The Mechanisms Of Epithelial Cell Survival That Govern Thymus Function
Funder
National Health and Medical Research Council
Funding Amount
$620,967.00
Summary
The thymus is an organ dedicated to the production of crucial immune cells, called T lymphocytes. Cancer treatments, such as radiation or chemotherapy, destroy thymic function and impair immune recovery in patients. We aim to uncover molecular processes that govern the life and death decisions of cells in the thymus. Our goal is to then use this information to develop treatments to protect this critical organ from damage and improve immune recovery following radiation or chemotherapy.
Overcoming Immunosenescence For Effective Stem Cell Therapies
Funder
National Health and Medical Research Council
Funding Amount
$419,180.00
Summary
An established treatment for blood cancers involves a stem cell transplant to replace the blood stem cells that are damaged by radiation and chemotherapy. However, treatment success is limited with advancing age due to multiple defects in the immune system. We will use new technologies to investigate how the ageing immune system copes with stem cell transplantation and explore new methods for improving recovery and immunity after HSCT.
Immune Dysregulation In HIV Patients With Immune Reconstitution After Highly Active Anti-retroviral Therapy
Funder
National Health and Medical Research Council
Funding Amount
$411,000.00
Summary
As HIV infection progresses to AIDS, there is a depletion of CD4 T-cells from the patient's blood and inhibition of the function of the remaining cells. Some immune defects resolve if the patient is given treatment with highly active anti-retroviral therapy (HAART), but it remains to be determined if the function of the imune system returns fully to normal. We have shown that problems with the regulation of the restored immune system in the first 6 months of treatment can lead to diseases associ ....As HIV infection progresses to AIDS, there is a depletion of CD4 T-cells from the patient's blood and inhibition of the function of the remaining cells. Some immune defects resolve if the patient is given treatment with highly active anti-retroviral therapy (HAART), but it remains to be determined if the function of the imune system returns fully to normal. We have shown that problems with the regulation of the restored immune system in the first 6 months of treatment can lead to diseases associated with Mycobacterial infections (eg: tuberculosis), CMV retinitis, hepatitis B virus or hepatitis C virus. We have defined these conditions as Immune Restoration diseases (IRD) and shown that they occur in one in four individuals who begin HAART from low baseline CD4 T-cell counts. IRD are likely to become common as therapy becomes available in Africa and Asia as patients begin treatment from low CD4 T-cell counts. There is also emerging evidence that dysregulated T-cell responses may cause disease later in the course of immune reconstitution. For example, some patients with undetectable HIV experience opportunistic infections or autoimmune disease after many months of HAART. This project will use West Australian patients receiving optimal therapy for their HIV infection. We will analyse immune activation and T-cell function in patients beginning HAART with low CD4 T-cell counts and patients who have had well-controlled HIV infection for at least 6 months. Blood samples will be collected for the measurement of immunological messengers (cytokines) known to be involved in different types of immune responses. The results will be correlated with the clinical outcome.Read moreRead less
This project will determine how viruses prevent transmission of messages within cells which orchestrate responses of our immune system to infection and whether our current therapies improve this defect. This knowledge will help us to better understand why our immune system is not able to control chronic virus infection and improve therapies for these diseases.
Inducible Caspase 9 Suicide Gene To Improve The Safety Of Donor T Cell Addback After Haploidentical Stem Cell Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$566,232.00
Summary
In bone marrow transplantation, donor immune cells are important for fighting cancer cells and infections but can also attack healthy tissues, causing graft-versus-host disease (GVHD). We will use gene technology to insert a safety switch called inducible capase 9 (iCasp9) into the donor immune cells which will make them susceptible to an otherwise non-toxic chemical. This will make it safer to boost the recipients’ immunity because these cells can be rapidly eliminated if GVHD occurs.
Macrophages are a key component of the immune system; thier functions include killing of pathogens as well as cancerous cells. Macrophage lineage cells are derived from stem cells within the bone marrow and thier differentiation, proliferation and survival is mediated by a particular growth factor termed colony stimulating factor-1 (CSF-1). The understanding of how macrophage lineage cells develop will help us to treat many diseases including certain cancers (such as leukemia), arthritis and inf ....Macrophages are a key component of the immune system; thier functions include killing of pathogens as well as cancerous cells. Macrophage lineage cells are derived from stem cells within the bone marrow and thier differentiation, proliferation and survival is mediated by a particular growth factor termed colony stimulating factor-1 (CSF-1). The understanding of how macrophage lineage cells develop will help us to treat many diseases including certain cancers (such as leukemia), arthritis and inflammation, and disorders of the immune system. The action of CSF-1 is mediated by the CSF-1 receptor (CSF-1R) which, when activated, controls gene regulation. In this proposal we will study CSF-1R activation and identify the genes regulated by CSF-1 with a view to characterize genes critical for macrophage development. These genes may provide potential targets for new pharmacological agents.Read moreRead less
HIV-1 infection is characterised by high levels of virus replication and a progressive loss of immune cells, particularly CD4+ T lymphocytes. Highly active antiretrovial therapy (HAART) for HIV-1 infection results in profound suppression of viral replication, a substantial increase in CD4+ T lymphocytes and a decrease in morbidity and mortality. The primary source of T lymphocytes in early human development is the thymus. Recently, it has been demonstrated that the thymus remains functional thro ....HIV-1 infection is characterised by high levels of virus replication and a progressive loss of immune cells, particularly CD4+ T lymphocytes. Highly active antiretrovial therapy (HAART) for HIV-1 infection results in profound suppression of viral replication, a substantial increase in CD4+ T lymphocytes and a decrease in morbidity and mortality. The primary source of T lymphocytes in early human development is the thymus. Recently, it has been demonstrated that the thymus remains functional throughout adult life. The role of the thymus in HIV-1 infection remains controversial. Studies of the role of the thymus in HIV-1-infected individuals has been limited by the lack of a marker of thymic function in vivo. We have recently developed a novel assay to quantify cells of recent thymic origin by taking advantage of certain molecular events that occur in the thymus during the production of new T lymphocytes. This molecular event creates a circular piece of DNA, called a T-cell receptor excision circles (TREC). TREC concentration in the periphery will increase with an increase in thymic output but will reduce in the presence of T cell proliferation or cell death. In order to determine the contribution of the thymus to immune reconstitution following HAART, we plan to study the dynamics of thymus function in HIV-1 infection by measuring TREC and T cell turnover in HIV-1 infection prior to and following HAART. In a subgroup of individuals, more commonly seen following treatment of HIV-1 infection in children, there is an increase in CD4+ T lymphocytes in the absence of a significant reduction in viral suppression. The role of the thymus in this unique subset of individuals will be studied.Read moreRead less
Cell Therapy To Prevent And Treat Graft-versus-host Disease After Allogeneic Haematopoietic Stem Cell Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$260,302.00
Summary
In bone marrow transplantation, donor immunity can fight the cancer but can also attack healthy tissues, causing graft-versus-host disease (GVHD). We will use two types of cell therapy to treat GVHD. The first study will use a safety switch called inducible capase 9 (iCasp9) to enable the donor immune cells to be rapidly eliminated if GVHD occurs. The second study will use regulatory T cells to treat patients with chronic GVHD. If successful, these treatment approaches will make transplantation ....In bone marrow transplantation, donor immunity can fight the cancer but can also attack healthy tissues, causing graft-versus-host disease (GVHD). We will use two types of cell therapy to treat GVHD. The first study will use a safety switch called inducible capase 9 (iCasp9) to enable the donor immune cells to be rapidly eliminated if GVHD occurs. The second study will use regulatory T cells to treat patients with chronic GVHD. If successful, these treatment approaches will make transplantation safer.Read moreRead less
Recipient Bone Marrow Macrophages Contribute To Haematopoietic Stem Cell Transplantation Success
Funder
National Health and Medical Research Council
Funding Amount
$608,906.00
Summary
We propose an innovative approach to reduce risk and increase success of blood stem cell transplantation. We will determine whether a specialized cell within the transplant patient is required for donor stem cells to successfully take up residence and recreate the blood and immune system. We will test whether fortifying these specialized cells will improve transplantation outcomes, consequently increasing the number of transplants that can proceed and reducing potentially fatal complications.