Identification Of The Molecular Genetic Basis Of The Hepatic Veno-occlusive Disease With Immunodeficiency Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$224,250.00
Summary
One of the most serious complications of bone marrow transplantation is veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS). This condition occurs in 10% of transplanted patients and is characterised by abnormalities of liver function, enlargement of the liver, clotting abnormalities, fluid retention and finally failure of multiple organs and death in 30-50% of cases. The cause of VOD is unknown, and its occurrence cannot be predicted in individual patients. Eight fam ....One of the most serious complications of bone marrow transplantation is veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS). This condition occurs in 10% of transplanted patients and is characterised by abnormalities of liver function, enlargement of the liver, clotting abnormalities, fluid retention and finally failure of multiple organs and death in 30-50% of cases. The cause of VOD is unknown, and its occurrence cannot be predicted in individual patients. Eight families have been described in whom a number of individuals have succumbed to a condition which is clinically and histologically indistinguishable from VOD. Affected individuals also have a form of immunodeficiency (hence termed VODI), and the abnormalities are inherited in an autosomal recessive pattern. All eight are of Lebanese origin, suggesting that a single genetic ancestral mutation was responsible for the disorder in all families, who are distantly related. We have access to genetic material from three of these families, and are on the way to identifying the causative genetic abnormality. We hypothesise that understanding this abnormality will lead to an understanding of VOD which occurs after bone marrow transplantation. We have used 800 polymorphic genetic markers scattered throughout the genome to identify the location of the genetic abnormality, and have localised the defect to a region of chromosome 2 which contains approximately 37 known and predicted genes. We now aim to determine which of the gene(s) in the candidate region is responsible for VODI, and plan to examine DNA from individuals who have had VOD after transplantation to determine if they have a related abnormality. Finding the VODI gene will benefit these families through the availability of carrier detection and may also lead to an understanding of the veno-occlusive disease that occurs after bone marrow transplantation.Read moreRead less
Targeting The Renin Angiotensin System In Liver Fibrosis And Portal Hypertension
Funder
National Health and Medical Research Council
Funding Amount
$643,958.00
Summary
Cirrhosis of the liver due to chronic hepatitis and other common liver diseases is now a major cause of illness and death in Australia. This project will examine how a hormone system called the renin angiotensin system contributes to the development of liver damage in these diseases. We will study whether drugs targeting this system can be used to reduce liver scarring and prevent the development of cirrhosis and its complications.
Does Immunosuppression Affect The Post-transplantation Hepatic Fibrogenic Response?
Funder
National Health and Medical Research Council
Funding Amount
$360,000.00
Summary
Liver transplantation is often the only treatment option for patients who progress to end-stage liver disease after initial treatment has failed. Unfortunately, re-emergence of disease is common and patients often develop fibrosis and cirrhosis (scarring of the liver) in the donor organ. In some cases it has been observed that this scarring often develops rapidly, sometimes in a year or less following transplantation. Re-transplantation is often required. This differs from the usual progression ....Liver transplantation is often the only treatment option for patients who progress to end-stage liver disease after initial treatment has failed. Unfortunately, re-emergence of disease is common and patients often develop fibrosis and cirrhosis (scarring of the liver) in the donor organ. In some cases it has been observed that this scarring often develops rapidly, sometimes in a year or less following transplantation. Re-transplantation is often required. This differs from the usual progression of cirrhosis pre-transplant which often takes years or decades to develop. While essential to prevent rejection of the transplanted organ, immunosuppression is not without side effects. To date, few studies have examined the effect of immunosuppressive agents on the development of hepatic fibrosis and the key fibrosis effector cell type, the hepatic stellate cell. These reports have shown that one of the most commonly used immunosuppressant agents (FK-506) may adversely influence fibrosis progression while rapamycin may prevent fibrosis progression. However little is known regarding the mechanisms through which this occurs. We propose to examine the effect of four different immunosuppressants on fibrosis development both in vitro and in vivo to determine whether scar development or scar breakdown pathways are altered post-immunosuppression. If the factors driving the fibrogenesis in the transplanted organ can be elucidated it may then be possible to develop therapeutic strategies to tackle the problem. This may result in a reduced need for re-transplantation which has obvious benefits to the transplant patient but would also reduce the numbers of donor organs required.Read moreRead less
Pharmacodynamics In Liver Disease And In Liver Surgery
Funder
National Health and Medical Research Council
Funding Amount
$899,646.00
Summary
The liver is the main organ in the body for drug metabolism and detoxification. This work seeks to address the poorly understood question: what is the in vivo disposition and response in liver of the drugs for treatment of liver diseases? The results of this work will help us better design new drugs and choose the most effective drugs for liver disease. The research may also help us find a better strategy for liver transplantation and thus improve success rates.
Basic Mechanism Of Spontaneous Tolerance Of Liver Allografts In A Rat Model.
Funder
National Health and Medical Research Council
Funding Amount
$374,625.00
Summary
Many thousands of Australians have a failing liver and the only treatment for this is a liver transplant. Liver transplantation is a major life-saving strategy and hundreds of Australians are rescued each year who would otherwise have died. Rejection of the transplant is the major problem affecting these patients. This project investigates an animal model where a transplanted rat liver is not rejected, even though the recipient receives no treatment. Previous studies from our group have shown th ....Many thousands of Australians have a failing liver and the only treatment for this is a liver transplant. Liver transplantation is a major life-saving strategy and hundreds of Australians are rescued each year who would otherwise have died. Rejection of the transplant is the major problem affecting these patients. This project investigates an animal model where a transplanted rat liver is not rejected, even though the recipient receives no treatment. Previous studies from our group have shown that acceptance is due to donor white blood cells transferred with the liver and based on this finding we are developing treatments that can be used in transplant patients. The current application for funding tests another breakthrough that we have recently made, that treatment of the recipient with a substance called interleukin 4 prevents liver acceptance. This finding shows that interleukin 4, which was previously thought to be involved in preventing transplant rejection, is actually involved in stimulating rejection of the liver. It might therefore be possible to prevent rejection by altering the pattern of its expression, for example, by using an antibody to remove it. This application also aims to examine the overall expression of a very large number of genes in liver transplant acceptance compared with rejection. This will use a new technology called gene array analysis to examine expression of at least 5,000 genes to identify those that are increased during liver acceptance. In addition, gene therapy will be used to increase expression of a single gene called IDO that we and others have found to be associated with transplant acceptance. This gene will be expressed in white blood cells of the liver donor after transplantation to promote liver acceptance and prevent rejection. Ultimately it is intended that these findings will be used to prolong the survival of liver transplant patients by revealing new ways to prevent rejection of liver transplants.Read moreRead less