A Preclinical Model Of Pig Islet Xenotransplantation As Treatment For Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$4,380,000.00
Summary
The object of this multi-disciplinary program grant is to develop a source of pig insulin secreting tissue that will be used to treat type 1 diabetic patients. At present the number of diabetic patients that would benefit from islet transplantation far outnumber any human source of this tissue. Pigs that have been genetically altered to avoid rejection and enhance survival could overcome this donor shortage problem.. It is our belief that with the appropriate genetic modification pig insulin-sec ....The object of this multi-disciplinary program grant is to develop a source of pig insulin secreting tissue that will be used to treat type 1 diabetic patients. At present the number of diabetic patients that would benefit from islet transplantation far outnumber any human source of this tissue. Pigs that have been genetically altered to avoid rejection and enhance survival could overcome this donor shortage problem.. It is our belief that with the appropriate genetic modification pig insulin-secreting tissue can avoid the aggressive rejection response that occurs with xenographs and provide normal blood glucose control without insulin. This project concentrates on the five main issues that need to be overcome before pig insulin-secreting tissue can be used in diabetics. These are: identifying the best source of insulin secreting tissue to use; adult islets, newborn or foetal islet cell clusters; overcoming the strong rejection response to pig tissue; identifying a safe and effective immunosuppressive regime; producing a new types of genetically modified pigs that will provide islets tissue that will work in humans; and demonstrating that pig islet transplantation will not pose undue infective risks for the patient or community. This truly collaborative program grant has brought together a large group of investigators with strong research records in diabetes, islet transplantation, xenotransplantation, pig transgenesis and pig genetics and includes scientists and clinicians who look after diabetic patients. Unique pig resources will be used including genetically manipulated pigs that have been shown to avoid some of the rejection mechanisms associated with transplanting pig tissue. There is a captive-bred baboon colony that provided a unique model of diabetes. A world class pig transgenesis facility has been enlisted to generate new lines of genetically altered pigs as new data is produced within the group. Finally because of the involvement of the National Pancreas Transplant Unit any proven therapeutic strategy can be brought quickly to clinical trials.Read moreRead less
This study will examine cellular immunity to the avian H5 influenza in people who have been previously infected with the currently circulating strains of H1 and H3 influenza, or in those who have been recently vaccinated with current influenza vaccines. This will give us an idea if there is any cross reactive immunity that may assist in developing immunity to pandemic strains of avian influenza, or may provide help in making antibody responses sooner to avian influenza vaccines once they are dev ....This study will examine cellular immunity to the avian H5 influenza in people who have been previously infected with the currently circulating strains of H1 and H3 influenza, or in those who have been recently vaccinated with current influenza vaccines. This will give us an idea if there is any cross reactive immunity that may assist in developing immunity to pandemic strains of avian influenza, or may provide help in making antibody responses sooner to avian influenza vaccines once they are developed. We will also establish assays to determine how immunogenic some new avian influenza vaccines are in mice.Read moreRead less
Gamma-ray Inactivated Influenza A Virus Vaccine For Cross-protective T Cell Immunity
Funder
National Health and Medical Research Council
Funding Amount
$239,963.00
Summary
Although there are new antiviral drugs that appear to be effective against influenza virus, the far more costeffective and efficient means to combat an influenza pandemic would be by vaccination. Current influenza vaccines employ virus preparations that are inactivated by chemical treatment. The inactivated vaccines, which function mostly by inducing antibody against the virus, have to be reformulated almost every year to take account of the changing virus because the antibodies recognize the vi ....Although there are new antiviral drugs that appear to be effective against influenza virus, the far more costeffective and efficient means to combat an influenza pandemic would be by vaccination. Current influenza vaccines employ virus preparations that are inactivated by chemical treatment. The inactivated vaccines, which function mostly by inducing antibody against the virus, have to be reformulated almost every year to take account of the changing virus because the antibodies recognize the viral surface which is prone to mutation. Accordingly, in terms of the threatening H5N1 avian influenza pandemic, it is not known if an inactivated vaccine based on the circulating H5N1 strain will be effective if the virus mutates to adapt to efficient growth and spread in the human population. In contrast to the antibody response against influenza virus, the cytotoxic T cell response is broadly crossreactive between heterologous influenza virus strains. Live virus infection efficiently induces cytotoxic T cell immunity which plays an important role in reducing disease severity and mortality following infection with a second, heterologous influenza virus, although infection per se is not prevented. Accordingly, vaccination strategies that elicit cytotoxic T cell memory should be given urgent consideration in the preparation against an influenza pandemic. We have found that the use of gamma-irradiation (in contrast to chemical treatment) for the preparation of inactivated experimental vaccines against influenza and other viruses does not destroy the ability of the vaccines to elicit cytotoxic T cell immunity. The gamma-ray inactivated vaccines conferred protection against lethal challenge with heterologous influenza virus strains in mice. This proposal is aimed at extending this novel finding to avian influenza viruses and to uncover the mechanisms involved in the cytotoxic T cell immunogenicity of gamma-ray inactivated vaccines.Read moreRead less
Early Intervention To Prevent Childhood Obesity Among A Disadvantaged Population: A Home-based Randomised Controlled Tri
Funder
National Health and Medical Research Council
Funding Amount
$675,082.00
Summary
This intervention research will conduct a randomised controlled trial, of a community-based early childhood home visiting intervention designed to improve family and behavioural risk factors for childhood obesity and overweight. This intervention which will be developed in collaboration with the Health Promotion Unit, Child and Family Health Nurses, university academic experts and mothers in the community promises to deliver significant health and social benefits, in particular, preventing early ....This intervention research will conduct a randomised controlled trial, of a community-based early childhood home visiting intervention designed to improve family and behavioural risk factors for childhood obesity and overweight. This intervention which will be developed in collaboration with the Health Promotion Unit, Child and Family Health Nurses, university academic experts and mothers in the community promises to deliver significant health and social benefits, in particular, preventing early onset of childhood obesity. It will result in a series of recommendations for policies and practical methods for promoting healthy feeding and physical activity of infants under two years of age with particular application to families who are socially and economically disadvantaged. These policies and practical methods for preventing childhood obesity could be used across Australia.Read moreRead less
Chimeric Virus-like Particles (VLPs) Displaying H1, H3 And H5 Haemagglutinins - Construction And Immunogenicity
Funder
National Health and Medical Research Council
Funding Amount
$207,543.00
Summary
Virus-like particles (VLPs) provoke strong immune responses in the body. We have developed a novel VLP system that allows the production of VLPs containing foreign vaccine antigens of much larger size than previously possible, and have shown that these VLPs provoke strong immune responses in mice without the use of adjuvants. The capacity of these VLPs is large enough to accommodate the most important vaccine antigen of influenza, the haemagglutinin (HA) molecule. We will test whether VLPs can b ....Virus-like particles (VLPs) provoke strong immune responses in the body. We have developed a novel VLP system that allows the production of VLPs containing foreign vaccine antigens of much larger size than previously possible, and have shown that these VLPs provoke strong immune responses in mice without the use of adjuvants. The capacity of these VLPs is large enough to accommodate the most important vaccine antigen of influenza, the haemagglutinin (HA) molecule. We will test whether VLPs can be produced containing each of the three most important HA types _ H1 and H3 that are currently circulating in man, and H5 (avian) that is considered a pandemic threat. VLPs will be tested for their ability to induce neutralizing antibody and cellular immune responses in mice, and for their ability to protect ferrets from influenza infection. If successful, the HA-VLP system would provide a method for the rapid production of new influenza vaccines using large-scale fermentation technology as for hepatitis B and many other vaccines, rather than eggs or cell culture as used for current influenza vaccines.Read moreRead less
Assessment Of Alpha-galactosylceramide As A Novel Adjuvant For Pandemic Influenza: A Virua Vaccine
Funder
National Health and Medical Research Council
Funding Amount
$220,042.00
Summary
The occurrence of human infections with pathogenic avian H5N1 Influenza A viruses was the first documentation of these viruses demonstrating an ability to directly transmit from birds to humans. The virulent nature of these infections, and the fact that there is no pre-existing immunity to these viruses in the human population has raised the concern that these viruses may emerge to cause the next influenza pandemic. Vaccination is our most effective way of protecting against influenza infection, ....The occurrence of human infections with pathogenic avian H5N1 Influenza A viruses was the first documentation of these viruses demonstrating an ability to directly transmit from birds to humans. The virulent nature of these infections, and the fact that there is no pre-existing immunity to these viruses in the human population has raised the concern that these viruses may emerge to cause the next influenza pandemic. Vaccination is our most effective way of protecting against influenza infection, however there are no commercially available avian influenza vaccines available. Moreover, recent evidence suggests current vaccines strategies may be less than effective. This proposal aims to evaluate the efficacy of a novel vaccine strategy that promotes immune protection against a potential pandemic influenza strain.Read moreRead less
They aim to create insulin-secreting B cells by identifying their progenitor cells and the moleculaes normally required for their development, in order to restore B-cell function in the people with type 1 diabetes. Mouse and human multipotent embryonic stem (ES) cells and fetal mouse panceas and adult pancreas duct cells will be used as sources of progenitor B cells. Comparative studies will provide a more complete picture of human B-cell ontogeny. Culture systems developed for ES cells-embryoid ....They aim to create insulin-secreting B cells by identifying their progenitor cells and the moleculaes normally required for their development, in order to restore B-cell function in the people with type 1 diabetes. Mouse and human multipotent embryonic stem (ES) cells and fetal mouse panceas and adult pancreas duct cells will be used as sources of progenitor B cells. Comparative studies will provide a more complete picture of human B-cell ontogeny. Culture systems developed for ES cells-embryoid bodies (EB) - EB-derived cells, fetal pancreas and adult pancreas duct cells, will be employed to screen for and identify novel growth-differentiation factors and to optimise parameters for creating B cells in vitro or (re) generating B cells in vivo. Genetic constructs allowing regulated expression of fluorescently-tagged marker genes and growth-transcription factors will be introduced into cultured cells or transgenic mice to enable progenitor B cells to be tracked and isolated. Progenitor B cells will be typed with panels of known novel markers molecules at the gene and protein level, and gene expression profiles of tissue yielding B cells will be analysed across time to reveal further candidate markers. Molecules and methods effective in mouse systems will be applied to human ES cell-derived or pancreatic duct cells. The capacity to progenitor cells or insulin-secreting cells to ameliorate diabetes when transplanted into the testis, under the kidney capsule or into the pancreas of mouse models would represent proof-of-concept. Functional B cells derived from human ERS cells or pancreas duct cells, or growth factors that regenerate B cells in vivo, could together with appropriate immunotherapy restore B-cell function in people with type 1 diabetes.Read moreRead less
Enhancing Australia's Pandemic Influenza Vaccine Output By Increasing The Yeild Of Vaccine From Eggs
Funder
National Health and Medical Research Council
Funding Amount
$251,517.00
Summary
Influenza epidemics cause significant morbidity and mortality, particularly amongst the young and elderly. Unlike other vaccines, a new flu vaccine formulation needs to be prepared each year from the currently circulating strain. This involves a long process of preparing new seed vaccine stock, which is then tested, manufactured and distributed. The situation is even more complicated by the ability of different influenza strains to reassort with others. An example of current major concern is the ....Influenza epidemics cause significant morbidity and mortality, particularly amongst the young and elderly. Unlike other vaccines, a new flu vaccine formulation needs to be prepared each year from the currently circulating strain. This involves a long process of preparing new seed vaccine stock, which is then tested, manufactured and distributed. The situation is even more complicated by the ability of different influenza strains to reassort with others. An example of current major concern is the possibility of deadly avian flu viruses, such as H5N1, to gain the capacity to directly infect humans by recombining with a human strain and thereby starting a new global pandemic. When the next influenza pandemic occurs, the availability of a vaccine will be of the highest priority and early supply of vaccines will save millions of lives. Since vaccination is the only sustainable defense, we face an urgent need to have the capacity to supply large numbers of vaccine doses of influenza vaccines within a short period of time. Currently, the only way of producing flu vaccines is in eggs. The speed of vaccine supply is totally dependant on the yield of vaccine from eggs and the number of eggs that can be processed at any one time. Since there are severe constraints on the number of eggs that can be simultaneously processed, the limiting factor that can be addressed is the actual yield of vaccine per egg. The aim of this project is the develop methods that allow higher levels of vaccine virus to grow in eggs. We will take a multi-pronged approach to enhancing influenza vaccine production that are directed toward increasing the capacity of eggs to promote virus replication, as well as towards the vaccine strain to boost its ability to replicate in the egg. The outcome will be an enhanced capacity for vaccine manufacturers to quickly and effectively expand vaccine supplies which will directly impact on global morbidity and mortality during a flu pandemic.Read moreRead less