How IL-4 Suppresses TNF And IL-1 Production By Activated Human Monocytes And Macrophages
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Chronic inflammatory diseases are an enormous and growing health problem. There is a continuing search for improved and more targeted treatments. We have been studying a cytokine called interleukin-4 which can suppress the production by blood cells of many of the inflammatory mediators that initiate and maintain inflammation. With the recognition that interleukin-4 has this anti-inflammatory activity on blood cells, there was considerable optimism that this molecule may not only be a natural reg ....Chronic inflammatory diseases are an enormous and growing health problem. There is a continuing search for improved and more targeted treatments. We have been studying a cytokine called interleukin-4 which can suppress the production by blood cells of many of the inflammatory mediators that initiate and maintain inflammation. With the recognition that interleukin-4 has this anti-inflammatory activity on blood cells, there was considerable optimism that this molecule may not only be a natural regulator of inflammation but also used in immunotherapy. However we do not know how this molecule downregulates inflammatory blood cells. It will be necessary to know this if it is to be used in human gene therapy for treatment of inflammatory diseases. Cells must be activated before a molecule which is anti-inflammatory can be effective. Different cell types from different inflammatory sites will be studied to better characterise different activation pathways. How interleukin-4 regulates these pathways will be studied. Once identified, treatments based on the properties of interleukin-4 may be designed-optimised.Read moreRead less
Cytokine Production By Human Dendritic Cells - Is Less More?
Funder
National Health and Medical Research Council
Funding Amount
$378,107.00
Summary
Dendritic cells (DC) are specialist white blood cells responsible for initiating and coordinating immune responses against pathogens and cancer. DC act as sentinels of the immune system and are found throughout the body where they are in constant surveillance for infections or danger signals. Once armed they traffic to the lymph nodes, where they activate T lymphocytes and NK cells, which are then responsible for mounting an attack against the infection or tumour. The complex mechanisms of how d ....Dendritic cells (DC) are specialist white blood cells responsible for initiating and coordinating immune responses against pathogens and cancer. DC act as sentinels of the immune system and are found throughout the body where they are in constant surveillance for infections or danger signals. Once armed they traffic to the lymph nodes, where they activate T lymphocytes and NK cells, which are then responsible for mounting an attack against the infection or tumour. The complex mechanisms of how dendritic cells respond to danger, and how they direct T and NK cells to induce specific immune responses appropriate for a particular infection are poorly understood. Most of our current knowledge of DC has been obtained from mouse studies, and it is believed that secretion of cytokines by dendritic cells play an important role. Human dendritic cells have been difficult to identify, however we have pioneered methods to isolate and characterise them from human tissue. We will therefore investigate the production of cytokines from human DC subsets and the role they play in the induction of immune responses. DC can be instructed in the test tube to recognise a cancer and mount an immune response, and this is a promising new therapy for cancer. Our work will uncover fundamental information about the most potent danger signal, the type of DC and the most important cytokines for inducing immune responses against cancers, and will therefore assist in the development of cancer vaccines.Read moreRead less
Molecular And Cellular Mechanisms Of Skeletal Disease Mediated By Plasma Cell Dyscrasias
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Osteolytic and osteosclerotic lesions of bone are common sequelae of primary and secondary bone cancers, including cancers of hematological origin. There is now strong evidence that tumor cells perturb the local balance between bone resorption and formation, and in cases of osteolysis, cause increased osteoclast (OC)-mediated bone resorption without a matching amount of bone formation. This proposal arises from our extensive clinical and basic science experience with multiple myeloma (MM) in add ....Osteolytic and osteosclerotic lesions of bone are common sequelae of primary and secondary bone cancers, including cancers of hematological origin. There is now strong evidence that tumor cells perturb the local balance between bone resorption and formation, and in cases of osteolysis, cause increased osteoclast (OC)-mediated bone resorption without a matching amount of bone formation. This proposal arises from our extensive clinical and basic science experience with multiple myeloma (MM) in addition to other skeletal tumors, and our strong background in both OC and osteoblast biology. MM is a hematological malignancy characterised by plasma cell dyscrasia, which typically causes progressive and severe destruction of the skeleton, with accompanying bone pain, fracture and finally, hypercalcaemia of malignancy. Two related diseases, MGUS and POEMS, have been chosen for study because of their key similarities and differences with MM, and are likely to shed new light on the activities of MM in the bone. MGUS does not cause identifiable bone defects, whereas POEMS can give rise to both osteolytic and osteosclerotic lesions. Comparison of these conditions will uniquely enable us to examine why these seemingly related neoplasms are able to mediate disparate skeletal disease states. Primarily, and since there are few curative therapies for MM at present, our proposed studies are designed to identify targets for therapy that will treat the most serious manifestation of this disease, namely its destruction of bone tissue.Read moreRead less
Characterisation Of Cell-mediated Immune Responses In Burkholderia Pseudomallei Infection
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
The bacterium Burkholderia pseudomallei, causes a life threatening condition known as melioidosis. Melioidosis is emerging as an important infectious disease in tropical regions of Australia and South East Asia. Death rates following acute disease are extremely high. Despite the importance of B. pseudomallei in tropical public health, very little is known regarding how the body's defence mechanisms prevent the spread of infection. The wide distribution of melioidosis in tropical Australia and ot ....The bacterium Burkholderia pseudomallei, causes a life threatening condition known as melioidosis. Melioidosis is emerging as an important infectious disease in tropical regions of Australia and South East Asia. Death rates following acute disease are extremely high. Despite the importance of B. pseudomallei in tropical public health, very little is known regarding how the body's defence mechanisms prevent the spread of infection. The wide distribution of melioidosis in tropical Australia and other parts of the world, and the lack of basic scientific information regarding this disease, has prompted this study. The bacterium lives within the body's cells and therefore does not respond well to standard antibiotic treatment. Although some of the basic immune mechanisms have been identified, how protection to the organism develops remains unclear. In this project we will investigate the effect of B. pseudomallei on immune cells or lymphocytes. This study will determine the patients' immune responses to the bacteria causing the disease. Our research team has already successfully carried out work on several different aspects of melioidosis. The characterisation of the basic immune function determined in the proposed study will provide the scientific basis for improvement in treatment and the development of possible preventive strategies against melioidosis.Read moreRead less
Molecular Cloning And Expression Of Cytokine Genes Related To Induction Of Allograft Transplantation Tolerance In Rats
Funder
National Health and Medical Research Council
Funding Amount
$212,371.00
Summary
Cytokines are soluble proteins produced by leucocytes, and in many cases other cell types, which act as chemical communicators between cells, but not as effector molecules in their own right. Most of the cytokines are growth or differentiation factors and they generally act on cells within the haematopoietic system. In this grant application we will focus on the production of cytokines and antibodies to these cytokines, that are likely to be important in organ transplantation tolerance or organ ....Cytokines are soluble proteins produced by leucocytes, and in many cases other cell types, which act as chemical communicators between cells, but not as effector molecules in their own right. Most of the cytokines are growth or differentiation factors and they generally act on cells within the haematopoietic system. In this grant application we will focus on the production of cytokines and antibodies to these cytokines, that are likely to be important in organ transplantation tolerance or organ rejection. We would like to synthesize these cytokines using molecular biological techniques. These biological materials will be used to treat animals and study their biological effect on transplanted graft survival. If the cytokine treatment does prolong graft survival, what is the mechanisms involved in the immune responses will be further studied. Our aim is to develop strategies that couold be applied to help pateints with organ transplants and receive most specific therapies.Read moreRead less
Activated Protein C Suppresses The Abnormal Immune Response In Rheumatoid Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$380,558.00
Summary
This project will determine whether activated protein C (APC) reduces the severity of rheumatoid arthritis (RA) by altering the abnormal response of a type of white blood cells known as the T cells. Experiments will utilise T cells isolated from patients with RA, normal controls and an animal model of RA, to examine a newly discovered immune pathway now thought to play a major role in causing RA. The results will help clarify whether and how APC prevents joint destruction in RA
Though vaccination has had a major impact on the number of persons becoming infected, chronic infection with the hepatitis B virus (HBV) still remains a major worldwide problem, with 350 million people chronically infected. The existence of HBV vaccine escape mutants and the fact that 5% of vaccinees fail to respond implies that HBV will remain a significant public health problem for the foreseeable future. Current treatments for chronic HBV infection have a low success rate (~20%) and patients ....Though vaccination has had a major impact on the number of persons becoming infected, chronic infection with the hepatitis B virus (HBV) still remains a major worldwide problem, with 350 million people chronically infected. The existence of HBV vaccine escape mutants and the fact that 5% of vaccinees fail to respond implies that HBV will remain a significant public health problem for the foreseeable future. Current treatments for chronic HBV infection have a low success rate (~20%) and patients with chronic infection are expected to die prematurely due to chronic liver disease or primary liver cancer. Interestingly, exposure to HBV can lead to either acute resolving or chronic HBV infection. Like chronic infections, acute infections involve spread of virus to virtually every hepatocyte, followed by rapid clearance of the virus mediated by the host immune response. Our immediate aim is to study the resolution of acute HBV infections to determine how the stable intracellular viral genome, covalently closed circular DNA (cccDNA), is cleared from the nucleus of infected hepatocytes. Our broad long-term aim is to develop new and effective treatments for chronic HBV infection based on a better understanding of how acute HBV infections are resolved by the host. Based on our previous work we believe that clearance of cccDNA requires hepatocyte death, together with compensatory proliferation of other infected hepatocytes. We will perform detailed studies in duck hepatitis B virus (DHBV) infected ducks to determine if hepatocyte death and compensatory proliferation are essential to clear the infection, or if mechanisms exist for clearance that do not involve cell destruction.Read moreRead less