Immunological Studies Of Adjutant Induced Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$412,104.00
Summary
This project stems from our interest in rheumatoid arthritis and a number of other forms of arthritis that affect many joints in a symmetrical fashion (the polyarthritides). In most instances, there is evidence that the diseases are caused by an attack on the joint lining (the synovium) by cells of the immune system. Rheumatoid arthriis is the most common and often the most severe of the polyarthritides. Neither the triggering event nor the target of the attack by the immune system is understood ....This project stems from our interest in rheumatoid arthritis and a number of other forms of arthritis that affect many joints in a symmetrical fashion (the polyarthritides). In most instances, there is evidence that the diseases are caused by an attack on the joint lining (the synovium) by cells of the immune system. Rheumatoid arthriis is the most common and often the most severe of the polyarthritides. Neither the triggering event nor the target of the attack by the immune system is understood and as a result, there are no specific preventative measures against the disease or specific therapies for the established disease. There is, however, strong evidence that the cells involved in the attack on the synovium are orchestrated by a white blood cell called the T lymphocyte. T lymphocytes cannot operate alone but require a second cell, the dendritic cell, to present the target in a special way which can be recognised and responded to by the T lymphocyte. The T cell and the dendritic cell are the two central aspects of this project. We will use an animal model of polyarthritis to allow access to these cells during the earliest phases of the disease, a silent period not recognisable in the earliest stages of rheumatoid arthritis. T lymphocytes from animals with experimental polyarthritis will be used as indicators in the search for the target of the disease process and dendritic cells from affected joints will be used as a natural source of that target. By the production of highly specific T lymphocytes (members of clones), we hope to identify the target molecules of the disease process. This information should lead ultimately to the identification of the triggering stimulus (and thence prevention) and to the development of highly specific therapies designed to treat the established disease.Read moreRead less
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
Discovery Of A Novel Immune Evasion Strategy Employed By Mosquito Borne Viruses To Suppress Antiviral Immune Responses
Funder
National Health and Medical Research Council
Funding Amount
$418,642.00
Summary
The transition from mosquitoes, ticks, or other invertebrate vectors to the human hosts represents a crucial step in the successful establishment of arthropod borne viruses (arboviruses). The incidence of arbovirus infections such as dengue virus, West Nile virus, Ross River virus is increasing at an alarming rate in various parts of the world. In addition, the emergence of new viruses resulting in significant mortality in the population is of utmost concern. Vaccines for many of these viruses r ....The transition from mosquitoes, ticks, or other invertebrate vectors to the human hosts represents a crucial step in the successful establishment of arthropod borne viruses (arboviruses). The incidence of arbovirus infections such as dengue virus, West Nile virus, Ross River virus is increasing at an alarming rate in various parts of the world. In addition, the emergence of new viruses resulting in significant mortality in the population is of utmost concern. Vaccines for many of these viruses remain elusive. One factor that contributes to this is the ability of viruses to develop ingenious strategies to avoid or suppress the host defence systems, which enable its successful establishment in the host. Understanding how viruses evade-suppress host defence machinery will certainly enhance and improve our approaches to fight them. For the first time internationally we have discovered a new and novel pathway employed by arboviruses to suppress antiviral immune responses in the host. We have discovered that naturally occurring carbohydrates on viruses derived from mosquito cells, would influence these virus s ability to evade-suppress host antiviral proteins such as interferons. This may be a general effect of arboviruses or may even extend to other viruses , which include a number of deadly pathogens (HIV, Influenza). This research has the potential to significantly expand our understanding of how these viruses establish infection and cause disease. Also this discovery has broader implications for understanding inflammatory processes and their regulation.Read moreRead less
Generating Tumour-Specific Dendritic Cells For Cancer Therapy
Funder
National Health and Medical Research Council
Funding Amount
$288,210.00
Summary
Therapies using the immune system are showing promise for cancer treatment, particularly for melanoma, but complete durable responses are few and improvements are needed. We believe that such immunotherapies, in their current form, fail to sufficiently mimic a natural immune reaction to disease, and therefore fall short of effectively controling cancer. In particular, an alarm (danger signal) is not produced within tumour as it would be when the body is challenged by infectious agents. Such dang ....Therapies using the immune system are showing promise for cancer treatment, particularly for melanoma, but complete durable responses are few and improvements are needed. We believe that such immunotherapies, in their current form, fail to sufficiently mimic a natural immune reaction to disease, and therefore fall short of effectively controling cancer. In particular, an alarm (danger signal) is not produced within tumour as it would be when the body is challenged by infectious agents. Such danger signals are critical for the immune system to respond effectively and for white blood cells of the immune system to find their way to the disease organism and eliminate it. The strongest danger signals are produced by a type of white blood cell known as a dendritic cell (DC). These cells detect infectious agents and produce biochemical alarm molecules that alert the entire immune system to the danger resulting in powerful action against the disease. However, tumours are really just a part of our own body and no danger signal is produced. It is our aim to use genetic modification to make DC see tumours as a threat and produce danger signals. These gene-modified DC either alone, or in combination with other immunotherapies, may lead to destruction of tumours.Read moreRead less
I am an immunologist determining the development and function of the dendritic cell system, including its role in autoimmunity and resistance to infection.
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 susceptibility to autoimmune disease, the mechanisms fail and the body's immune system attacks normal tissues or organs. We have developed a new approach, using the cells which train the immune system, to re-educate the cells that would otherwise attack normal healthy tissues in autoimmune-prone individuals. The ....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 susceptibility to autoimmune disease, the mechanisms fail and the body's immune system attacks normal tissues or organs. We have developed a new approach, 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 the harmful cells present in the immune system.Read moreRead less