Receptors And Ligands Regulating Human NK Cell Proliferation
Funder
National Health and Medical Research Council
Funding Amount
$692,040.00
Summary
A white blood cell called a Natural Killer (NK) cell is critical in the early control of viral infections and cancer. NK cells kill the diseased cells and secrete immunological hormones (cytokines) that alter how cells of the blood and immune systems respond. These functions of NK cells are markedly increased when NK cells are stimulated to divide. This project seeks to understand how NK cell proliferation is controlled. Receptors that recognise 'self' inhibit NK cell function and cell division ....A white blood cell called a Natural Killer (NK) cell is critical in the early control of viral infections and cancer. NK cells kill the diseased cells and secrete immunological hormones (cytokines) that alter how cells of the blood and immune systems respond. These functions of NK cells are markedly increased when NK cells are stimulated to divide. This project seeks to understand how NK cell proliferation is controlled. Receptors that recognise 'self' inhibit NK cell function and cell division thereby preserving self and destroying diseased cells. Yet many NK cells express both an inhibitory and activating receptor for this same 'self' protein. We will investigate what determines the outcome of this competing information. Many NK cell receptors remain to be identified and we will use a gene expression approach and monoclonal antibodies to identify these and determine how they affect NK cell proliferation. We will use molecular engineering to construct multimeric arrays of new NK cell receptors to search for the ligand molecules that they interact with on other cells. Identifying NK cell receptors and their ligands regulating NK cell proliferation and function will enable us to understand the role of these cells in health and in inflammatory diseases and cancer.Read moreRead less
I am cellular immunologist determining the important host immune cell types and effector molecules that control tumour initiation, growth, and metastasis.
Role Of NK Cell-dendritic Cell Interactions In The Induction Of T Cell Responses Involved In Malarial Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$338,154.00
Summary
Cerebral malaria is a devastating neurological syndrome. Recent data indicate that NK cells are involved in disease induction. NK cell function is controlled by receptors encoded by a genetic region named the Natural Killer Complex (NKC). We showed that the differential expression of NKC genes controls the degree of susceptibility to cerebral malaria. Here we will identify and characterise NKC receptors involved in pathogenesis and the mechanism by which these molecules mediate disease.
Analysis Of The Molecular Functions Of Perforin: A Critical Role In Tumor Immunosurveillance
Funder
National Health and Medical Research Council
Funding Amount
$318,916.00
Summary
Over the past decade, great steps have been made in defining the key molecules used by killer cells of the immune system that eliminate cancerous- and virus-infected cells and many of these advances have originated in our laboratory. It is now clear that granule-mediated cytolysis is a key mechanism for controlling both primary and metastatic cancers in transplanted syngeneic, allogeneic and xenogeneic tumor models in mice. The pore-forming protein, perforin is indispensable for effective killer ....Over the past decade, great steps have been made in defining the key molecules used by killer cells of the immune system that eliminate cancerous- and virus-infected cells and many of these advances have originated in our laboratory. It is now clear that granule-mediated cytolysis is a key mechanism for controlling both primary and metastatic cancers in transplanted syngeneic, allogeneic and xenogeneic tumor models in mice. The pore-forming protein, perforin is indispensable for effective killer cell function in these models. But the role for perforin expressing killer cells in tumor surveillance against spontaneous tumorigenesis is still hotly debated. Our proposal to study tumor development in perforin-deficient p53-mutant tumor prone mice will enable us to answer this question. Furthermore, the molecular mechanisms by which perforin functions are poorly understood. We therefore also propose to complete a structure-function analysis of perforin using unique tools and information that our laboratory has at its disposal. The long-term goal will be to better understand the function of perforin at the molecular level such that the rationale design of therapeutic perforin inhibitors may become a reality for future regulation of killer cell effector functions in disease.Read moreRead less
The Structural Basis For Recognition Of HLA-E By Both Innate And Adaptive Immune Systems.
Funder
National Health and Medical Research Council
Funding Amount
$206,255.00
Summary
Biochemistry and structural biology can be used to understand and visualize the three dimesional shape of molecules and the way they interact with other molecules. We will use these approaches to understand how various cells of the immune system recognise the protein HLA-E. This protein is normally present on the surface of healthy cells while it frequently retained inside both tumours and cells infected with viruses. This acts a signal for the immune system to kill these cells. However to avoid ....Biochemistry and structural biology can be used to understand and visualize the three dimesional shape of molecules and the way they interact with other molecules. We will use these approaches to understand how various cells of the immune system recognise the protein HLA-E. This protein is normally present on the surface of healthy cells while it frequently retained inside both tumours and cells infected with viruses. This acts a signal for the immune system to kill these cells. However to avoid being recognized by the immune system some viruses have developed ways to maintain HLA-E expression. This grant will attempt to understand exactly how the immune sytem recognizes HLA-E and how it discriminates between HLA-Eexpressed by healthy cells compared with HLA-E expressed by a virus-infected cell.Read moreRead less
A Congenic Approach To Analysing The Genomic Control Of Innate Immunity In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$240,156.00
Summary
In addition to the lymphocytes, which are specialised white cells that can learn to defeat the infections that the body has been previously exposed, the body has a number of other defences. These non-learning systems have been honed by evolution and usually form an effective first-line of defence. This proposal deals with three: complement, and two highly specialised types of white blood cell, the Natural Killer cells and the NKT cells. The project will study mice especially bred to carry differ ....In addition to the lymphocytes, which are specialised white cells that can learn to defeat the infections that the body has been previously exposed, the body has a number of other defences. These non-learning systems have been honed by evolution and usually form an effective first-line of defence. This proposal deals with three: complement, and two highly specialised types of white blood cell, the Natural Killer cells and the NKT cells. The project will study mice especially bred to carry different versions of the genes which control these defences. Particular attention will be paid to their involvement in the autoimmune diseases, type 1 diabetes and lupus.Read moreRead less
Although the immune system has the ability to reject tumours, this sometimes does not occur, leading to cancer. There are many different types of cells that make up the immune system, including some which respond very early, called natural killer (NK) and NKT cells. These cells are the first line of defence against some tumours, although we do not understand how they recognise and respond to tumour cells. The aim of this project is to investigate the functional importance of both NK and NKT cell ....Although the immune system has the ability to reject tumours, this sometimes does not occur, leading to cancer. There are many different types of cells that make up the immune system, including some which respond very early, called natural killer (NK) and NKT cells. These cells are the first line of defence against some tumours, although we do not understand how they recognise and respond to tumour cells. The aim of this project is to investigate the functional importance of both NK and NKT cells in response to a range of different tumour types, including melanoma (skin cancer), lung carcinoma, breast carcinoma and sarcoma (connective tissue tumour). We will test the importance of each of these subsets by injecting these tumours into mice that have specific deficiencies in NK and-or NKT cells. If the NK or NKT cells are important, the tumours should grow more effectively when these immune cells are absent. We will also be able to put NK and-or NKT cells back into the mice to show directly that they are responsible for tumour rejection. Using a modification of this cell transfer approach, we will be able to inhibit special molecules that are normally produced by these cells that help them interact with other cells, and also help them attack the tumour cells. Collectively, the approaches outlined in this application allow us to determine which types of cells are important in response to a broad range of different tumour types, and also should tell us how these cells are able to attack the tumours. This information will be invaluable for the development of new strategies to use the patients immune system to attack cancer (known as immuno-therapy).Read moreRead less