Immunotherapeutic Strategies In Anti Myeloperoxidase ANCA Associated Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$615,998.00
Summary
Kidney disease is the 10th most common cause of death in Australia. Glomerulonephritis (GN) is a major cause of kidney disease. Autoimmunity underpins disease in most patients with the most severe forms. Following the discovery of the peptide that is the target of this autoimmunity promising new biological treatments are possible. This grant will assess the capacity of four emerging therapies to turn off injurious autoimmunity and treat disease.
The Therapeutic Role Of Complement Inhibition In ANCA Associated Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$600,964.00
Summary
ANCA associated vasculitis is an inflammatory disease involving the kidney filters which is a major cause of chronic kidney failure. Current drugs to treat it are toxic. Less toxic treatments are required. In this study we will explore the potential for new treatments targeting complement (a normal blood protein involved in inflammation) to attenuate this disease in mice. We hope to define the role of complement in this disease and the benefits of inhibiting it before we use it in humans.
Current therapy for AAV has major toxicities and 30% of Patients are dead or on dialysis within 3 years. This proposal aims to study a unique form of cell death termed Neutrophil extracellular traps (NETs) that initiates and perpetuates inflammation in this disease. We will use an animal model of the disease that mirrors human disease. We will inhibit crucial molecules in NET production to attenuate disease. This will provide proof of concept evidence to promote clinical trials in patients.
Targeting Tregs Using Chimeric Antigen Receptors (CARs) For The Treatment Of Autoimmune Renal Disease
Funder
National Health and Medical Research Council
Funding Amount
$845,519.00
Summary
Chronic Kidney Disease is one of the major causes of death in Australia. Therapeutic success with regulatory T cells (Tregs) capable of targeting autoimmune kidney disease would have major clinical implications. In the proposed study, we will use Chimeric Antigen Receptors (CARs) T cells by redirecting them to diseased organs, protect against kidney injury. These CAR T cells will recognise renal antigens and target immune cells and antibodies to limit kidney damage.
The glomerulus is the filtering component of the kidney. In many diseases, it can be the target of an inappropriate inflammatory response. As part of this response, white blood cells accumulate in the glomerulus where they cause damage. The aim of the project is to determine how these white blood cells accumulate in the glomerulus, specifically asking the question, what molecules present on the white blood cells and the glomerular blood vessels are required for this accumulation?
Glomerulonephritis (Bright's Disease) is the commonest cause of destruction of kidney function that leads to patients requiring artificial kidney treatment (dialysis) and renal transplantation. The glomeruli or filters of the kidney are attacked by inflammation and destroyed. The attack is usually auto-immune, that is the bodys' immune system loses tolerance to kidney tissue and mounts a destructive attack on the glomeruli. In many patients, this attack is mild and resolves with current treatmen ....Glomerulonephritis (Bright's Disease) is the commonest cause of destruction of kidney function that leads to patients requiring artificial kidney treatment (dialysis) and renal transplantation. The glomeruli or filters of the kidney are attacked by inflammation and destroyed. The attack is usually auto-immune, that is the bodys' immune system loses tolerance to kidney tissue and mounts a destructive attack on the glomeruli. In many patients, this attack is mild and resolves with current treatments to dampen the immune response. In others, current treatment is inadequate to dampen the attack and the kidney is destroyed. This research uses experimental models of nephritis to examine how the immune system injures the glomeruli. In particular, how T cells attack and mediate injury. This is a novel concept, as hither to it has been thought antibodies and other factors in the blood (complement) mediate injury. Our group was one of the first to identify T cells mediate injury in forms of glomerulonephritis, previously thought to be solely mediated by antibody and complement. This project will further define which molecules produced by the T cell effect injury of glomeruli. With the potential aim of turning off the T cell attack mechanisms in a more specific way than is achieved by non specific immunosuppressive drugs such as corticosteroids, cytotoxic (anti-cancer) drugs or cyclosporine (an anti-rejection drug). A major part of this project will be to examine the role of cytokines, hormone like molecules that are produced by white cells and mediate injury or regulate other white cells, in effecting injury and in turning off the immune injury.Read moreRead less
New Roles For The Spleen Tyrosine Kinase In Antibody-independent Renal Injury.
Funder
National Health and Medical Research Council
Funding Amount
$574,890.00
Summary
This study investigates the novel hypothesis that a particular cell activation pathway (called Syk) is important not only in antibody-based kidney disease, but that it also plays a previously unrecognised role in other forms of antibody-independent kidney disease. Drugs that inhibit the Syk pathway are in clinical development for treatment of diseases such as arthritis. Hence, a positive outcome of this project could lead to the use of Syk inhibitors in many different types of kidney disease.
Resolvin E1 Is A Novel Anti-inflammatory And Anti-fibrotic Lipid Mediator For The Treatment Of Chronic Kidney Disease.
Funder
National Health and Medical Research Council
Funding Amount
$519,246.00
Summary
This project will ascertain whether a naturally occurring compound, Resolvin E1 with potent anti-inflammatory properties, can effectively halt the progression of experimental kidney disease. We will also test whether Resolvin E1 can exert other potential benefits in suppressing progressive fibrosis of the kidney. The outcome of this study will allow us to evaluate the therapeutical potential of Resolvin E1 for the treatment of acute and chronic kidney diseases.
Distinct Pathogenic Roles For JNK Signalling In Glomerular And Interstitial Injury In Kidney Disease.
Funder
National Health and Medical Research Council
Funding Amount
$555,892.00
Summary
Our studies have identified a stress-activated mechanism (the JNK signalling pathway) as a therapeutic target in the treatment of kidney disease. The current project will define the role of JNK signaling in individual cell types in the development of different types of kidney disease. These studies will provide new insights into the pathogenesis of kidney disease, and will be highly relevant to other diseases, including atherosclerosis, lung fibrosis and arthritis.
Immunoregulation In The Pathogenesis And Therapy Of Autoimmune Anti Myeloperoxidase Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$283,880.00
Summary
Glomerulonephritis (GN) is a major health burden and crescentic GN is the most severe form. Most patients have autoantibodies to their own white blood cell ANCA, causing the disease. This study will use a mouse model of ANCA associated autoimmunity causing crescentic GN to define the normal mechanisms preventing the development of this disease (immunoregulation) and test the potential of new cell based therapies to prevent and treat the disease.