Respiratory Viral Infections As Triggers Of Acute Severe Asthma Exacerbations In Atopics: Mechanistic Studies In An Experimental Model
Funder
National Health and Medical Research Council
Funding Amount
$659,494.00
Summary
An important unresolved issue in asthma research is why almost all the children who present in hospital emergency with very severe asthma attacks are both allergic and virally infected. This project will seek to define how immune responses to viruses and aeroallergens interact to create very severe inflammation in the airways thus precipitating the severest type of asthma attacks. Understanding the underlying mechanisms will hopefully provide new clues towards better treatments.
Developmental Stages Of In Vivo And In Vitro-generated Dendritic Cell Subsets And Regulation Of T Cell Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$88,087.00
Summary
Dendritic cells (DC) represent a diverse family of white blood cells that form a sentinel network throughout the body involved in the detection and eradication of pathogens and cancer cells. DC can originate from different precursor cells in the bone marrow. It is therefore possible that different types of DC perform differing functions. For instance, DC not only initiate immune responses but are also able to silence them. However, the ability of DC to instruct and orchestrate the immune respons ....Dendritic cells (DC) represent a diverse family of white blood cells that form a sentinel network throughout the body involved in the detection and eradication of pathogens and cancer cells. DC can originate from different precursor cells in the bone marrow. It is therefore possible that different types of DC perform differing functions. For instance, DC not only initiate immune responses but are also able to silence them. However, the ability of DC to instruct and orchestrate the immune response may not only depend upon their origins but also on where they encounter pathogens or cancer cells and what other signals are associated with this encounter. Due to their specialized capacity to instruct the immune response (e.g. T cells, B cells and NK cells) of impending danger, DC are used experimentally to more efficiently deliver vaccines to the immune response so as to eradicate cancer or infectious disease. However, in order to successfully use DC to deliver vaccines, one must first understand how these cells normally behave in the body and what signals can alter their functional ability to orchestrate immune responses. We can generate DC outside the body from their precursors. We can also isolate DC from the circulation. This project seeks to identify how various physiologic stimuli differentially regulate the functional behaviour of DC subsets and how this then influences the DC's ability to instruct the developing T cell immune response. Furthermore, whether these signals are the same for DC generated outside the body with those isolated from the blood. Of particular interest is whether differing types of DC and differing stages of their maturity will differentially influence the T cell's ability to secrete immune response hormones and to recognize and kill cancer cells. The findings of this study have direct implications of how to best harness DC to effectively deliver vaccines and generate potent immune responses against cancer and infectious disease.Read moreRead less
Dendritic cells are a very rare type of white blood cell which play a critical role in the initiation of the immune response. They are of particular interest to scientists interested in vaccination, as for a vaccine to work effectively, the vaccine must be presented to the rest of the immune system by the dendritic cell. It has only recently become apparent that there are several types of dendritic cell, and these different types of dendritic cell vary in their ability to present a vaccine to th ....Dendritic cells are a very rare type of white blood cell which play a critical role in the initiation of the immune response. They are of particular interest to scientists interested in vaccination, as for a vaccine to work effectively, the vaccine must be presented to the rest of the immune system by the dendritic cell. It has only recently become apparent that there are several types of dendritic cell, and these different types of dendritic cell vary in their ability to present a vaccine to the immune system. We have already identified some proteins that are expressed on the surface of only one type of dendritic cell. We will explore the possible use of these proteins as a means of delivering a vaccine to only one type of dendritic cell. This project will also identify new genes that are expressed in some types of dendritic cells but not others. These new genes whose expression does differ amongst the dendritic cells are potential targets for manipulating the immune system and ensuring more efficient vaccination.Read moreRead less
The Role Of The Dendritic Cell Surface Molecule Clec9A In Dendritic Cell Subset Function And Dead Cell Recognition
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
Dendritic cells (DC) are sentinels of the immune system. DC monitor the environment and regulate tolerance to self versus immunity to dangerous material. Different types of DC perform different jobs. We have identified a new surface molecule, Clec9A, on some mouse and human DC. We will investigate the function of Clec9A in the immune response. We will also use Clec9A to help unite mouse and human DC biology, since until now there have been few useful marker molecules common to both species.
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
Mechanisms Of Action Of The Antigen Presenting Cells That Impair Lymphoma-specific Cytotoxic T Lymphocytes
Funder
National Health and Medical Research Council
Funding Amount
$295,983.00
Summary
Our immune systems are continually fighting cancer. However, the cancer cells occasionally acquire mutations that enable them to subvert the immune system. Usually they do this by hiding under the appearance of normal tissue, but sometimes they activate the very mechanisms that are in place to shut-down immune responses when these are no longer necessary. The goal of this proposal is to identify such mechanisms and find ways of bypassing them, thus restoring anti-tumour activity in patients.
Autoimmune diseases constitute a significant medical problem in the developed world and are increasing in incidence. Many control mechanisms exist in the body, but in people with genetic susceptibility to autoimmune disease, the mechanisms fail and the body's immune system attacks normal tissues or organs. We have developed a new approach, using the cells which train the immune system, to re-educate the cells that would otherwise attack normal healthy tissues in autoimmune-prone individuals. The ....Autoimmune diseases constitute a significant medical problem in the developed world and are increasing in incidence. Many control mechanisms exist in the body, but in people with genetic susceptibility to autoimmune disease, the mechanisms fail and the body's immune system attacks normal tissues or organs. We have developed a new approach, using the cells which train the immune system, to re-educate the cells that would otherwise attack normal healthy tissues in autoimmune-prone individuals. These cells (dendritic cells) are genetically modified to express the molecular targets of the autoimmune response. This in turn switches off the response to these targets. In this project, we will explore how these cells can be used to turn off the harmful cells present in the immune system.Read moreRead less
Role Of Dendritic Cell Subsets In The Generation Of CD4 T Cell Memory
Funder
National Health and Medical Research Council
Funding Amount
$563,554.00
Summary
This project studies the mechanisms responsible for establishing immunologic memory that is generated by vaccination and determines its efficacy. We aim to identify and study previously unacknowledged factors that critically affect the efficacy of vaccination. The results will be significant for both preventative and therapeutic vaccination (cancer, autoimmunity) and will help us to design new vaccines to improve immune function in infection, autoimmunity and cancer.
Dissecting The Contribution Of CD103+ DC To Priming Of Virus-specific CD8 T Cells
Funder
National Health and Medical Research Council
Funding Amount
$336,767.00
Summary
Dendritic cells are key regulators of T cell responses against pathogens. This project will examine the contribution and individual function of distinct dendritic cell to the initiation of adaptive immune responses against herpes-simplex virus. Unraveling the delicate interplay between different dendritic cells will provide novel insights into host-pathogen interactions and will have important implications for the development of efficient vaccination strategies.