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Approaches To Allogeneic Chimerism For The Induction Of Transplantation Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
All patients with organ failure who receive a transplant require lifelong immunosuppressive medications to prevent the body from rejecting the foreign tissue. Indefinite immunosuppressive therapy is associated with significant side-effects which include infections and cancers. In addition, long-term loss of the transplants due to slow rejection (chronic rejection) remains high. Achieving a state of immunological tolerance in which transplanted tissue is regarded as self, but reactivity to all ot ....All patients with organ failure who receive a transplant require lifelong immunosuppressive medications to prevent the body from rejecting the foreign tissue. Indefinite immunosuppressive therapy is associated with significant side-effects which include infections and cancers. In addition, long-term loss of the transplants due to slow rejection (chronic rejection) remains high. Achieving a state of immunological tolerance in which transplanted tissue is regarded as self, but reactivity to all other foreign tissues (e.g. harmful viruses, bacteria) remain normal, would solve all these problems. Tolerance would eliminate the need for immunosuppressive medications and prevent rejection of transplanted organs. The production of mixed bone marrow chimerism is a potent method of inducing tolerance. Chimerism is a state in which bone marrow tissue from two genetically different individuals coexists in one person. This can be achieved by bone marrow transplantation from a specific donor, and if chimerism is achieved, the recipient will accept all tissues from the bone marrow donor without the need for ongoing immunosuppressive therapy. This study will attempt to examine the use of different therapeutic reagents (e.g. antibodies alone or antibodies linked to idarubicin, a drug which prevent cells dividing) to develop safe protocols for the production of bone marrow chimerism and tolerance for routine clinical use in humans. The study will also examine different cellular components of the donor bone marrow which may induce tolerance.Read moreRead less
Stem Cell Engineering To Establish Tolerance And Reverse Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$497,250.00
Summary
The immune system is designed to protect us from harmful invaders such as bacteria, viruses and parasites. It should not attack our own tissues. However, in certain individuals, the immune system does attack our own tissues leading to life threatening conditions such as diabetes, multiple sclerosis and rheumatoid arthritis. To date, there is no cure for autoimmune diseases. Treatment is designed to treat the destructive effects of the disease. A strategy for achieving a cure is to program the im ....The immune system is designed to protect us from harmful invaders such as bacteria, viruses and parasites. It should not attack our own tissues. However, in certain individuals, the immune system does attack our own tissues leading to life threatening conditions such as diabetes, multiple sclerosis and rheumatoid arthritis. To date, there is no cure for autoimmune diseases. Treatment is designed to treat the destructive effects of the disease. A strategy for achieving a cure is to program the immune system to remove the harmful immune cells. Autoimmune gastritis which leads to pernicious anaemia is an autoimmune disease which affects the acid secreting cells of the stomach. To get a better understanding of autoimmune diseases, animal models are often used. We use a number of mouse models of autoimmune gastritis which closely resembles the human disease and thus makes a very good working model. Using these models we are exploring novel techniques aimed at reversing or curing established disease. This relies on removing the disease causing cells from the body and re-programming the immune system so as not to produce these cells.Read moreRead less
Identification Of The Molecular Genetic Basis Of The Hepatic Veno-occlusive Disease With Immunodeficiency Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$224,250.00
Summary
One of the most serious complications of bone marrow transplantation is veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS). This condition occurs in 10% of transplanted patients and is characterised by abnormalities of liver function, enlargement of the liver, clotting abnormalities, fluid retention and finally failure of multiple organs and death in 30-50% of cases. The cause of VOD is unknown, and its occurrence cannot be predicted in individual patients. Eight fam ....One of the most serious complications of bone marrow transplantation is veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS). This condition occurs in 10% of transplanted patients and is characterised by abnormalities of liver function, enlargement of the liver, clotting abnormalities, fluid retention and finally failure of multiple organs and death in 30-50% of cases. The cause of VOD is unknown, and its occurrence cannot be predicted in individual patients. Eight families have been described in whom a number of individuals have succumbed to a condition which is clinically and histologically indistinguishable from VOD. Affected individuals also have a form of immunodeficiency (hence termed VODI), and the abnormalities are inherited in an autosomal recessive pattern. All eight are of Lebanese origin, suggesting that a single genetic ancestral mutation was responsible for the disorder in all families, who are distantly related. We have access to genetic material from three of these families, and are on the way to identifying the causative genetic abnormality. We hypothesise that understanding this abnormality will lead to an understanding of VOD which occurs after bone marrow transplantation. We have used 800 polymorphic genetic markers scattered throughout the genome to identify the location of the genetic abnormality, and have localised the defect to a region of chromosome 2 which contains approximately 37 known and predicted genes. We now aim to determine which of the gene(s) in the candidate region is responsible for VODI, and plan to examine DNA from individuals who have had VOD after transplantation to determine if they have a related abnormality. Finding the VODI gene will benefit these families through the availability of carrier detection and may also lead to an understanding of the veno-occlusive disease that occurs after bone marrow transplantation.Read moreRead less
Manipulation Of Haematopoietic Stem Cell Niches To Improve Their Clinical Use
Funder
National Health and Medical Research Council
Funding Amount
$434,883.00
Summary
Haematopoietic stem cells (HSC) reside in adult bone marrow (BM) and make all blood and immune cells. HSCs can be damaged by chemotherapy leading to blood and BM failure. We have identified an adhesion molecule in the BM which regulates HSC behaviour. We anticipate that inhibiting this molecule will i) help minimise HSC damage during chemotherapy and ii) enhance the success of BM transplantation.
The Role Of Alloantigen Presentation In Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$508,003.00
Summary
Bone marrow transplantation (BMT) is the most effective treatment for a number of haematological conditions, especially leukemia. Graft versus host disease (GVHD) is a complication of BMT and results in the death of up to 50% of transplant recipients. GVHD occurs when the newly transplanted immune system recognizes the recipient as foreign and mounts and immune reponse against the patients tissues. These studies will focus on identifying and understanding the function of the immune cells which d ....Bone marrow transplantation (BMT) is the most effective treatment for a number of haematological conditions, especially leukemia. Graft versus host disease (GVHD) is a complication of BMT and results in the death of up to 50% of transplant recipients. GVHD occurs when the newly transplanted immune system recognizes the recipient as foreign and mounts and immune reponse against the patients tissues. These studies will focus on identifying and understanding the function of the immune cells which drive GVHD.Read moreRead less
The Clinical Value Of Serology And Molecular Tests For Diagnosing Invasive Aspergillosis In At-risk Hematology Patients
Funder
National Health and Medical Research Council
Funding Amount
$1,095,500.00
Summary
Aspergillus is a fungus found in soil, on farms and on construction sites. In those whose immune system is impaired it causes severe infection. The people who are particularly at high-risk of Aspergillus infection (called Invasive Aspergillosis) are those with acute leukaemia on chemotherapy or post bone marrow transplantation. Currently 15% of those at high-risk get Invasive Aspergillosis and 58-93% of those infected die. The main reason for this high death rate is that our current diagnostic t ....Aspergillus is a fungus found in soil, on farms and on construction sites. In those whose immune system is impaired it causes severe infection. The people who are particularly at high-risk of Aspergillus infection (called Invasive Aspergillosis) are those with acute leukaemia on chemotherapy or post bone marrow transplantation. Currently 15% of those at high-risk get Invasive Aspergillosis and 58-93% of those infected die. The main reason for this high death rate is that our current diagnostic tests are not good at detecting infection or often only detect the infection at advanced stages when treatment is ineffective. Because of the limitations of current diagnostic tests the current practice is to give empiric antifungal therapy (EAFT) early to treat Invasive Aspergillosis. However studies have demonstrated that this therapy has only resulted in a minor reduction in the mortality rates and it causes significant drug toxicity. It is a suboptimal treatment modality. New tests have been developed to diagnose Invasive Aspergillosis. These tests are for the detection of an Aspergillus protein in blood and for the detection of Aspergillus DNA in the blood. Available data suggests that these new tests are sensitive in the detection of Invasive Aspergillosis. Also other studies suggest that these new tests make an early diagnosis and seem to be able to monitor responses to treatment. However no study has been performed to date which demonstrates that the use of these tests can impact on important patient outcomes. This trial is designed to determine whether the use of the new tests to guide therapy will help improve treatment of Invasive Aspergillosis, reduce drug toxicity and reduce the death rate in the high-risk patients as compared with the current standard method of diagnosis and treatment with EAFT. If the trial is successful then this represents a significant advancement in the treatment and survival of leukaemic and bone marrow transplantation patients.Read moreRead less
Hematopoietic Effects Of Activating The Hedgehog Pathway.
Funder
National Health and Medical Research Council
Funding Amount
$410,551.00
Summary
The hedgehog proteins are important for normal human development. They are expressed on cells of the brain and developing limbs and provide important signals to neighbouring cells so that development of the brain and limbs can occur normally. Mutations in genes within the hedgehog signalling pathway lead to congenital abnormalities such as failure of the brain to fold properly and shortened limbs or extra digits. Hedgehog proteins also stimulate the growth of adult stem cells that are responsibl ....The hedgehog proteins are important for normal human development. They are expressed on cells of the brain and developing limbs and provide important signals to neighbouring cells so that development of the brain and limbs can occur normally. Mutations in genes within the hedgehog signalling pathway lead to congenital abnormalities such as failure of the brain to fold properly and shortened limbs or extra digits. Hedgehog proteins also stimulate the growth of adult stem cells that are responsible for the maintenance of many adult tissues such as the skin, bone and hair. Excessive hedgehog signalling however can lead to cancers, particularly of the brain and skin. The ability of hedgehog proteins to stimulate the growth of stem cells raises their use for expansion of stem cells. This would be particularly useful for umbilical cord blood stem cells, which could be used to treat patients with leukemia if there were sufficient numbers. This project will examine the potential use of hedgehog proteins for stimulating blood stem cells.Read moreRead less