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
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.
The Effect Of Innate Immune Responses On The Induction Of Protective Immunity In Murine Typhoid Fever
Funder
National Health and Medical Research Council
Funding Amount
$136,500.00
Summary
Salmonella are important pathogens of humans causing diseases ranging from gastroenteritis, typhoid fever to arthritis. Like most if not all infections, the early interaction between the host and the bacterium is characterised by very non-specific symptoms. These non-specific symptoms arise because the so-called innate immune system is activated by the infection. The purpose of this grant is to establish whether these non-specific symptoms, caused by the release of immunological homrones called ....Salmonella are important pathogens of humans causing diseases ranging from gastroenteritis, typhoid fever to arthritis. Like most if not all infections, the early interaction between the host and the bacterium is characterised by very non-specific symptoms. These non-specific symptoms arise because the so-called innate immune system is activated by the infection. The purpose of this grant is to establish whether these non-specific symptoms, caused by the release of immunological homrones called cytokines, are essential to the development of an effective immune response which can protect against subsequent re-infection. This study has important implications for vaccines, of our understanding of how bacteria cause disease, and the role-capacity of the innate immune system in the development of immunity.Read moreRead less
Characterisation Of The Genetic Networks Underlying Macrophage Differentiation And The Resolution Of Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$405,000.00
Summary
Chronic inflammation is a central player in many common diseases, impacting on the health and well being of millions of Australians. By using innovative genomic approaches to build a map of all of the gene products involved in the inflammatory process, this project aims to identify which are the critical molecules that normally switch off inflammation. Our ultimate aim is to develop new approaches to treating inflammatory disease.
Lung infections are the most frequent triggers of asthma exacerbations. While different infections cause exacerbations by they all result in the same type of lung inflammation. Using novel disease models, we have identified key molecules involved in a range of viral and bacterial induced asthma exacerbations. We will define these shared pathways that link viral and bacterial-mediated asthma exacerbations, thus these studies will pave the way for the development of unified treatments.
TOLL LIKE RECEPTORS AGGRAVATE GLOMERULONEPHRITIS AND KIDNEY INJURY IN RENAL VASCULITIS
Funder
National Health and Medical Research Council
Funding Amount
$110,068.00
Summary
Anti neutrophil cytoplasmic antibody associated vasculitis (AAV) is a significant cause of morbidity and mortality. My thesis will explore the role of Toll Like Receptor (TLR) 2 and TLR9 in the initiation and pathogenesis of AAV and the therapeutic potential of TLR2/9 inhibitors. I will use both a murine experimental model and human kidney biopsy samples in this work. My thesis will further define the critical molecular events that underlie the disease whilst addressing potential new therapies.
Inflammasome Sensors And Immune Protection Against Tumorigenesis
Funder
National Health and Medical Research Council
Funding Amount
$750,110.00
Summary
Intestinal cancer is a leading cause of death in Australia and worldwide. Defects in the immune system can lead to the development of intestinal cancer. In this project, we will investigate the critical role of an immune sensor in inhibiting the development of intestinal cancer. This project will provide new insights into the interplay between the immune system and cancer biology and will potentially inform the development of new immunotherapies.