ....All patients with organ failure who receive a transplant require lifelong immunosuppressive medications to prevent the body from rejecting the foreign tissue. Indefinite immunosuppressive therapy is associated with significant side-effects which include infections and cancers. In addition, long-term loss of the transplants due to slow rejection (chronic rejection) remains high. Achieving a state of immunological tolerance in which transplanted tissue is regarded as self, but reactivity to all other foreign tissues (e.g. harmful viruses, bacteria) remain normal, would solve all these problems. Tolerance would eliminate the need for immunosuppressive medications and prevent rejection of transplanted organs. The production of mixed bone marrow chimerism is a potent method of inducing tolerance. Chimerism is a state in which bone marrow tissue from two genetically different individuals coexists in one person. This can be achieved by bone marrow transplantation from a specific donor, and if chimerism is achieved, the recipient will accept all tissues from the bone marrow donor without the need for ongoing immunosuppressive therapy. This study will attempt to examine the use of different therapeutic reagents (e.g. antibodies alone or antibodies linked to idarubicin, a drug which prevent cells dividing) to develop safe protocols for the production of bone marrow chimerism and tolerance for routine clinical use in humans. The study will also examine different cellular components of the donor bone marrow which may induce tolerance.Read moreRead less
The Role Of T-cell Apoptosis In Transplantation Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$173,380.00
Summary
Organ transplantation is the treatment of choice for patients with end-stage heart, lung, liver or kidney failure and there have been spectacular improvements in the early success of these procedures. However the 10 year graft survival rate has not changed much in the past 15 years. One way of overcoming this problem is to manipulate the immune system so that the transplant is accepted indefinitely. This is called tolerance and it works by giving intense immunosuppression for a short period so t ....Organ transplantation is the treatment of choice for patients with end-stage heart, lung, liver or kidney failure and there have been spectacular improvements in the early success of these procedures. However the 10 year graft survival rate has not changed much in the past 15 years. One way of overcoming this problem is to manipulate the immune system so that the transplant is accepted indefinitely. This is called tolerance and it works by giving intense immunosuppression for a short period so that the transplant is accepted indefinitely without the need for long term immunosuppression. The immune mechanism responsible for this phenomenon is complex and is poorly understood. This project aims to study the early events in the immune system that leads to transplantation tolerance. In particular, factors involved in programmed cell death in white blood cells will be studied. Specially bred mice that have blocks in the cell death mechanisms will used to determine what effects these blocks have on the ability to induce tolerance. Other mice that have been genetically altered to allow their white cells to be tracked will be used to study the fate of these cells. If the mechanisms involved in tolerance induction are better understood, then it will be possible to design specific immunosuppressive drugs that will be used to produce tolerance in transplant patients.Read moreRead less