TOLERANCE OR REJECTION – THE ROLE OF INNATE IMMUNITY IN DETERMINNG THE FATE OF A KIDNEY ALLOGRAFT
Funder
National Health and Medical Research Council
Funding Amount
$506,413.00
Summary
Transplantation is the optimal management for people with organ failure. Tolerance, to retain transplant function without immunosuppression, remains the key goal but is seldom achieved. We propose to block Toll-like receptor signalling to achieve kidney transplant tolerance in mice. If successful, we would translate this into clinical trials in human, seeking to achieve organ transplantation without the risks of cancer, infection and premature death that are currently faced by organ recipients.
Selective Targeting Of Acute Renal Injury By Inhibition Of The Receptor Tyrosine Kinase, C-fms.
Funder
National Health and Medical Research Council
Funding Amount
$443,007.00
Summary
The progression of kidney disease to end-stage renal failure is a major health problem in our community. We have identified that macrophages, a type of white blood cell, plays an important role in causing inflammatory kidney injury. This project will use clinically relevant animal models to test the therapeutic potential of our new approach to selectively remove these cells from the inflamed kidney and thereby protect it from injury.
Interplay Between Innate And Adaptive Immunity In Kidney Allograft Rejection
Funder
National Health and Medical Research Council
Funding Amount
$403,101.00
Summary
Acute allograft rejection (AR) still occurs in up to 40% of patients and is the major cause of graft loss during the first year after kidney transplantation. Even when treated, AR causes graft damage and is a major risk factor for premature graft loss due to chronic allograft nephropathy. Graft loss due to rejection returns the patient to dialysis and thus incurs medical costs in excess of $50,000 p.a. and reduces the duration and quality of life of the patient. Thus, AR directly and indirectly ....Acute allograft rejection (AR) still occurs in up to 40% of patients and is the major cause of graft loss during the first year after kidney transplantation. Even when treated, AR causes graft damage and is a major risk factor for premature graft loss due to chronic allograft nephropathy. Graft loss due to rejection returns the patient to dialysis and thus incurs medical costs in excess of $50,000 p.a. and reduces the duration and quality of life of the patient. Thus, AR directly and indirectly places a major burden upon patients, transplant services and the Australian community. AR occurs because of an adaptive alloimmune response mediated by T cells. The allografts also elicit an innate response and recent work has demonstrated both the prominence of the innate response and its essential role in facilitating adaptive alloimmunity. T cells are a component of the adaptive response and are prominent within rejecting allografts. NKG2D and toll like receptors (TLRs) are components of innate immune system. Our data demonstrates that ischemia reperfusion injury (IRI) causes upregulation of NKG2D ligand RAE-1 by kidney cells and TLR4 expression in kidney IRI and AR and that NKG2D expression is upregulated during kidney AR, and is expressed by intragraft CD8+ cells. Our results indicate that an interaction between innate and adaptive immunity may promote AR. We aim to determine whether: 1) TLR4 is required for the development of IRI to kidney and RAE-1 expression. 2) blockade of the interaction between NKG2D and its ligand RAE-1 expressed on the graft can attenuate AR and consequently prolong graft survival. 3) combined blockade of innate plus adaptive co-stimulatory molecules is more effective than either alone. This work will dissect the key interactions between innate and adaptive immunity in the allograft response and identify new targets for the prevention and treatment of allograft rejection.Read moreRead less
Investigating New Pathways In Acute Kidney Injury That Are Regulated By CD47
Funder
National Health and Medical Research Council
Funding Amount
$508,848.00
Summary
Acute kidney injury (AKI) is a widespread problem affecting both native and transplanted kidneys. Studies indicate that the incidence has increased more than 200-fold in the last decade, as has mortality. AKI also predisposes to the development of chronic kidney disease. There is no effective therapeutic for treatment or prevention of AKI. This project will investigate new cell signalling pathways regulating AKI with a view to developing these as novel clinical therapies.
Phosphate And Fibroblast Growth Factor 23 (FGF-23) In Early Chronic Kidney Disease – Their Importance In Bone Mineral Metabolism And As Cardiovascular Risk Factors.
Funder
National Health and Medical Research Council
Funding Amount
$140,949.00
Summary
In the chronic kidney disease (CKD) population, serum phosphate and fibroblast growth factor-23 (FGF-23), a phosphate regulating hormone, are strongly associated with mortality and cardiovascular disease (CVD). This thesis will examine phosphate homeostasis in clinical studies necessary to address this problem, as phosphate and FGF-23 are potential therapeutic targets.
20% of transplanted kidneys undergo rejection. This can permanently damage or destroy the transplant. Presently, rejection is identified when the kidney function deteriorates. This can occur late after rejection has started. To confirm the diagnosis of rejection, an invasive biopsy associated with discomfort and risks is required. This study will evaluate the use of a simpler blood test to monitor for rejection, allowing earlier and safer identification and treatment.
Strategies To Achieve Kidney Transplant Tolerance In A Clinically-relevant Model
Funder
National Health and Medical Research Council
Funding Amount
$663,490.00
Summary
The acceptance of kidney transplants without immunosuppression (tolerance) would avoid the side effects of these powerful drugs and improve long-term graft survival. Donor brain death causes inflammation in transplanted kidneys which can block tolerance. In this project, we aim to determine whether expression of a naturally-occurring soluble anti-inflammatory molecule in the liver can prevent this inflammation, allowing tolerance to develop.
Targetting Monocytes With Microparticles To Prevent Kidney Allograft Rejection
Funder
National Health and Medical Research Council
Funding Amount
$967,005.00
Summary
Whilst transplantation is lifesaving for many Australians with organ failure, it is a treatment rather than cure as recipients are dependent upon lifelong immunosuppression to prevent transplant rejection. Risks of death due to infection and cancer therefore remain high. We will test a new strategy in mice which modifies recipients of monocytes at the time of transplantation, to enable them to accept and tolerate the organ without ongoing need for expensive and dangerous immunosuppressive drugs.
Vitamin D And Chronic Kidney Disease: The Effects On Mineral Metabolism, Vascular Calcification And Transplant Outcomes
Funder
National Health and Medical Research Council
Funding Amount
$103,582.00
Summary
Kidney disease is a major health issue in the community. Vitamin D deficiency has been associated with an increased burden of cardiovascular disease and mortality in these patients. Vitamin D also has been shown to have a significant role in modulating our immune system. This study aims to assess the potential of vitamin D therapy to reduce the burden of cardiovascular disease and its effects on the immune function of renal transplant recipients in the laboratory and clinical setting.