Genetic Determinants Of Interleukin-10 Response After Infectious Stimuli
Funder
National Health and Medical Research Council
Funding Amount
$276,000.00
Summary
Interleukin-10 is a key protein in the immune defense against infection, being the principal brake for the immune response. An diminished production of interleukin-10 has been implicated as a major cause of a number of devestating medical conditions including septic shock and acute respiratory distress syndrome. An excessive production of interleukin-10 may also be very harmful, and may be the primary cause of the reduction in immune function in many critically ill patients that leads to hospita ....Interleukin-10 is a key protein in the immune defense against infection, being the principal brake for the immune response. An diminished production of interleukin-10 has been implicated as a major cause of a number of devestating medical conditions including septic shock and acute respiratory distress syndrome. An excessive production of interleukin-10 may also be very harmful, and may be the primary cause of the reduction in immune function in many critically ill patients that leads to hospital acquired infections. These potential key roles of interleukin-10 in seriously ill patients makes it an attractive candidate to target for immune therapies. However, past experience with trials of immune-based therapies such as tumor necrosis factor alpha have taught us that we need to be much better at predicting individual immune responses if we are to 'interfere' with the immune system successfully. In the case of interleukin-10 there is substantial individual variation in the amount produced, with studies suggesting up to 70% of this variation is due to genetic differences. This project will establish the basis for this genetic variation by identiying both the genetic markers of high and low interleukin-10 response and the mechanisms by which these genetic markers change interleukin-10 production. This information will not only enable us to better target patients who may need an 'adjustment' of their immune function, but may also lead to novel therapeutic targets or therapeutic agents.Read moreRead less
A Randomised, Controlled Trial Of 10% Dextran 40 In The Prevention Of Stroke Complicating Carotid Endarterectomy
Funder
National Health and Medical Research Council
Funding Amount
$200,667.00
Summary
The operation to remove blockages in the carotid arteries (carotid endarterectomy) is of proven benefit in the prevention of stroke. The procedure itself, however, unfortunately carries approximately a 1 in 20 risk of immediate and early postoperative stroke. Most strokes are caused by blood clots forming at the operation site, breaking off and travelling to the brain (embolism). The up front operative risk is usually accepted by most patients in order to achieve the significantly greater long t ....The operation to remove blockages in the carotid arteries (carotid endarterectomy) is of proven benefit in the prevention of stroke. The procedure itself, however, unfortunately carries approximately a 1 in 20 risk of immediate and early postoperative stroke. Most strokes are caused by blood clots forming at the operation site, breaking off and travelling to the brain (embolism). The up front operative risk is usually accepted by most patients in order to achieve the significantly greater long term benefits of future stroke risk reduction. This study is designed to test a medication (dextran) thought to possibly prevent stroke associated with the operation. Dextran acts in part, by preventing blood clots forming at the operation site . In a pilot study undertaken by the researchers, dextran significantly reduced the downstream shedding of small blood clots (microemboli) detected by monitoring brain arteries using specialised ultrasound techniques. It remains to be proven, however, whether this effect on microemboli actually translates into the prevention of stroke complicating surgery. The DICE (Dextran In Carotid Endarterectomy) Trial aims to assess whether dextran can reduce the risk of stroke associated with carotid surgery by 50% or more. It has important implications for the increasing numbers of Australians being offered this operation (5,000-6,000 each year). If the therapy is proven effective there will be the potential to prevent 350-450 strokes and stroke related deaths each year.Read moreRead less
MODIFICATION OF TUBULE CELL CYTOKINES REGULATING INTERSTITIAL INFLAMMATION IN CHRONIC PROTEINURIC RENAL DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$294,121.00
Summary
Current treatments for chronic kidney disease are ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or transplantation to remain alive. Every year 1500 Australians commence dialysis for this reason, and many more die of kidney failure or its complications. One of the major reasons for progression of kidney failure is that kidney cells produce a complex network of inflammatory mediators (cytokines) which attract inflammatory cells into the suppo ....Current treatments for chronic kidney disease are ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or transplantation to remain alive. Every year 1500 Australians commence dialysis for this reason, and many more die of kidney failure or its complications. One of the major reasons for progression of kidney failure is that kidney cells produce a complex network of inflammatory mediators (cytokines) which attract inflammatory cells into the supporting tissue of the kidney (the interstitium). Recently, drugs that inhibit these cytokines have been used in animal models of chronic kidney disease. Such treatment regimens have been at most only partially effective because they have been directed against only one cytokine, and because they have ignored the fact that the profile of cytokines varies with stage of disease. This project will use a rodent model (Adriamycin nephrosis) of human chronic kidney disease to define strategies for preventing interstitial inflammation using anti-cytokine therapy. Our laboratory has identified three cytokines which appear to play a pivotal role in the development of interstitial inflammation in Adriamycin nephrosis, and shown that their production varies with time. Knowledge of the time-dependent interactions among and regulation of these cytokines will be used to define optimal delivery of therapy directed against all three cytokines. As anti-cytokine therapy is already being trialled in other types of (non-kidney) disease in humans, the success of such a therapeutic approach to treating progressive kidney disease in this animal model will have important and immediate implications for the treatment of chronic kidney disease in humans.Read moreRead less