Structural Basis For Inhibition Of Malaria Invasion By Targeting The Apical Membrane Antigen Of Plasmodium Falciparum.
Funder
National Health and Medical Research Council
Funding Amount
$434,134.00
Summary
3 million children die every year from malaria infections. A leading vaccine candidate is a protein from the malaria parasite called AMA1. Humans that have been infected with malaria make antibodies to this protein which can kill parasites, however little is known about how this occurs. We aim to identify regions of the protein that generate antibodies that prevent malaria parasites from invading human cells and help in the search for a vaccine against malaria.
Using The Information Inherent In Immune Responses To Design Vaccines
Funder
National Health and Medical Research Council
Funding Amount
$526,571.00
Summary
The parts of viruses, bacteria and of cancer cells that are recognised by the immune system are called epitopes. Epitopes are generated from these agents by dendritic cells which are found in many parts of the body where they act as sentinels on the look out for dangerous organisms. Epitopes are very small pieces of the proteins against which immune responses are mounted and can be readily synthesised in the laboratory. If we were to design vaccines that are made of epitopes such that the immune ....The parts of viruses, bacteria and of cancer cells that are recognised by the immune system are called epitopes. Epitopes are generated from these agents by dendritic cells which are found in many parts of the body where they act as sentinels on the look out for dangerous organisms. Epitopes are very small pieces of the proteins against which immune responses are mounted and can be readily synthesised in the laboratory. If we were to design vaccines that are made of epitopes such that the immune response is focussed to those exact regions of infectious agents it could lead to an immune response that eliminates the agent. The problem is, however, that we usually do not know which part of the virus, bacterium or cancer cell is recognised as an epitope. So the identification of epitopes is a limitation to the design of epitope-based vaccines. Anyone who has encountered a virus, bacterium or tumour cell and who has raised an immune response will have developed antibodies and immune cells able to recognise the right parts of the infectious agent or cancer cell. These antibodies and immune cells now contain information about the epitopes. We will use antibodies and blood cells obtained from people immune to the disease to extract epitopes from a panel of protein fragments that represent the agent against which we wish to make vaccines. These newly discovered epitopes will then be incorporated into totally synthetic vaccines. These vaccines will also incorporate a simple lipid molecule which specifically targets and activates the dendritic cell that is key for the induction of potent immune responses. All of the technologies we propose are in place and we have proof of principle that the approach leads to the successful design of vaccines that are effective against infectious diseases and cancers.Read moreRead less
CONTAINMENT OF THE T-CELL RESPONSE TO GLUTEN IN COELIAC DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$324,270.00
Summary
Coeliac disease affects about 1% of Casucasians and West Asians, about 250,000 Australians. Diagnosis of coeliac disease is problematic, less than one fifth of Australians with coeliac disease have been diagnosed, while many more adopt a gluten free diet and strictly avoid foods made from wheat, barley, rye and oats mistakenly thinking that they have coeliac disease. New diagnostics and therapies that are easy to perform and acceptable to patients are badly needed if the public are to benefit fr ....Coeliac disease affects about 1% of Casucasians and West Asians, about 250,000 Australians. Diagnosis of coeliac disease is problematic, less than one fifth of Australians with coeliac disease have been diagnosed, while many more adopt a gluten free diet and strictly avoid foods made from wheat, barley, rye and oats mistakenly thinking that they have coeliac disease. New diagnostics and therapies that are easy to perform and acceptable to patients are badly needed if the public are to benefit from emerging understanding of coeliac disease. It is an unfortunate mistake that the immune system recognizes and reacts to gluten in people with coeliac disease. The immune cells that sense gluten and damage the intestine, T-cells, detect only very specific short fragments (epitopes) of gluten proteins. Understanding which gluten fragments cause coeliac disease would enable new tests to diagnose coeliac disease, design of non-toxic gluten, and may even allow new treatments that could desensitise the immune system to gluten in the same way that desensitisation therapy works for allergy. Understanding of the gluten fragments causing coeliac disease is improving but it is still incomplete. We have developed a simple test that can pin-point the gluten fragments recognized by any individual with coeliac disease. With the help of volunteers with coeliac disease and a library of fragmented gluten proteins, we will be able to map all the regions of gluten in wheat, barley, rye, and oats that stimulate T-cells. We will find the most potent epitopes that could be used in diagnostic tests, food tests, and desensitisation therapy. Studying individuals with coeliac disease when they eat oats, normally a forbidden food for coeliac suffers yet fewer than 1:4 actually react to oats, will define the changes in intestinal tissue following destructive or tolerant responses to this grain and provide a tool to assess future desensitisation therapies for coeliac disease.Read moreRead less
Structure-function Relationships Of Rye Grass Pollen Allergens And Preparation Of Hypoallergenic Mutants For Therapy
Funder
National Health and Medical Research Council
Funding Amount
$223,928.00
Summary
Grass pollen is an important cause of allergy (eg. hayfever, allergic asthma) world-wide affecting up to 30% of the population. In Australia, rye grass pollen is a clinically significant health problem costing $83-160 million per annum. At present, the main treatment of seasonal allergy is by pharmacotherapy with the use of crude extracts in specific immunotherapy which often causes large and annoying local skin reactions and may even cause anaphylaxis. Moreover, the use of crude extracts in dia ....Grass pollen is an important cause of allergy (eg. hayfever, allergic asthma) world-wide affecting up to 30% of the population. In Australia, rye grass pollen is a clinically significant health problem costing $83-160 million per annum. At present, the main treatment of seasonal allergy is by pharmacotherapy with the use of crude extracts in specific immunotherapy which often causes large and annoying local skin reactions and may even cause anaphylaxis. Moreover, the use of crude extracts in diagnosis of allergy among some atopic individuals may be inaccurate or ineffective. In the last eight years of my research, I have contributed significantly to the identification, characterisation and molecular cloning of grass pollen allergens. In this proposal, I aim to evaluate recombinant rye grass pollen allergens as standardised and more effective diagnostic reagents and, through the identification and better understanding of the allergenic segments of these proteins, to prepare recombinant mutants of the same proteins which are no londer allergenic. Avaliability of such non-allergenic protein reagents will provide safer immunotherapy in the future. Moreover, since the biolgical role, function and structure of such allergens in the grass pollen still remain largely unknown, I will aim to investigate this with the clinically significant allergens of rye grass pollen. Determination of biological function and structure of such allergens will allow their importance for the pollen-plant to be determined and, since function may be relevant to sensitisation of suceptible individuals to these allergens, these findings will stimulate the development of novel concepts in allergen prevention and therapy.Read moreRead less
Couch Grass Allergy: Cellular And Molecular Studies Directed At Improved Specific Immunotherapy
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
Couch grass pollen is increasingly important in Australia and other temperate and subtropical regions as a seasonal allergen causing asthma and hay fever. In our allergy clinic 85% of patients with seasonal asthma and-or hay fever are allergic to both couch grass pollen and rye grass pollen. Standard allergy treatment shots usually cover the rye grass pollen allergens but there is no cross-reactivity with couch grass pollen and therefore symptoms due to couch grass pollen are not controlled. The ....Couch grass pollen is increasingly important in Australia and other temperate and subtropical regions as a seasonal allergen causing asthma and hay fever. In our allergy clinic 85% of patients with seasonal asthma and-or hay fever are allergic to both couch grass pollen and rye grass pollen. Standard allergy treatment shots usually cover the rye grass pollen allergens but there is no cross-reactivity with couch grass pollen and therefore symptoms due to couch grass pollen are not controlled. These shots are seldom used in asthmatic patients because of the risk of severe asthma or generalised allergic reactions. We plan to examine human blood cell responses to couch grass pollen allergens before and after allergy shots with a preparation that includes couch grass pollen and rye grass pollen. A comparable control group of patients receiving only drug therapy will also be investigated. This study will identify dominant sites of couch grass pollen allergen immunoreactivity and reveal mechanisms of desensitisation. Based on this information, we will develop novel couch grass pollen proteins that retain the positive features needed for a successful desensitising vaccine but without the ability to bind to allergy antibodies and possibly cause severe adverse events such as asthma attacks. These preparations could be used to provide safer and more effective allergy treatments that can be used in hay fever sufferers and asthmatics.Read moreRead less