CD39 Protects Against Renal Ischaemic-reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$441,584.00
Summary
In many medical settings, such as heart attacks, strokes, transplantation, heart surgery, shock and infection, the blood supply to an organ may be compromised resulting in damage. The cessation of blood flow depletes the organ of oxygen and generates a number of toxic changes. Re-establishing blood flow to the organ is essential to prevent further damage, however the reestablishment of blood flow itself can be harmful to the organ. The return of blood flow, oxygen and energy can actually promote ....In many medical settings, such as heart attacks, strokes, transplantation, heart surgery, shock and infection, the blood supply to an organ may be compromised resulting in damage. The cessation of blood flow depletes the organ of oxygen and generates a number of toxic changes. Re-establishing blood flow to the organ is essential to prevent further damage, however the reestablishment of blood flow itself can be harmful to the organ. The return of blood flow, oxygen and energy can actually promote more widespread injury - a process known as ischaemia-reperfusion injury (IRI). A greater understanding of IRI should aid in the development of drugs that minimise its impact. The overall aim of this work is to examine the role of a molecule - CD39 - in IRI. This molecule is ideally situated to minimise injury - it is located on cells that line blood vessels and, as such, is able to directly neutralise toxins released in response to this injury. We, therefore, believe that it will be protective in this setting. We have developed animals that express this molecule and have preliminary results to suggest that these animals are protected in experimental models of IRI as well as in several other models including heart transplantation surgery; processes that share many features with IRI. Moreover, mice deplete of this molecule are prone to more severe IRI. We aim to investigate this by using animals both lacking and expressing CD39. Blood flow to the kidneys will be interrupted for 30 minutes and kidney function assessed at 24 and 48 hours. We will then delve into the potential mechanisms underpinning IRI by determining whether the kidney itself or the blood cells afford protection, which has direct clinical implications.Read moreRead less
Investigation Into The Role Of Regulatory B Cells In Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$400,385.00
Summary
Solid organ transplantation is the most effective therapy for treating organ failure and some cancer. However, a common complication that occurs is graft rejection. The current aim is to develop procedures that reduce the risk of graft rejection without the use of immunosuppressive drugs, which can be toxic and make recipients more susceptible to infection. We are investigating the ability of a cell that is part of the immune system to down-regulate over-reactive immune responses and therefore r ....Solid organ transplantation is the most effective therapy for treating organ failure and some cancer. However, a common complication that occurs is graft rejection. The current aim is to develop procedures that reduce the risk of graft rejection without the use of immunosuppressive drugs, which can be toxic and make recipients more susceptible to infection. We are investigating the ability of a cell that is part of the immune system to down-regulate over-reactive immune responses and therefore reduce rejection.Read moreRead less
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
Developing Clinical Islet Transplantation For Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$387,337.00
Summary
This fellowship will provide me the opportunity to advance islet transplantation as a curative treatment for people with type 1 diabetes. The ultimate goal is to use cell-based therapy to achieve insulin independence for all people with type 1 diabetes. It aims to do this by developing a collaborative network between scientists and clinicians to advance human islet transplantation as a treatment for type 1 diabetes and to develop genetically engineered pig cells as a novel source of insulin prod ....This fellowship will provide me the opportunity to advance islet transplantation as a curative treatment for people with type 1 diabetes. The ultimate goal is to use cell-based therapy to achieve insulin independence for all people with type 1 diabetes. It aims to do this by developing a collaborative network between scientists and clinicians to advance human islet transplantation as a treatment for type 1 diabetes and to develop genetically engineered pig cells as a novel source of insulin producing cellsRead moreRead less
The Role Of Th17 And Tregs In The Development Of Tolerance And Rejection In A Murine Model Of Renal Allograft Rejection
Funder
National Health and Medical Research Council
Funding Amount
$110,068.00
Summary
In clinical transplantation, rejection remains the greatest problem in determining both short and long-term patient outcomes. Tolerance, the ability of the body to accept a transplant without immunosuppressive drugs, remains an as yet unattained goal. The aim of this project is to examine the mechanisms by which the initial immune response (innate immunity) affects the development of tolerance or rejection in a mouse model of kidney transplantation.
Mechanisms Of Regulatory T Cell Induction By Soluble Immunomodulatory Molecules
Funder
National Health and Medical Research Council
Funding Amount
$729,414.00
Summary
The purpose of this work is to identify how a select population of cells (T regulatory cells) function to prevent or dampen down the sometimes-harmful effects of the immune system. Understanding how these cells function may have broad implications for general immune regulation.
Elucidating The Mechanism Of IL-2 Cytokine/antibody Mediated Transplantation Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$624,429.00
Summary
Organ transplantation is a life-saving treatment for end-stage organ failure. However, patients must take immunosuppressive drugs to prevent rejection, a lifetime of which increases the risk of infection and cancer. An alternative to drugs is to manipulate the immune system from within. We discovered a way to boost the immune ‘regulators’ so that they stifle the graft-destroying response. We are optimising this approach with the aim of transplanting organs without long-term immunosuppression.
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
The Structural Basis For Recognition Of HLA-E By Both Innate And Adaptive Immune Systems.
Funder
National Health and Medical Research Council
Funding Amount
$206,255.00
Summary
Biochemistry and structural biology can be used to understand and visualize the three dimesional shape of molecules and the way they interact with other molecules. We will use these approaches to understand how various cells of the immune system recognise the protein HLA-E. This protein is normally present on the surface of healthy cells while it frequently retained inside both tumours and cells infected with viruses. This acts a signal for the immune system to kill these cells. However to avoid ....Biochemistry and structural biology can be used to understand and visualize the three dimesional shape of molecules and the way they interact with other molecules. We will use these approaches to understand how various cells of the immune system recognise the protein HLA-E. This protein is normally present on the surface of healthy cells while it frequently retained inside both tumours and cells infected with viruses. This acts a signal for the immune system to kill these cells. However to avoid being recognized by the immune system some viruses have developed ways to maintain HLA-E expression. This grant will attempt to understand exactly how the immune sytem recognizes HLA-E and how it discriminates between HLA-Eexpressed by healthy cells compared with HLA-E expressed by a virus-infected cell.Read moreRead less
Dendritic Cells In Graft-versus-Host Disease Following Bone Marrow Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$180,859.00
Summary
Bone marrow transplantation (BMT) is the only available curative therapy for many blood cancers such as leukaemia. Graft-versus-host disease (GVHD) occurs after BMT and is a major cause of transplant-related death. GVHD occurs when transplanted donor cells “attack” recipient tissues causing widespread damage. Gaining a more comprehensive understanding of this disease process is critically important for the design of new therapies and improvement of outcomes for transplant recipients.