How BANK1 Pathway Defects In B Cells Cause Human Lupus
Funder
National Health and Medical Research Council
Funding Amount
$1,316,839.00
Summary
Autoimmune diseases affect 1 in 20 Australians and are incurable. To find effective therapies, we need to understand the genes that cause disease in humans. We have sequenced the entire genome of patients with an autoimmune disease and found several patients carrry two mutations in genes important for activation of B cells and shown these mutations cause disease. We plan to understand how these genes prevent autoimmunity, and to identify the best treatment for patients with these mutations.
Development Of A Safer New Treatment For Systemic Lupus Erythematosus That Preserves B Cell Immunity
Funder
National Health and Medical Research Council
Funding Amount
$672,008.00
Summary
Lupus is an illness characterized by the body’s immune system attacking the body itself. More than 5 millions of people worldwide suffer from lupus, in particular Indigenous Australians who are 4 times more likely to develop lupus. Current treatments are toxic and/or lack efficacy. In this proposal we use strong new evidence from the laboratory to support the design of a much safer and more effective treatment for lupus that will be validated for future use in patients.
I am the leading scientist studying a factor named BAFF and discovered its role in autoimmunity. BAFF inhibitors are effective in late stage clinical trials treating lupus patients. Our new work shows that BAFF has other fascinating roles, in particular the ability to control effects from some microbes capable of activating autoimmune and inflammatory reactions. This new work is leading us to the development of an entirely new generation of therapeutics treating autoimmunity and inflammation.
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.
There has been no significant breakthrough in the treatment of Systemic Lupus Erythematosus (SLE) for over 50 years. Treatment continues to rely on non-specific immunosuppressant drugs and glucocorticoids (GC, or ‘steroids’), and the impact on patients includes high mortality and poor quality of life. In this proposal, I will validate novel endpoints which will break the impasse in SLE drug development and develop tools for minimising GC use in SLE.
Translational Study Of The Genetics Of Systemic Autoimmunity Based On Mouse Mutagenesis
Funder
National Health and Medical Research Council
Funding Amount
$518,500.00
Summary
Lupus is the prototypic autoimmune disease. It is characterised by inflammation that can damage virtually any organ in the body. This inflammation is the outcome of a complex interplay between the environment and genetic predisposition, resulting in production of antibodies against components of normal tissue. Better characterisation of the genetic basis of lupus is a priority because it is the single best path towards a clearer understanding of the mechanism of this debilitating disease, and ul ....Lupus is the prototypic autoimmune disease. It is characterised by inflammation that can damage virtually any organ in the body. This inflammation is the outcome of a complex interplay between the environment and genetic predisposition, resulting in production of antibodies against components of normal tissue. Better characterisation of the genetic basis of lupus is a priority because it is the single best path towards a clearer understanding of the mechanism of this debilitating disease, and ultimately, new therapeutic options. Strategies used to identify the genetic basis of human disease fall into two categories. The first involves gathering genetic information from families with more than one affected member, which is then compared with genetic information from unaffected people. This can identify genetic regions likely to contain disease-causing genes, but so far, this approach has met with limited success in lupus. Although regions of the genome that harbour disease-associated genes have been found, few actual disease causing genes have been confirmed. The second approach begins with known genes that might plausibly cause the disease, based on prior knowledge then tests are performed to see whether particular variants of these genes are more common in patients than in healthy controls. Obviously this approach is usually biased towards investigation of candidate genes that are already well-characterised. In this project, we will combine information obtained from a large-scale mouse-based programme in which genetic changes that cause features of lupus are generated randomly. In other words, there is an unbiased search for candidate genes, which should lead to the discovery of new disease pathways. Since the mouse and human immune systems are remarkably similar, genetic abnormalities that cause features of lupus in mice are highly likely to be informative about the genetic basis of human lupus, a hypothesis we will test with genetic studies in humans with lupus.Read moreRead less
Targeting Autophagy As A Means Of Control Of Cytokine Production In SLE
Funder
National Health and Medical Research Council
Funding Amount
$616,518.00
Summary
Systemic lupus erythematosus (SLE, or lupus) is a common immune disease that causes organ damage and loss of life, chiefly affecting young women. There is no cure for SLE. We have discovered that a natural process called 'autophagy' could be a way to limit inflammation during SLE. In this project we will discover whether this could lead to a new way to treat this disease.
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.