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.
Mechanisms Of T Cell Mediated Injury In Renal Vasculitis
Funder
National Health and Medical Research Council
Funding Amount
$133,351.00
Summary
Anti-MPO glomerulonephritis (GN) is an aggressive disease causing severe and permanent injury to kidneys. This disease is thought to be due to an immune-mediated response to a protein (MPO) in neutrophils (a type of white blood cell). There is some evidence that other immune cells, CD4+ T cells, may be important in this disease. Experiments using models of anti-MPO GN will aim to define the role and mechanisms by which CD4+ T cells cause inflammation in the kidney.
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.
Defining The Cellular And Molecular Mechanisms Underlying Autoimmunity Using A Model Of SLE
Funder
National Health and Medical Research Council
Funding Amount
$624,960.00
Summary
The immune system has to recognize the difference between foreign pathogens, which it should attack, and ourselves, which it should not. Autoimmune diseases, like lupus, occur when our immune systems attack our own tissues due to problems in regulation. We have developed an animal model of lupus that has allowed us to identify major points where immune regulation has failed. Identifying these checkpoints will allow us to design and trial novel therapeutics in lupus.
Dissecting The Role Of The Lyn Tyrosine Kinase In B Cell Differentiation And The Development Of Autoimmunity.
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
The immune system has to be capable of responding to an unlimited array of pathogens, but at the same time remain unresponsive to, or tolerant of self-antigens. A breakdown in the tolerance to self-antigens results in autoimmunity. Autoimmune diseases include more than 70 chronic disorders that affect about 1 in 20 people in the Western population. Improving our understanding of the mechanisms that underlie autoimmune disease is essential for the design of more effective treatments. The Lyn tyro ....The immune system has to be capable of responding to an unlimited array of pathogens, but at the same time remain unresponsive to, or tolerant of self-antigens. A breakdown in the tolerance to self-antigens results in autoimmunity. Autoimmune diseases include more than 70 chronic disorders that affect about 1 in 20 people in the Western population. Improving our understanding of the mechanisms that underlie autoimmune disease is essential for the design of more effective treatments. The Lyn tyrosine kinase is a member of a family of genes that participate in transmitting information across the cell membrane. This enzyme is expressed in blood cells, and is involved in mechanisms pertaining to infection, immunity and allergic responses. To further our understanding of the role of this enzyme in the context of the whole animal, we have generated two strains of mice, one that is unable to make Lyn (Lyn-deficient mice) and one that expresses an activated form of the Lyn enzyme (Lyn-up mice). We have found that both strains of mice develop autoimmune disease with characteristics similar to the human autoimmune disease systemic lupus erythematosus (SLE). These studies suggest that Lyn is an important severity gene in autoimmunity. In this study we will examine in detail the role that Lyn plays in B cell development, function and autoimmunity, and we intend to identify the pathways that lead to autoimmune disease in Lyn mutant mice. On completion of these studies we will have developed a catalogue of the molecules and pathways perturbed in Lyn mutant mice. These studies will greatly improve our knowledge and understanding of the mechamisms behind certain autoimmune diseases, and may indeed lead to improved diagnosis, prognosis and treatment of patients with these conditions.Read moreRead less
Defining The Immunoregulatory Function Of Roqin: A Novel Gene Essential For Preventing Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$721,250.00
Summary
Lupus is a systemic autoimmune disease that carries significant morbidity and mortality. Virtually any organ can be affected, including kidneys, brain and blood. Lupus is the result of a breakdown in normal regulation of the immune system. Although there is clearly a significant genetic contribution to lupus, few causative genes have been found in humans with this disease. Recently, we discovered a novel mutation in a new gene (named roqin), that cases lupus in mice. Based on preliminary investi ....Lupus is a systemic autoimmune disease that carries significant morbidity and mortality. Virtually any organ can be affected, including kidneys, brain and blood. Lupus is the result of a breakdown in normal regulation of the immune system. Although there is clearly a significant genetic contribution to lupus, few causative genes have been found in humans with this disease. Recently, we discovered a novel mutation in a new gene (named roqin), that cases lupus in mice. Based on preliminary investigations and prediction based on the structure of Roqin, we suspect that this gene may be a key immune regulator. Specifically, it is likely to be involved in maintenance of immunological self-tolerance, which normally prevents development of autoimmunity. Mice carrying the Roqin mutation have an abnormality of their T cells, which causes them to be abnormally activated, divide more readily and survive for longer. Hyperactivated T cells induce B cells to proliferate and secrete antibodies against self-tissues that eventually lead to loss of platelets, kidney damage, enlarged spleen and lymph nodes, and early death. We now want to investigate precisely how Roqin causes abnormal T cell activation. The protein sequence of Roqin predicts the existence of two zinc finger domains that are highly conserved across species and play critical functions in regulating cell growth. One of the zinc fingers is a RING domain known to have a ubiquitin-ligase activity, which is known to play a crucial role in negative regulation of lymphocyte signalling, and maintenance of tolerance. The other zinc finger domain is known to be important for destabilizing mRNA of cytokines, thereby influencing communication between lymphocytes. Elucidation of this novel mechanism of disease will help understand the cause of human lupus. It will also provide clues about more specific drug therapies that might be more efficacious, and carry less toxicity than those currently available.Read moreRead less
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.
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.
Mechanisms Of Disease In Humans With MPO-ANCA Associated Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
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 plans to assess immune cells and kidney biopsies from patients with anti-MPO GN to define more precisely the immune mechanisms causing disease.