Honours and PhD projects

The immune system in infection and disease

The immune system is central to most disease processes. In its positive form, it protects us from infections by viruses, microbes and parasites and also plays an important role in the suppression of tumor formation. In its negative form, the immune system can mistakenly react against our own body cells, causing autoimmune diseases, or can overreact against foreign antigens causing immunopathology and allergies.  Projects are designed to (1) gain a better understanding of how the immune system works to  fight infection and how we can use this knowledge to make more effective vaccines, and (2) to gain a better understanding of mechanisms causing allergies and asthma and how we can translate this knowledge into better preventative and therapeutic treatments.

The following projects are available for honors, masters or PhD studies. Further projects can be developed in consultation with the supervisors for any areas of particular interest to the student. Please contact the relevant supervisor(s) for further details and application processes.

Project titles:

• Immunity and vaccine development against parasitic diseases
• How do eosinophils kill parasites and cause allergies?
• Immunostimulation of the mammary gland to cure mastitis
• Understanding innate immunity for the development of novel vaccines
• Why are some individuals susceptible to allergies?
• Evaluating new approaches for the treatment of asthma
• Preventing airway plugging in asthma
• Defining the progression to an altered airway smooth muscle phenotype in asthma
• Investigating the effects of intrauterine inflammation on the developing immune system before and after birth
• Effects of antenatal corticosteroids on the fetal immune system.

Project descriptions:

Immunity and vaccine development against parasitic diseases

The immune response to parasites is characterised by the recruitment of eosinophils to sites of infection. Eosinophils are white blood cells containing specific intracellular granules and lipid bodies which, once activated, are capable of releasing a battery of potent cytotoxic and pro-inflammatory agents including peptide, cytokine and lipid mediators. These effector molecules are thought to contribute to the killing of parasites. This project will focus on determining the cells and molecules responsible for creating a killer eosinophil. Identification of these molecules may lead to new ways to protect humans and animals from a range of parasite infections. In addition, as eosinophils are also key mediators of allergic reactions, these studies may discover new targets for therapy and drug development in allergy and asthma. The student will be exposed to a range of cellular and molecular techniques including tissue culture, flow cytometry, confocal microscopy and gene expression analysis.

How do eosinophils kill parasites and cause allergies?

Worm parasites such as the liver flukes, blood flukes and gastrointestinal nematodes infect grazing ruminants, particularly in Asia and Africa, resulting in enormous economic loss to the agricultural sector or subsistence farmers and negatively impacting on efficient food production in developing countries. Some of these parasites also cause significant human disease. At present there are few drugs and no molecular vaccines effective against these parasites.
Knowledge of how parasites and hosts interact will provide us with the information we need to understand disease susceptibility and design better vaccines or drugs to prevent and treat parasitic disease. Our projects are integrated and will study both the genetics and protein biochemistry of parasite molecules involved in pathogenesis as well as host genes and gene products determining host resistance. Students will gain experience in molecular biology, immunology, recombinant protein expression, and vaccine design and development. The Laboratory has a number of international collaborations and frequently hosts visitors from overseas laboratories and Institutes.

Immunostimulation of the mammary gland to cure mastitis

Mastitis is an infection of the mammary gland that affects both lactating and non-lactating mammals, and may be caused by a number of bacterial species. Research in our laboratory indicates that certain cells of the immune system known as dendritic cells play an important role in directing the mammary gland to resist infection. Using cattle and sheep, we have found that specific proteins (cytokines) direct the growth and activation of dendritic cells, as well as their ability to respond to mastitic bacteria. In this project the student will conduct in vitro and in vivo studies that aim to improve the ability of the animal to resist mastitis.

Understanding innate immunity for the development of novel vaccines

The innate immune system detects and responds to many pathogenic invaders as a first line of defence.  Following detection of pathogens, the innate immune system activates and instructs the "flexible" adaptive immune system to respond in a more specific manner.  Accurate stimulation of the innate immune system is therefore of critical importance for developing vaccines that attempt to mimick a natural immune response.  We are studying how new classes of immune stimulators or adjuvants activate the innate immune system. We use unique procedures to harvest dendritic cells from sheep lymphatic vessels and then measure activation using state of the art molecular biological techniques (microarrays, real time PCR) coupled with cell biology and flow cytometry assays. We have projects available to investigate the innate responses to adjuvants, allergens and bacteria.  These projects are aimed at developing an understanding of fundamental pathways involved in shaping the immune system, with implications for vaccine development and treatment of diseases such as allergies and asthma.

Why are some individuals susceptible to allergies?

A proportion of humans are prone to develop allergic reactions to innocuous environmental antigens (allergens), while others do not. We have replicated this variability in responsiveness to allergens in a standardised animal model which also allows detailed examination of the earliest, innate events active in allergen sensitisation.  Using state of the art molecular biological techniques (microarrays, real time PCR) coupled with cell biology and flow cytometry assays we will gain insights into the earliest molecular pathways responsible for allergen reactivity in predisposed individuals. These studies may offer new approaches for allergy vaccines and therapies.
Collaborators: Prof. Robyn O'Hehir and A/Prof. Jenny Roland

Evaluating new approaches for the treatment of asthma

Asthma affects over 2 million Australians with 300 deaths each year. Current treatments are not very specific and have significant side effects with prolonged use. We have developed a novel sheep model of allergic asthma that displays many similarities with human allergic asthma and serves as a valuable tool to study the complex mechanisms underlying the disease. Several projects will be on offer, with work in vitro and in vivo employing a range of cellular, immunological and biochemical/molecular techniques (cell and tissue culture, immunochemistry, ELISA, FACS, protein chemistry, RT-PCR, gene therapy).  The student will gain an in-depth understanding of immunological and physiological interactions, and will be exposed to aspects of drug discovery and biotechnology.
Collaborators: Dr. Ken Snibson, Melbourne University

Preventing airway plugging in asthma

Mucus plugging of airways is a major cause of fatal asthma attacks in both adults and children, and is due to the abnormal viscosity and adhesiveness of asthmatic mucus. We have discovered a novel molecule that is secreted into the airway mucus of sheep sensitized to the major human allergen, house dust mite. We hypothesize that this molecule may be responsible for changing the properties of airway mucus and for its increased viscosity and adhesiveness. Using specific inhibitors of this molecule, we will examine its effect on airway mucus both in vitro and in vivo using our recently developed sheep asthma model. These studies may result in a new treatment for severe asthma.

Defining the progression to an altered airway smooth muscle phenotype in asthma

Current drugs are poorly effective at limiting the airway smooth muscle thickening that is associated with deteriorating asthma. Studies to elucidate the onset and critical pathways for the progression of altered muscle properties can only be performed in a relevant animal model amenable to repeated tissue sampling during life. Using our newly developed sheep asthma model, several projects are available to define the progression of airway smooth muscle (ASM) changes in asthma to identify new ways to treat asthma by (1) determining the kinetics of change in ASM proliferative and synthetic properties following chronic airway allergen exposures, (2) correlating altered ASM cell function in vitro with other indices of airway remodelling and lung function decline in vivo; (3) establishing whether airway tissue remodelling, and ASM phenotypic changes in particular, can be reversed or halted with early introduction of targeted anti-asthma therapy.

Investigating the effects of intrauterine inflammation on the developing immune system before and after birth.

Exposure to infection or inflammation before birth is a common complication of human pregnancy, and can be life-threatening for the fetus or newborn. In addition, exposure to inflammation before birth can have an effect on the developing immune system that may lead to decreased capacity to fight infection or increase susceptibility to allergic and autoimmune diseases in later life. The fetal thymus is the organ responsible for maturation of T cells before birth and its development is likely to be affected by exposure to intrauterine inflammation.
The aim of this project is to determine the effects of exposure to intrauterine inflammation, induced by amniotic fluid injection of lipopolysaccharide, on lymphocyte development and maturation in the fetal thymus of sheep.

Effects of antenatal corticosteroids on the fetal immune system.

Women at risk of preterm birth routinely receive injections of synthetic glucocorticoids to induce fetal maturation. In addition to being critical regulators of prenatal development, glucocorticoids are also potent inhibitors of inflammation. However, the effects of exposure to glucocorticoids on the developing immune system are poorly defined.
The aim of this project is to make serial measurements of cellular immune function in fetal sheep, after exposure to maternal glucocorticoid injection.