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.
Mechanisms Of Dendritic Cell-induced T-cell Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$314,773.00
Summary
Autoimmune diseases constitute a significant medical problem in the developed world and are increasing in incidence. Many control mechanisms exist in the body, but in people with genetic suceptibility to autoimmune disease, the mechanisms fail and the body's immune sytem attacks normal tissues or organs. We have developed a new approach to using the cells which train the immune system to re-educate the cells that would otherwise attack normal healthy tissues in autoimmune-prone individuals. Thes ....Autoimmune diseases constitute a significant medical problem in the developed world and are increasing in incidence. Many control mechanisms exist in the body, but in people with genetic suceptibility to autoimmune disease, the mechanisms fail and the body's immune sytem attacks normal tissues or organs. We have developed a new approach to using the cells which train the immune system to re-educate the cells that would otherwise attack normal healthy tissues in autoimmune-prone individuals. These cells (dendritic cells) are genetically modified to express the molecular targets of the autoimmune response. This in turn switches off the response to these targets. In this project we will explore how these cells can be used to turn off cells of the immune system and if cells of the immune system in turn control the dendritic cell's ability to do this.Read moreRead less
The Role Of 14-3-3 Proteins In Regulating The Innate Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$517,989.00
Summary
The immune response is the body's defense system. It's malfunction leads to many diseases such as immune deficiency, asthma and cancer. Thus, it is important to find genes controlling immunity. Significantly, mammals have amazing similarities with flies, in terms of genes controlling immunity. We have found a new regulator of fly immunity and will define how this gene functions in the immune system. This project will identify potential points of intervention for treating immune system disorders.
The immune system plays an important role in protecting us from infectious diseases. To do this it regulates a series of cell types that must decide upon an appropriate course. In general, this response is successful and protective. However, occasionally the cells make an inappropriate decision leading to problems. For example, allergies are an incorrect response against pollens and dust mites. Similarly, autoimmune disease such as diabetes and multiple sclerosis result from inappropriate attack ....The immune system plays an important role in protecting us from infectious diseases. To do this it regulates a series of cell types that must decide upon an appropriate course. In general, this response is successful and protective. However, occasionally the cells make an inappropriate decision leading to problems. For example, allergies are an incorrect response against pollens and dust mites. Similarly, autoimmune disease such as diabetes and multiple sclerosis result from inappropriate attack upon our own tissues. Despite the clear importance of immune regulation for health, the number of different cell types involved and the complexity of their behaviour has made it difficult to predict and control the response. In this research program a new theory of immune regulation enables the reduction of the complex system to separate components that can be modelled by computer to predict the outcome. An improved predictive framework promises to have a major effect on our understanding and ability to control immune related diseases.Read moreRead less
The Role Of T Cell Receptor Avidity In Determining T Cell Repertoires And Responses
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
T cells are an essential component of the immune system. CD8 T cells, in particular, play a vital role in the immune response to viruses and tumors, predominantly via killing of virally infected cells and tumor cells, as well as the release of inflammatory mediators. T cells must be activated before they can mediate such anti-viral or anti-tumor effects and this activation occurs through the binding of pathogen or tumor fragments (peptides) by a receptor on the surface of T cells (T cell recepto ....T cells are an essential component of the immune system. CD8 T cells, in particular, play a vital role in the immune response to viruses and tumors, predominantly via killing of virally infected cells and tumor cells, as well as the release of inflammatory mediators. T cells must be activated before they can mediate such anti-viral or anti-tumor effects and this activation occurs through the binding of pathogen or tumor fragments (peptides) by a receptor on the surface of T cells (T cell receptor). Each individual has an entire repertoire of T cells with unique T cell receptors which interact with peptides with varying binding strengths. After stimulation of T cells by e.g. viral infection, a subset of the T cell repertoire will become expanded and dominate the anti-viral immune response. This study aims to investigate how, during a viral infection, the strength (or 'avidity') of the interaction between the T cell receptor and the peptide influences (i) whether or not a T cell clone is recruited into the immune response and, if so, its dominance over other clones within that response, and (ii) how efficiently a T cell is activated. It is anticipated that particular virus peptide-specific T cell populations with an overall high avidity will be better able to produce inflammatory mediators and kill infected cells compared to lower avidity T cell populations specific for a different virus peptide. It is also expected that the higher avidity populations will exhibit greater diversity of TCRs. Further, within peptide-specific populations, it is anticipated that the relatively high avidity T cell clones will dominate the specific response. This study will contribute to a greater understanding of factors contributing to T cell recruitment and activation. Armed with this knowledge we will be better able to design vaccines to elicit optimal T cell responses to viral infection.Read moreRead less
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
Unravelling The Mechanism Of MHC Class-I Associated Drug Hypersensitivities
Funder
National Health and Medical Research Council
Funding Amount
$566,308.00
Summary
Some drugs cause adverse reactions that are life threatening. We think these reactions are mediated by killer T cells as they are genetically controlled by immune response genes that normally guide immunity to microbes. We will study immune reactions to the drug abacavir, used to treat HIV (AIDS); allopurinol used to prevent gout and carbamazepine, used to treat epilepsy. The study may also help devise better treatments for patients who experience severe forms of these reactions.
Regulation Of T Follicular Helper Cell Development And Effector Function In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$419,197.00
Summary
Immune cells mature into distinct populations with specialized functions. One subsets are T follicular helper (TFH) cells which are important for instructing B cells to produce antibodies following infection or vaccination. The means by which TFH cells are generated are unknown. We will determine mechanisms whereby TFH cells are produced and how they function. We hope to design approaches that will modulate the function of TFH cells in cases of immunodeficiencies, autoimmunity or vaccination.
CD4 T-cell Deficiency And Dysfunction In HIV Patients Receiving Effective Antiretroviral Therapy
Funder
National Health and Medical Research Council
Funding Amount
$490,020.00
Summary
Large numbers of people throughout the world will commence antiretroviral treatment for HIV infection over the next 5 years. This treatment partially corrects CD4 T-cell deficiency (the most characteristic immune defect caused by HIV infection) but does not restore the immune system to normal in patients who were very immunodeficient before treatment. This study will determine the cause of residual immune defects in patients receiving antiretroviral drugs with the aim of introducing new therapie ....Large numbers of people throughout the world will commence antiretroviral treatment for HIV infection over the next 5 years. This treatment partially corrects CD4 T-cell deficiency (the most characteristic immune defect caused by HIV infection) but does not restore the immune system to normal in patients who were very immunodeficient before treatment. This study will determine the cause of residual immune defects in patients receiving antiretroviral drugs with the aim of introducing new therapies to correct those defects. Our previous studies have demonstrated that the production of new T-cells in HIV patients receiving antiretroviral durgs is affected by the function of the thymus, but that this does not account for the production of all new T-cells. We will investigate other sites of T-cell production in the body. We have also previously shown that poor recovery of CD4 T-cells in patients successfully treated with antiretroviral drugs is associated with immune activation and that the T-cells do not function adequately, even when CD4 T-cell counts are substantially increased. We will determine whether these abnormalities are the result of a persistent defect in T cell activation by monocytes and-or dendritic cells. The findings of our studies will improve the treatment and life-expectancy of individuals with HIV infection.Read moreRead less