Induction Of Natural T-Regulatory Cells By Thymic Dendritic Cell Populations
Funder
National Health and Medical Research Council
Funding Amount
$413,775.00
Summary
In this study, we will determine the roles of the antigen presenting cells, namely denderitic cells, in the induction of T-regulatory cell (T-reg) developemnt in the thymus. T-reg cells play important roles in controlling the development of autoimmunity. This study will help to understand the possible causes of autoimmune diseases and to develop new treatments for these diseases.
Immune Dysregulation In HIV Patients With Immune Reconstitution After Highly Active Anti-retroviral Therapy
Funder
National Health and Medical Research Council
Funding Amount
$411,000.00
Summary
As HIV infection progresses to AIDS, there is a depletion of CD4 T-cells from the patient's blood and inhibition of the function of the remaining cells. Some immune defects resolve if the patient is given treatment with highly active anti-retroviral therapy (HAART), but it remains to be determined if the function of the imune system returns fully to normal. We have shown that problems with the regulation of the restored immune system in the first 6 months of treatment can lead to diseases associ ....As HIV infection progresses to AIDS, there is a depletion of CD4 T-cells from the patient's blood and inhibition of the function of the remaining cells. Some immune defects resolve if the patient is given treatment with highly active anti-retroviral therapy (HAART), but it remains to be determined if the function of the imune system returns fully to normal. We have shown that problems with the regulation of the restored immune system in the first 6 months of treatment can lead to diseases associated with Mycobacterial infections (eg: tuberculosis), CMV retinitis, hepatitis B virus or hepatitis C virus. We have defined these conditions as Immune Restoration diseases (IRD) and shown that they occur in one in four individuals who begin HAART from low baseline CD4 T-cell counts. IRD are likely to become common as therapy becomes available in Africa and Asia as patients begin treatment from low CD4 T-cell counts. There is also emerging evidence that dysregulated T-cell responses may cause disease later in the course of immune reconstitution. For example, some patients with undetectable HIV experience opportunistic infections or autoimmune disease after many months of HAART. This project will use West Australian patients receiving optimal therapy for their HIV infection. We will analyse immune activation and T-cell function in patients beginning HAART with low CD4 T-cell counts and patients who have had well-controlled HIV infection for at least 6 months. Blood samples will be collected for the measurement of immunological messengers (cytokines) known to be involved in different types of immune responses. The results will be correlated with the clinical outcome.Read moreRead less
Asthma Prevention And Treatment Using UVB Radiation-induced Immunomodulation
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
Summary
The prevalence of asthma is increasing despite the adoption of modern expensive drugs. Our studies suggest that exposure of skin to an erythemal dose of the wavelengths of UVB radiation found in sunlight can suppress responses to allergens encountered in the airways. We are requesting support to study the mechanisms in mice by which exposure to UVB radiation on their shaved backs can reduce inflammation in the airway mucosa upon allergen exposure. Whole body immunomodulatory effects of UVB radia ....The prevalence of asthma is increasing despite the adoption of modern expensive drugs. Our studies suggest that exposure of skin to an erythemal dose of the wavelengths of UVB radiation found in sunlight can suppress responses to allergens encountered in the airways. We are requesting support to study the mechanisms in mice by which exposure to UVB radiation on their shaved backs can reduce inflammation in the airway mucosa upon allergen exposure. Whole body immunomodulatory effects of UVB radiation have been previously described but have not been scientifically linked with asthma development. This is a very new and novel research area which supports century-old anecdotal reports that holidays at beach and mountain resorts associated with increased UVB exposure are beneficial in asthma treatment. This is a proof of principle study. If we can confirm that UVB is immunomodulatory and better understand the mechanisms by which UVB suppresses inflammation in the airways, we will investigate the potential of non-carcinogenic, UVB-induced, skin-derived intermediary molecules to have the same regulatory effects.Read moreRead less
Characterization Of Neutralizing Antibody Responses In HCV Infected Individuals.
Funder
National Health and Medical Research Council
Funding Amount
$478,076.00
Summary
Hepatitis C virus is a major human pathogen infecting 200 million people world-wide. Currently, there is no vaccine to prevent infection and treatment regimes are only partially effective. IInitial HCV infection is frequently asymptomatic and 30% of people spontaneously clear the virus. The remaining 70% of people develop a life-long chronic infection that causes progressive liver disease, cirrhosis and in some cases liver cancer. The reason why some people are able to clear virus has been attri ....Hepatitis C virus is a major human pathogen infecting 200 million people world-wide. Currently, there is no vaccine to prevent infection and treatment regimes are only partially effective. IInitial HCV infection is frequently asymptomatic and 30% of people spontaneously clear the virus. The remaining 70% of people develop a life-long chronic infection that causes progressive liver disease, cirrhosis and in some cases liver cancer. The reason why some people are able to clear virus has been attributed to the development of a strong cellular immune response and antibody is belived to play a monir role in achieving viral clearance. However, measurememnt of antibody responses in HCV infected pateints is routinely performed using conventional diagnostic tests that do not measure antibody that can help neutralize and clear virus. We have developed an assay that accurately measures the level of NAb in patient sera. We have found that chronically infected patients have broadly reactive neutralizing antibodies but that patients who clear virus, naturally or through treatment do not have broadly reactive neutralizing antibodies. Possibly explaining this phenomenon is that early during infection, antibody is frequently specific only to the infecting virus therefore to detect neutralizing antibodies, homologous viral sequences must be examined. In addition, we have found evidence that HCV can evade neutralzing antibodies through masking of sites to which antibodies bind. We propose to explore whether acutely infected patients develop NAb to autologous viral sequences, and how do these viral sequences and the antibody titre change throughout the course of infection and treatment. We also plan to determine the mechanism of neutralization resistance through the use of mutagenesis of resistant HCV glycoproteins. These studies are aimed at gaining a thorough understanding of the true role of antibody in HCV infection and its influence on viral evolution.Read moreRead less
Parkinson s disease (PD) is a progressively disabling movement disorder afflicting over 25,000 Australians. It is caused by the degeneration of specific nerve cells in the brain that produce certain chemcials and patients suffer from an inability to move fluently (or ultimately at all). At present we do not know what triggers this neurodegeneration. Current symptomatic treatments give sufferers some relief for a period of time by boosting the amount of these depleted chemicals in the brain. Howe ....Parkinson s disease (PD) is a progressively disabling movement disorder afflicting over 25,000 Australians. It is caused by the degeneration of specific nerve cells in the brain that produce certain chemcials and patients suffer from an inability to move fluently (or ultimately at all). At present we do not know what triggers this neurodegeneration. Current symptomatic treatments give sufferers some relief for a period of time by boosting the amount of these depleted chemicals in the brain. However, the underlying cellular degeneration continues unabated until such treatments are no longer effective. It is necessary to determine the reason for the cell loss in the brain in order to develop successful long-term treatments for this disabling disorder. There have been a number of animal models for PD developed. Comparing the type of tissue damage associated with the cell loss in these models shows that signs of brain inflammation occur prior to the loss of nerve cells. This feature consistently occurs regardless of the method used to produce the disease model. However, inflammation has been poorly studied in PD. Part of the present proposal is to analyse the brain tissue from patients with PD in order to document whether inflammation is also a consistent feature in the regions affected by the disease. Other central nervous system disorders in which inflammation is thought to play a pivotal role often have some genetic predisposition to the disorder and there is evidence of an immune response in their blood. We also wish to examine these aspects in patients with PD. Overall, our study will provide the necessary evidence for or against a primary role for inflammation in the disease process causing the ongoing degeneration in PD. If significant indications for a primary role for inflammation are found, treatments specifically targeting inflammation (already available) can be trialled to slow or stop the neurodegeneration.Read moreRead less
Investigation Of The Roles Of TNFa-related Apoptosis-inducing Ligand, TRAIL, In The Immune System.
Funder
National Health and Medical Research Council
Funding Amount
$436,980.00
Summary
TRAIL, is a newly described member of the tumour necrosis factor (TNF)-family of cytokines, which can kill a wide range of tumour cells, and virus infected cells, but not most normal cells. TRAIL has proven to be safe when administered to normal, tumour bearing, and virally-infected mice, and causes no detectable side-effects in these animals. As such it holds huge potential and is being widely investigated for use as a new anti-cancer therapy. Despite these findings, little is known about the t ....TRAIL, is a newly described member of the tumour necrosis factor (TNF)-family of cytokines, which can kill a wide range of tumour cells, and virus infected cells, but not most normal cells. TRAIL has proven to be safe when administered to normal, tumour bearing, and virally-infected mice, and causes no detectable side-effects in these animals. As such it holds huge potential and is being widely investigated for use as a new anti-cancer therapy. Despite these findings, little is known about the true physiological role of TRAIL in vivo. To define the normal roles of TRAIL, CIA has been characterising TRAIL gene knock-out mice. These studies have confirmed that TRAIL contributes to control of tumours in vivo, and in early events during anti-viral responses. However, these studies have also revealed novel roles for TRAIL in T cell biology, and B cell memory. Understanding how TRAIL contributes to these processes, will shed significant light on the potential of TRAIL to be used as a therapeutic agent for humans with lymphoproliferative disease, for illiciting better long-lived antibody responses such as after vaccination, and as an anti-viral reagent in immunocompromised individuals during virus infection.Read moreRead less
Co-ordinating The Intrinsic And Extrinsic Arms Of Hematopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$615,286.00
Summary
The cell types of the blood, such as red and white blood cells, are produced in the bone marrow from a rare stem cell. The stem cell uses a handfull of important master-regulatory genes that act in a hierarchy to promote the blood cell differentiation process. This research aims to understand how these master-regulators function in isolation and together in producing the white blood cells that are required for our immune response to microbes, vaccination and to prevent cancer.
Regulation Of Arthritis And Skin Inflammation By Annexin-1
Funder
National Health and Medical Research Council
Funding Amount
$612,885.00
Summary
Annexin-1, an antiinflammatory substance, mediates many of the actions of steroids. Our studies will reveal whether annexin-1 will reduce inflammatory and immune responses, and secondly, determine the substances regulated by annexin-1 in immune responses. If annexin-1 is found to mediate the immune regulatory effect of steroids, its capacity to be involved in the beneficial effect of steroids may have an important impact in treatment of arthritis and other inflammatory diseases.
Consequences Of Disulfide Exchange In CD4 For Function
Funder
National Health and Medical Research Council
Funding Amount
$332,580.00
Summary
CD4 is a particular type of receptor on the surface of immune cells that participates in our response to infection. CD4 is also the primary receptor for the HIV virus which causes AIDS. We have discovered that a particular type of chemistry is occurring in CD4. This chemistry, which is known as redox chemistry, changes the shape of CD4. The shape change appears to be controlled by the immune cell. We have suggested that the redox chemistry in CD4 is important for controlling how immune cells res ....CD4 is a particular type of receptor on the surface of immune cells that participates in our response to infection. CD4 is also the primary receptor for the HIV virus which causes AIDS. We have discovered that a particular type of chemistry is occurring in CD4. This chemistry, which is known as redox chemistry, changes the shape of CD4. The shape change appears to be controlled by the immune cell. We have suggested that the redox chemistry in CD4 is important for controlling how immune cells respond to infection and how the HIV virus infects immune cells. Moreover, we have designed a small synthetic compound that blocks the redox chemistry in CD4 and prevents HIV infection in the test tube. We propose to investigate how the redox chemistry in CD4 controls the function of immune cells and infection by HIV.Read moreRead less