Organ-specific Autoimmunity: The Role Of The Thymus And Periphery In Shaping The Gastric-specific T Cell Repertoire
Funder
National Health and Medical Research Council
Funding Amount
$579,763.00
Summary
The immune system normally protects against invasion by pathogens such as harmful viruses and bacteria. In autoimmune diseases the same mechanisms that are used to protect us are erroneously targeted to our own tissues. White blood cells, called T lymphocytes are responsible for attacking our own tissues in autoimmune diseases. Our studies will employ a range of molecular, genetic and imaging technologies to track the rare and potential harmful white blood cells. Our studies should reveal the me ....The immune system normally protects against invasion by pathogens such as harmful viruses and bacteria. In autoimmune diseases the same mechanisms that are used to protect us are erroneously targeted to our own tissues. White blood cells, called T lymphocytes are responsible for attacking our own tissues in autoimmune diseases. Our studies will employ a range of molecular, genetic and imaging technologies to track the rare and potential harmful white blood cells. Our studies should reveal the mechanisms by which these self destructive T lymphocytes are silenced in healthy individuals on the one hand, and on the other hand escape to cause destruction in individuals with autoimmune diseases. This fundamental information will allow the development of therapeutic strategies to selectively turn-off these destructive T lymphoctyes in individuals with autoimmune disease and thereby remove the damaging immune response and cure the disease.Read moreRead less
Investigating T Cell Tolerance And Organ-specific Auotimmunity Using Autoantigen Deficient Mice
Funder
National Health and Medical Research Council
Funding Amount
$441,000.00
Summary
The immune system normally protects against invasion by pathogens such as harmful viruses and bacteria. In autoimmune diseases the same mechanisms that are used to protect us are erroneously targeted to our own tissues. Our studies will employ technologies to genetically manipulate mice to further our knowledge of this class of disease and to uncover the normal mechanisms that allow the immune system to prevent autoimmune attack. In particular we will gain information on the way that a new class ....The immune system normally protects against invasion by pathogens such as harmful viruses and bacteria. In autoimmune diseases the same mechanisms that are used to protect us are erroneously targeted to our own tissues. Our studies will employ technologies to genetically manipulate mice to further our knowledge of this class of disease and to uncover the normal mechanisms that allow the immune system to prevent autoimmune attack. In particular we will gain information on the way that a new class of lymphocytes, known as regulatory lymphocytes, are able to protect against autoimmune disease. Such regulatory lymphocytes have been identified in humans and are attractive therapeutic agents to prevent a variety of immune-mediated diseases, including autoimmune diseases, allergy and transplantation rejection.Read moreRead less
The Cellular And Molecular Basis To The Paradox Of Positive Versus Negative T Cell Selection
Funder
National Health and Medical Research Council
Funding Amount
$278,090.00
Summary
The protection against disease requires the generation of white blood cells called T lymphocytes that are produced in the thymus. Each T cell has a specific surface receptor, generated by random gene switching, that can react against foreign pathogens. Since there is a very high conservation of molecules used in all organisms, some of these receptors could by chance also react against normal cells in the host. Eliminating all such self-reactive cells would mean, however, the repertoire remaining ....The protection against disease requires the generation of white blood cells called T lymphocytes that are produced in the thymus. Each T cell has a specific surface receptor, generated by random gene switching, that can react against foreign pathogens. Since there is a very high conservation of molecules used in all organisms, some of these receptors could by chance also react against normal cells in the host. Eliminating all such self-reactive cells would mean, however, the repertoire remaining for eliminating infection would be too low and immunodeficiency develops. This project investigates the mechanisms controlling the balance between defence infection and the need to prevent immune-based self destruction termed autoimmunity.Read moreRead less
The Generation, Fate And Functional Potential Of Recent Thymic Emigrants
Funder
National Health and Medical Research Council
Funding Amount
$318,856.00
Summary
A particular kind of white blood cell, called a T lymphocyte, is responsible for controlling our immune responses to foreign invaders. These cells develop in the thymus, where they learn to distinguish between foreign invaders and self tissue, before emigrating to other organs. The regulation of this process is important to maintain a pool of T lymphocytes in the body. It is important that T lymphocytes do not respond against self tissue, as this can lead to a Oself destructO disease called auto ....A particular kind of white blood cell, called a T lymphocyte, is responsible for controlling our immune responses to foreign invaders. These cells develop in the thymus, where they learn to distinguish between foreign invaders and self tissue, before emigrating to other organs. The regulation of this process is important to maintain a pool of T lymphocytes in the body. It is important that T lymphocytes do not respond against self tissue, as this can lead to a Oself destructO disease called autoimmunity. Since these developing T lymphocytes will not see all kinds of self tissue while in the thymus, we propose that their education to prevent self-tissue reactivity may continue for some time after they leave the thymus.Read moreRead less
Changes In The Fate Of Thymic Emigrants During Foetal And Postnatal Development In Sheep
Funder
National Health and Medical Research Council
Funding Amount
$62,744.00
Summary
SIGNIFICANCE The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cell, has considerable implications for the development of the T cell repertoire. Recent thymic emigrants represent a wide diversity of positively selected thymocytes but mature T cell pool expansion results in reduced diversity because of a predominant expansion of a l ....SIGNIFICANCE The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cell, has considerable implications for the development of the T cell repertoire. Recent thymic emigrants represent a wide diversity of positively selected thymocytes but mature T cell pool expansion results in reduced diversity because of a predominant expansion of a limited number of clones. A high rate of continuous substitution of mature T cells in the peripheral pool with freshly arriving recent thymic emigrants exhibiting newly arising TCR not previously existing will produce higher adaptive capabilities for the immune system. We have developed techniques for labeling the thymus in vivo by intra-thymic injection with the long-term lymphocyte tracking dye CFSE. We can establish a cohort of labeled recent thymic emigrants and we can, for the first time in any experimental system, track directly the survival, death or division of recent thymic emigrants and their progeny together with their tissue homing properties and surface markers for periods of many months after they leave the thymus. This will enable us to determine the way in which the pool of mature T cells is built up during the formation of the foetal immune system and the way the mature T cell population is established and maintained in postnatal life.Read moreRead less
DETERMINING THE ROLE OF ER STRESS INDUCED APOPTOSIS IN THYMIC NEGATIVE SELECTION
Funder
National Health and Medical Research Council
Funding Amount
$558,189.00
Summary
Apoptosis is an evolutionarily conserved mechanism for killing unwanted cells that are no longer needed, damaged, infected with pathogens or dangerous. Defects in apoptosis can cause a number of diseases. For example, abnormal survival of cells can cause cancer or autoimmune disease. Bim is a protein that induces apoptosis and act as a barrier against cancer and autoimmune diseases. This work is aimed at understanding how Bim acts as a barrier against the development of autoimmunity.
The establishment of an immune system that is able to distinguish between self and non-self is of fundamental importance for good health and survival. How this specificity is achieved has been an area of intense investigation for many years because a breakdown of this process leads to the development of autoimmune diseases, such as diabetes, or an inability to fight pathogenic organisms. It has been known for many years that the development T cells, a subset of cells involved in mounting immune ....The establishment of an immune system that is able to distinguish between self and non-self is of fundamental importance for good health and survival. How this specificity is achieved has been an area of intense investigation for many years because a breakdown of this process leads to the development of autoimmune diseases, such as diabetes, or an inability to fight pathogenic organisms. It has been known for many years that the development T cells, a subset of cells involved in mounting immune responses, occurs in the thymus. The thymus produces large numbers of immature T cells (called thymocytes) from which a small number receive the appropriate signals to survive and develop into mature T cells. These tailor-made T cells can then enter the blood and peripheral lymphoid organs where they fight infectious organisms without reacting against host (i.e. self) tissues. The work for this project is aimed at determining how proteins inside thymocytes transmit signals that determine whether thymocytes either survive, and develop into T cells, or are eliminated because they react too strongly with self proteins. We have established that a protein called c-Cbl is central to this process as it regulates the initial strength of the signal that determines the fate of thymocytes. Our aim is to identify the putative key protein regulated by c-Cbl that can sense when a signal is too strong following the binding of a thymocyte to a self protein and directs a cell death signalling response. From this critical point of signal splitting we also aim to identify proteins that relay the death signal to the nucleus where they trigger the production of well-characterised proteins required to mediate cell death. By identifying the proteins in this signalling pathway we will have a greater capacity to control the magnitude of immune responses and therefore be able to lessen tissue damage caused by autoimmune reactions.Read moreRead less