BIOLOGICAL SCIENCES

INFLAMMATION AND IMMUNOLOGY UNIT

The unit’s research is focused on i) inflammatory mediators (the kallikrein-kinin cascade, prostaglandins, leukotrienes) and immune modulation of dendritic cells, ii) Kallikreins (serine proteases), Kinin B1 and B2 receptors and Neuropetide Y and its receptors in lung cancer iii) Joint research with the Genetics Unit of the Institute on the Kinin B1 and B2 receptors.

Current Research Programmes

Inflammation

Asthma

Asthma, with a rising prevalence that is greater 10% of the Australian adult population, causes considerable morbidity and mortality. Asthma is characterised by the migration of inflammatory and immune cells (eosinophils, neutrophils and dendritic cells) to and from the lung. It has long been recognised that eosinophils and neutrophils are important effector cells in the airway inflammation observed in many asthmatic patients. Allergic asthma is considered to be a T-lymphocyte-mediated disorder, characterised by airway inflammation, bronchial hyper-responsiveness and eosinophilia. A wide variety of mediators, including major basic protein (MBP) and cysteinyl leukotrienes (cysLT) which cause lung tissue damage are synthesize and released by eosinophils. The kallikrein-kinin cascade is one of the most important inflammatory pathways in the lung. The pathophysiology of asthma is linked multiple cellular mediators, namely kinins, prostaglandins and leukotrienes.

The unit’s projects are focused on inflammatory and immune cells, and the regulatory enzymes, mediators and receptors that may be important in the asthma and chronic obstructive lung disease (COPD). Current and recent studies have examined the expression of kinin receptors on eosinophils and dendritic cells and the functional effects of kinins on eosinophil and dendritic cells. Other projects include assessment of leukotrienes and prostaglandins in urine and induced sputum of asthmatic patients with different phenotypes and severity of disease, expression of prostaglandin, leukotriene and kinin receptors on dendritic cells and their role in the modulation of dendritic cell function in asthma.

Cancer: An additional interest is the role of the kallikrein-kinin cascade and neuropetide Y in carcinogenesis, in particular lung cancer. Projects have been designed to determine the cellular expression of the proteins of the kallikrein-kinin cascade and neuropeptide Y and its receptors, and signal transduction and molecular apoptosis pathways involved in the activation of kinin receptors on lung carcinoma cells.

Immunology

Dendritic cells

Dendritic cells (DC) are the most efficient antigen-presenting cells and crucial players in the initiation of immune responses. In the respiratory tract, DC play a major role in balancing immunity and tolerance. In inflammatory disease such as asthma, DC function is deregulated and contribute to a changes in the balance of T cell response. Our research investigates the activation of DC by pro-inflammatory mediators such as kinins. This research may offer the potential for discovering new and novel target for inflammatory diseases. Furthermore, to understand the pathways involved in the induction and maintenance of respiratory tolerance to pathogens/allergens we are investigating the molecular mechanisms underlying Transforming growth factor β1-induced suppression of DCs.

Neuropeptides

There is increasing evidence of an association and interdependence between the immune and nervous systems. Along with the endocrine system, the immune and nervous systems are responsible for the regulation of homeostasis within the body. Using neurones and DC immunostaining, anatomical connections between DC and nerve fibres have been documented. Neuropeptides have been shown to influence DC priming abilities and, as such, are considered to play a role in inflammation and have capacity to modulate immune responses. In particular, they can influence DC maturation, modulate the function of mature DC, arrest them at inflammatory sites and act as strong chemoattractants for immature DC. Substance P (SP) stimulates the immune cells (macrophages, lymphocytes) to produce inflammatory cytokines IL-1, IL-6, IL-12, TNF and chemokines. Not only are these neuropeptides released from nerve terminals, but recent evidence suggests that DC can produce them as well. DC also express -Synuclein, a small neuroprotein, initially considered to be a neurospecific protein. A number of possible functions have been described for -synuclein. We recently found that -Synuclein increases the migration of DC.

Contract Research

1. The effects of Port Hedland crustal dust on lung cell biology.
This project is comparing the cellular activation caused by dust from Port Hedland, urban or non-urban coastal regions on airway epithelial cells, macrophages, dendritic cells and lung fibroblasts. IL-6, IL-8, IL-10, IL-12 mRNA and protein expression, as well as nitric oxide production, iNOS mRNA, ERK phosphorylation, LDH release and DNA damage will be assessed following in vitro exposure of the different cell types to a range of concentrations of dust from the various locations.

2. Measurement of biomarkers during allergen exposure in subjects with allergic rhinitis.
This project is investigating changes in nasal and systemic biomarkers following allergen challenge of patients with allergic rhinitis. Prostaglandin D2, 9-prostaglandin F2 and histamine are measured in nasal secretions, and 9-prostaglandin F2 and histamine are measured in blood at various times after intra-nasal allergen challenge in subjects with seasonal allergic rhinitis.

Potential PhD projects

1. Expression and mitogenic role of kinin B1 and B2 receptors in human lung and pleural
Cell lines: Gprotein linked signal transduction and effect of kinin receptor antagonists
2. Regulation of apoptotic pathways in mesothelial cell lines by dimeric kinin antagonists
3. Expression of the kallikrein proteases and kinin receptors in circulating and sputum
leukocytes of patients with cystic fibrosis
4. Interactions between kinins, prostaglandins and leukotrienes in the modulation
of dendritic cell function in asthma
5. DC migration require expression of kinin receptors
6. The role of the substance-P in the immunology of human dendritic cells

Supervisor: 1, 2, 3, 4 Prof Kanti Bhoola and Dr Niel Misso; 5, 6 Dr Mirjana Fogel-Perovic

Potential Honours Projects

1 Expression of prostaglandin and leukotriene pathway enzymes and receptors,
and interactions with kinins in dendritic cells of asthmatic patients
2. Effects of des-Arg9-bradykinin on migration of mature DC
3. Analysis of functional correlation between signalling pathways of
transforming growth factor B1 and kinin receptors

Supervisor: 1 Dr Niel Misso; 2 and 3 Dr Mirjana Fogel-Perovic

Potential Cadetship projects

1. Expression of the extended members of the kallikrein family (hK2-hK15)
in human carcinomas of the lung and pleura

Supervisor: 1 Prof Kanti Bhoola,