Improving Adaptive Anti-viral Responses: A Key To Eliminating Persistent Viral Infection
Funder
National Health and Medical Research Council
Funding Amount
$402,391.00
Summary
Cytomegalovirus (CMV) can cause a persistent infection that can result in adverse clinical outcomes. Our previous work established that suboptimal adaptive immunity is responsible for viral persistence. This proposal will define the defect in adaptive immunity, its causes and how to improve it. The understanding gained from the proposed studies will provide crucial information for the development of improved anti-viral therapies and vaccines.
Improved Vaccines Against Tuberculosis Based On Dendritic Cell Manipulation
Funder
National Health and Medical Research Council
Funding Amount
$257,036.00
Summary
The incidence of tuberculosis (TB) is increasing throughout the world. BCG, the only currently available vaccine is only partially protective and better vaccines are urgently required to help limit the spread of TB. We have recently prepared naked DNA vaccines with the genes for three mycobacterial proteins and found that they partially protected against lung TB in mice. Further improvement is required and this project is to design and test improved DNA vaccines. Vaccines will be more effective ....The incidence of tuberculosis (TB) is increasing throughout the world. BCG, the only currently available vaccine is only partially protective and better vaccines are urgently required to help limit the spread of TB. We have recently prepared naked DNA vaccines with the genes for three mycobacterial proteins and found that they partially protected against lung TB in mice. Further improvement is required and this project is to design and test improved DNA vaccines. Vaccines will be more effective if they generate stronger cellular immune response to mycobacteria. Dendritic cells (DC) are the major cells that present mycobacterial antigens to T lymphocytes and thus stimulate T lymphocytes to generate immune responses that protect against TB. Therefore the aim of this project is to identify ways to manipulate DC to improve their ability to activate protective immunity. We will target membrane molecules on DC to activate the antigen- presenting function of these cells by fusing the genes for mycobacterial proteins to genes either for antibodies to surface molecules on DC or receptors for these molecules. These novel DNA vaccines will be tested for their effects on DC function and their capacity to stimulate the protective pattern of immunity in mice. The cytokine environment at the time of stimulation will be modified by giving the DNA vaccine together with two cytokine-expressing vaccines, to 'push' the T lymphocytes to respond more vigorously. Finally, we shall test whether a combination of the new DNA vaccines and BCG is more effective than BCG at protecting against virulent TB infection.Read moreRead less
The Differentiation And Function Of T Follicular Helper (TFH) Cells And Their Role In Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$143,758.00
Summary
Antibody production is essential for immune responses and regulated by a subset of lymphocytes named T follicular helper (TFH) cells. Consequently, dysregulation of TFH cell function, or expression of TFH cell-associated molecules most likely contributes to the pathogenesis of certain autoimmune or immunodeficient diseases. Knowledge on TFH cells can greatly facilitate the development of new diagnosis and therapy.
The Role Of Non-classical MHC Class I Molecules In Adaptive Immunity
Funder
National Health and Medical Research Council
Funding Amount
$443,834.00
Summary
Specialised proteins called MHC class Ia molecules (MHC-Ia) stimulate killer T cells to lyse virus infected cells. In contrast, the function of the closely related MHC-Ib is uncertain. Recent findings have demonstrated that MHC-Ib can also be recognised by T cells and this interaction is important in the control of viral infections. However, despite the similarity to MHC-Ia, it is unclear how this interaction occurs. This project aims to investigate how killer T cells recognise MHC-Ib molecules.
Apoptosis Amongst Specific And Bystander T Cells In Chronic Bacterial Infection
Funder
National Health and Medical Research Council
Funding Amount
$317,545.00
Summary
When an infection occurs the immune cells (lymphocytes) proliferate in order to initiate and expand the immune response. If the body had no mechanisms to limit proliferation, the numbers of cells would soon overwhelm the body. Working with simple protein antigens rather than infection, other workers have found that once T lymphocytes have been activated and the immune response triggered, they soon undergo a process of self destruction called apoptosis. However, during infection, if the limits to ....When an infection occurs the immune cells (lymphocytes) proliferate in order to initiate and expand the immune response. If the body had no mechanisms to limit proliferation, the numbers of cells would soon overwhelm the body. Working with simple protein antigens rather than infection, other workers have found that once T lymphocytes have been activated and the immune response triggered, they soon undergo a process of self destruction called apoptosis. However, during infection, if the limits to lymphocyte proliferation are imposed before the infecting bacterium is eliminated, full expression of immunity does not occur and chronic infection may result. We believe that this contributes to the chronicity of such infections as tuberculosis and leprosy. We also suspect that, during infection, not only protective T lymphocytes proliferate, but also nonspecific bystander cells. This exaggerates the problem of lymphocyte proliferation and adds to immunopathology (immune damage). We have established an animal model of chronic bacterial infection in order to study how apoptosis is induced in T lymphocytes and how its adverse effects may be overcome. We hypothesize that apoptosis may be induced by one or more of a number of mechanisms, and that they may differ for the specific protective cells and the bystander cells. Once we understand the mechanisms apoptosis of specific lymphocytes may be prevented without harming the body. This has the potential to open new areas of immunotherapy (manipulating the immune response) of these diseases.Read moreRead less
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.