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Development Of Hepatitis B Surface Antigen As A Generic Vector For The Delivery Of Foreign CTL Epitopes.
Funder
National Health and Medical Research Council
Funding Amount
$439,642.00
Summary
Many kinds of cancer and infections display unique proteins which the body's immune system can recognise as ' foreign', and mount an immune response which, if correctly harnessed, will kill the cancer or infected cells . A way to harness the immune response is to vaccinate with these unique proteins. However, new ways need to be found to deliver the unique proteins to produce the maximal possible anti- cancer or pathogen response, and one that is long lived. In particular one needs to stimulate ....Many kinds of cancer and infections display unique proteins which the body's immune system can recognise as ' foreign', and mount an immune response which, if correctly harnessed, will kill the cancer or infected cells . A way to harness the immune response is to vaccinate with these unique proteins. However, new ways need to be found to deliver the unique proteins to produce the maximal possible anti- cancer or pathogen response, and one that is long lived. In particular one needs to stimulate the cellular arm of the immune response to produce killer cells named CTLs which specifically kill cancer or infected cells. In this project we plan to use an already-licensed human vaccine - the Hepatitis B surface antigen vaccine , or HBsAG, - and genetically modify it to contain important regions of cancer or pathogen proteins termed 'epitopes'. We surmise that immunisation with these modified HBsAg will elicit powerful CTL responses which will killer cancer or infected cells.Read moreRead less
Mechanisms Regulating Establishment Of Persistent Herpesvirus Infection
Funder
National Health and Medical Research Council
Funding Amount
$511,446.00
Summary
Herpesviruses are a major cause of disease worldwide and are amongst the most successful human pathogens, with some viruses infecting more than 80% of the world's population. This group of viruses persist and reactivate in hosts and induce immunosuppression.The control of herpesviruses infections thus represents an important clinical goal. Understanding the mechanisms involved in the induction of viral persistence and immunosuppression is a crucial step towards developing better therapies.
The Phenotype Of Protective Cytotoxic T Cell Responses During Viral Infections
Funder
National Health and Medical Research Council
Funding Amount
$841,114.00
Summary
T cell responses are important to establish protection against pathogens and some cancer via generation of memory cells that can be maintained long term and defeat promptly re-infections. This proposal aim at determining important factors that drive the success of immunological memory by employing single cell technologies and unique longitudinal samples from subjects infected with hepatitis C virus. The finding of this study will inform current vaccine research and immunotherapies.
Specialised Subsets Of T Follicular Helper Cells In The Control Of Infection And Immune Pathology
Funder
National Health and Medical Research Council
Funding Amount
$593,888.00
Summary
Defective or uncontrolled production of antibodies leads to increased susceptibility to infection, allergies, and autoimmune diseases. A type of T cell called follicular helper (Tfh) has emerged as a key controller of both protective and pathologic antibody production. We have data suggesting there are specialised Tfh subsets, each controlling different stages and outcomes of antibody responses. Identifying how each subset is regulated and functions will provide novel targets to treat these chro ....Defective or uncontrolled production of antibodies leads to increased susceptibility to infection, allergies, and autoimmune diseases. A type of T cell called follicular helper (Tfh) has emerged as a key controller of both protective and pathologic antibody production. We have data suggesting there are specialised Tfh subsets, each controlling different stages and outcomes of antibody responses. Identifying how each subset is regulated and functions will provide novel targets to treat these chronic debilitating diseases.Read moreRead less
Targeting Caspase 8 In T-Cell Homeostasis And Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,215,780.00
Summary
Chronic infectious diseases such as HIV, hepatitis B and tuberculosis impose a massive global health burden and new treatments are desperately needed. This proposal investigates a new approach to improve immune responses and clear chronic infections. Our multidisciplinary team will define the molecular and cellular biology underlying this approach and translate our findings by re-purposing a drug already approved for other indications in humans.
NK Cell Subsets And Their Role In Immune Responses
Funder
National Health and Medical Research Council
Funding Amount
$173,522.00
Summary
Natural killer (NK) cells are 5-10% of white blood cells of the immune system that represent one of our first lines of defense against microbes and cancer development. Recent evidence strongly suggests that NK cells are major cells of importance in the immune system, not only in acting as killers of cancer cells or virus-infected cells, but also in regulating the adaptive memory components of the immune response. Despite our greater knowledge of NK cell biology, we still know very little about t ....Natural killer (NK) cells are 5-10% of white blood cells of the immune system that represent one of our first lines of defense against microbes and cancer development. Recent evidence strongly suggests that NK cells are major cells of importance in the immune system, not only in acting as killers of cancer cells or virus-infected cells, but also in regulating the adaptive memory components of the immune response. Despite our greater knowledge of NK cell biology, we still know very little about the diversity that exists within the NK cell population. The development and maturation of NK cells requires far greater study and this proposal aims to examine this question in the best experimental model, the mouse. We have recently made an important breakthrough concerning the distinct functional behavior of newly discovered NK cell subsets. We now aim to develop a more integrated model of NK cell development, such that vaccines and adjuvants designed to prevent and ameliorate lethal and chronic infectious diseases and cancer can be more rationally designed.Read moreRead less
Immunoregulation And Adoptive Immunotherapy Of Glioblastoma Multiforme
Funder
National Health and Medical Research Council
Funding Amount
$391,784.00
Summary
This project is investigating link between a common herpesvirus and brain cancer. We are also aiming to develop new killer T cell-based therapy to target herpesvirus proteins in cancer cells with a long-term objective to use this information to develop a therpeutic vaccine against brain cancer.
The Genetics Governing The Specificity Of T Cell Receptors For Peptide-MHC
Funder
National Health and Medical Research Council
Funding Amount
$303,828.00
Summary
T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue through the use of highly specific cell surface receptors. These T cell receptors (TCR) recognise viral peptides (p) presented by MHC molecules on the surface of virus-infected cells. For a TCR to be successfully triggered, it must lock onto an exact 3-dimentional pMHC match. In this way, any given TCR must simultaneously recognise both the viral peptide and the MHC presenting it. Such recognition must be ....T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue through the use of highly specific cell surface receptors. These T cell receptors (TCR) recognise viral peptides (p) presented by MHC molecules on the surface of virus-infected cells. For a TCR to be successfully triggered, it must lock onto an exact 3-dimentional pMHC match. In this way, any given TCR must simultaneously recognise both the viral peptide and the MHC presenting it. Such recognition must be sensitive and precise since a false positive could result in destruction of healthy tissue. There are a huge variety of TCRs and pMHCs, but there are only a few examples where the precise molecular interactions within the TCR-pMHC complex are known. Surprisingly, these studies have shown very limited consistency in the way the TCRs bind the pMHCs and therefore, the structural rules that underlie why TCRs consistently bind MHC remains a mystery of critical importance to this fundamental feature of the immune system. In this proposal, we will attempt to elucidate the rules of TCR-pMHC engagement. Another question to be addressed in this proposal is: During a viral infection, why are certain TCRs chosen above others that also have the capacity to recognise the same viral peptide? By investigating exactly which feature-s of these receptors predisposes their supremacy, we may be better able to predict the outcome of a pathogen attack and to even one day build our own super receptors. Finally, this proposal will also investigate how natural mutations in TCR genes across the human population affect our individual responses to viruses. Overall, advances in each of these core areas of medical research will aid in the development of new intelligent vaccines and individualised drugs for the treatment of cancer and infectious disease.Read moreRead less