Innovative Stem Cell-based Strategies To Establish Immune Tolerance And Tissue Repair
Funder
National Health and Medical Research Council
Funding Amount
$5,554,618.00
Summary
Diseases such as autoimmune gastritis, multiple sclerosis and diabetes arise because a rogue immune system has turned inwards to attack our organs. The organ destruction follows from recognition by the immune system of specific molecules in these organs. These autoimmune diseases are incurable and controlled mainly by long-term administration of substances that suppress the immune system, often with serious side-effects. A rational approach is to render the rogue immune system harmless by removi ....Diseases such as autoimmune gastritis, multiple sclerosis and diabetes arise because a rogue immune system has turned inwards to attack our organs. The organ destruction follows from recognition by the immune system of specific molecules in these organs. These autoimmune diseases are incurable and controlled mainly by long-term administration of substances that suppress the immune system, often with serious side-effects. A rational approach is to render the rogue immune system harmless by removing the cells that recognize these particular molecules. This can be achieved by a Trojan horse approach in which the molecules are delivered to the immune system such that that the immune cells that recognize them are removed. To deliver these molecules to the immune system we will genetically engineer bone marrow stem cells, or embryonic stem cells that generate these stem cells, because they are precursors of mature immune cells. Rejection of organ transplants arise in a similar way and also require long-term immunosuppression. A similar approach can therefore be taken to promote acceptance of foreign organ grafts. In the aged, we will combine these approaches with rejuvenation of the immune system by blockade of sex steroid production and-or by creation of a new immune organ.Read moreRead less
The Pathogenesis Of PR3-ANCA Associated Vasculitis
Funder
National Health and Medical Research Council
Funding Amount
$128,224.00
Summary
ANCA-associated vasculitis (AAV) is a rare but severe cause of autoimmune renal disease, which can lead to renal failure and death. Our research and understanding of AAV until now has been largely limited to MPO-AAV. This proposal provides a unique opportunity to further understand PR3-AAV by utilising a new mouse model of the disease. This knowledge will inform further research regarding therapeutic targets, thereby improving care of patients affected by PR3-AAV.
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
The Role Of Interleukin-21 In The Pathogenesis Of Autoimmune Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$519,000.00
Summary
T cells are a component of our blood (white blood cells) and a major component of the body's defense system against infection, known as immunity. Without T cells, we would fail to resist infection by foreign agents, such as viruses, bacteria and fungi. Autoimmune (type 1) diabetes is a disease in which T cells attack our own pancreatic islet self tissues as if they were foreign. T cells that react against the islets of the pancreas cause destruction of the insulin producing beta cells so that th ....T cells are a component of our blood (white blood cells) and a major component of the body's defense system against infection, known as immunity. Without T cells, we would fail to resist infection by foreign agents, such as viruses, bacteria and fungi. Autoimmune (type 1) diabetes is a disease in which T cells attack our own pancreatic islet self tissues as if they were foreign. T cells that react against the islets of the pancreas cause destruction of the insulin producing beta cells so that the pancreas can no longer make insulin. Diabetes is a life-threatening disease because insulin is a hormone that enables people to get energy from food. Type 1 diabetes is usually diagnosed in childhood and insulin must be administered daily by injection or through a pump in order to survive. Unfortunately, taking insulin doesn t cure diabetes and people continue to suffer from an extensive list of complications affecting most vital organs. Interleukin-21 (IL-21) is a soluble protein that is produced by cells enabling them to communicate with other cells. IL-21 helps cells to produce factors that cause inflammation and assist in clearance of viruses and bacteria from the body. However, our studies show that IL-21 is a major factor in the development of the T cells that destroy beta cells and cause diabetes. Our studies show that IL-21 is over-expressed in an important murine model of spontaneous type-1 diabetes. We have isolated the T cells that cause diabetes and show that they are distinguished from other T cells by very high levels of the receptor for IL-21. This project focuses on the IL-21-responsive T cells that cause diabetes and aims to determine the mechanisms by which the cytokine IL-21 causes destructive immune responses and ways to modulate its production. This project applies basic science to the important public health issue of type 1 diabetes for the development of therapeutic intervention strategies.Read moreRead less