Induction Of Antigen-specific Tolerance Through Inhibition Of RelB Function In Dendritic Cells
Funder
National Health and Medical Research Council
Funding Amount
$421,980.00
Summary
This proposal builds on preliminary data showing the possibility that responses of the immune system to antigens can be suppressed by modifying cells known as dendritic cells using an inhibitory drug. The drug appears to be able to control the ability of dendritic cells to educate the immune system about antigens. When antigens presented continuously are harmful to the immune system, they produce diseases such as rheumatoid arthritis and allergies. The experiments to be undertaken specifically l ....This proposal builds on preliminary data showing the possibility that responses of the immune system to antigens can be suppressed by modifying cells known as dendritic cells using an inhibitory drug. The drug appears to be able to control the ability of dendritic cells to educate the immune system about antigens. When antigens presented continuously are harmful to the immune system, they produce diseases such as rheumatoid arthritis and allergies. The experiments to be undertaken specifically look at means to prevent and reverse diseases like rheumatoid arthritis through the use of dendritic cells.Read moreRead less
Migration And Differentiation Of Dendritic Cells And Monocytes In Inflammatory Arthritis.
Funder
National Health and Medical Research Council
Funding Amount
$280,000.00
Summary
Dendritic cells and monocytes are of critical importance to the development and persistence of inflammatory disease in rheumatoid arthritis. Blocking this process at key strategic intervention points is a major focus of research to improve disease treatment. These studies examine the critical processes and molecules that control the entry of these cells to the joint in mice, and the derivation of cells that contribute directly to bone damage in the disease.
The Immunological Microenvironment In The Synovium During Experimental Polyarthritis In The Rat
Funder
National Health and Medical Research Council
Funding Amount
$473,250.00
Summary
In this project, we aim to understand the process by which some forms of arthritis, as exemplified by rheumatoid arthritis (RA), cause inflammation and destruction of multiple joints. Such forms of arthritis are referred to collectively as polyarthritis. There is a strong evidence that RA has an immunological basis and that abnormal recognition of components of the joints by T lymphocytes orchestrates the inflammation that is characteristic of the disease. We believe that dispersal of disease-ca ....In this project, we aim to understand the process by which some forms of arthritis, as exemplified by rheumatoid arthritis (RA), cause inflammation and destruction of multiple joints. Such forms of arthritis are referred to collectively as polyarthritis. There is a strong evidence that RA has an immunological basis and that abnormal recognition of components of the joints by T lymphocytes orchestrates the inflammation that is characteristic of the disease. We believe that dispersal of disease-causing activated T lymphocytes in the blood accounts for the involvement of many joints. We have used a model of polyarthritis in rats to study the nature of the activated T lymphocytes, where they come from, how they are delivered to the blood stream and how they enter the joints. This project focuses on the crucial tissues that line the joints. We want to understand how the disease-causing activated T cells cause inflammation and how the immune system reacts to restrain them. We can undertake this work because we have developed three unique tools. Firstly, we can transfer arthritis with activated T lymphocytes and, therefore, study their behavior in an otherwise normal body. In this way, we can see how the body responds to the presence of disease causing cells. Secondly, we have introduced a genetic marker, which is essential if one wishes to distinguish the separate activities of the donor' and host cells. Thirdly, we can collect cells from the diseased paws, allowing us to examine their activities in vitro as well as in vivo. This model offers the opportunity to study the activities of the disease-causing cells and to identify points at which the disease cycle can be broken. It will allow us to design and-or test new treatments aimed at these points.Read moreRead less
Control and effective treatment of autoimmune diseases remain major challenges to our health system. Diseases such as multiple sclerosis, systemic lupus erythematosus, diabetes and pernicious anaemia are serious conditions that are essentially incurable. Current treatment is only effective in providing temporary relief as it is not directed against the underlying disease process. This project will manipulate the immune system in such a way that early disease processes in autoimmunity will be blo ....Control and effective treatment of autoimmune diseases remain major challenges to our health system. Diseases such as multiple sclerosis, systemic lupus erythematosus, diabetes and pernicious anaemia are serious conditions that are essentially incurable. Current treatment is only effective in providing temporary relief as it is not directed against the underlying disease process. This project will manipulate the immune system in such a way that early disease processes in autoimmunity will be blocked with the ultimate goal to cure the disease. Using an experimental model of pernicious anaemia in mice, where the basic pathology is immune-mediated gastritis, the disease will be treated by presenting the disease causing autoantigen via modified, or immature, antigen presenting cells to the immune system. In other experimental models which form the background to this project we have shown that this approach leads to down-regulation of the immune response by generating cells which specifically suppress the immune system. In our studies of autoimmune gastritis we will obtain modified antigen presenting cells from the skin, the blood, the spleen and thymus and use these cells to define optimal conditions for presenting the auto-antigen molecules to achieve the ultimate goal, which is antigen specific suppression of autoimmune gastritis. Our hypothesis is that immature antigen presenting cells are unable to present antigen to induce an effective immune response, but instead induce a response that results in antigen specific suppression. We intend to use this antigen specific suppression to prevent the establishment of autoimmune gastritis as well as treatment of established disease. This is a unique and potentially valuable strategy to treat autoimmune gastritis and offers the potential to apply this approach to other autoimmune conditionsRead moreRead less
Conversion And Function Of Regulatory T Cells In The Periphery: The Role Of The RelB Transcription Factor
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
There is limited understanding of the molecular mechanisms regulating immune tolerance, or protection from autoimmune diseases, like childhood diabetes. This proposal studies RelB-deficient mice. They present a novel opportunity to study tolerance and autoimmune disease development, as we have discovered that autoimmunity in these mice is correctable by treatment with dendritic cells expressing RelB. This may be relevant to treatment of patients with certain forms of autoimmune disease.
The Role Of Dendritic Cell Subsets In The Decision Between T Cell Tolerance And Immunity
Funder
National Health and Medical Research Council
Funding Amount
$445,009.00
Summary
The immune system protects the body against infection by means of a population of circulating white blood cells called lymphocytes. Each lymphocyte has on its surface its own particular receptor which recognises only one out of the universe of possible substances. Receptors are generated in a semi-random way, using a combination of elements encoded by the genes, and it is possible to generate receptors that react with the body itself, rather than with invading organisms. If the cells bearing the ....The immune system protects the body against infection by means of a population of circulating white blood cells called lymphocytes. Each lymphocyte has on its surface its own particular receptor which recognises only one out of the universe of possible substances. Receptors are generated in a semi-random way, using a combination of elements encoded by the genes, and it is possible to generate receptors that react with the body itself, rather than with invading organisms. If the cells bearing these self-reactive receptors become activated, an autoimmune disease ensues. The question of how lymphocytes can tell the difference between the body itself and foreign organisms is of major interest to immunologists. One of the first ideas was that self-reactive lymphocytes are inactivated by making reactions early in life. Despite the simplicity and intellectual appeal of this idea, it is inconsistent with a large body of experimental evidence. On the basis of number of new experiments, I have proposed an alternative model of self tolerance for one of the subsets of lymphocytes. In this model, the cells that help lymphocytes to recognise particular substances possess the property of distinguishing self from foreign, and pass that information on. The aim of this project is to provide direct experimental evidence in support of the model. Many of our attempts to deal with medical problems related to the immune system have been hampered by our lack of understanding of exactly how immune tolerance is controlled. If my model proves to be correct, it will be possible to manipulate immune responses with far greater effectiveness, providing new treatments for autoimmune disease, allergy, graft rejection and vaccination.Read moreRead less