1. School of Paediatrics and Child Health Princess Margaret Hospital for Children ● The School of Paediatrics and Child Health (SPACH) is based at Princess Margaret Hospital  75 staff members (clinical and postdoctoral academic staff, professional research staff and administrative staff)  50 PhD and Masters students  7 Honours students ● We collaborate closely with researchers at both PMH and the Telethon Institute for Child Health Research (TICHR)  Students conducting projects with supervisors at PMH and TICHR are often enrolled with SPACH

2. OVERVIEW OF SPECIFIC RESEARCH CONTRIBUTIONS TO THE FIELD: The CAIR research programme focuses on the processes that influence the developing human immune system, particularly processes which predispose to allergic diseases and asthma in early childhood. With strong clinical and laboratory activities the group has been ideally placed to investigate to underlying immunological mechanisms, and to also examine clinically relevant applications and practical solutions. This includes a number of clinical intervention studies for the prevention of allergic diseases. Key activities and discoveries have been in the following areas: 1. Defining patterns of perinatal immunity that predispose to immune dysfunction Since the publication by Lancet of Prof Prescott’s (still highly cited) landmark studies on early immune development 1, 2 there has been enormous ongoing interest in how early immune dysregulation leads to the development of disease, particularly allergic disease. These publications made a major and significant contribution to the field and the current disease paradigm. More recently we have just demonstrated novel difference in the innate immune development 3. There are a number of ongoing projects which are extending these findings to investigate the underlying molecular mechanisms, and to this end we have recently defined novel differences in T cell signalling (PKC zeta expression) in children that go on to develop allergic disease (below) 4. We have also initiated microarray studies (not yet complete) to study the patterns of gene expression during the first 5 years of life in allergic and nonallergic children. Primarily, this is likely to lead to a better understanding of disease pathogenesis, and could ultimately provide novel molecular targets for future prevention strategies. 2. Identifying better early markers of allergic disease. This is becoming more critical as more effective allergy prevention strategies (such as primary allergen immunotherapy) are being developed. For the first time, the team has recently discovered that the ‘fingerprint’ pattern of neonatal T cell PKC isozyme expression significantly predicts subsequent allergic disease 4, and that the predictive effect was stronger than any other biological marker (including Th1 IFNg responses). Moreover, we have demonstrated that an intervention designed to prevent allergic disease (maternal dietary supplementation with fish oil) significantly modified the expression of the same neonatal PKC pathway4. With epidemic rates of allergic disease this highly original finding addresses several key issues that are central to reducing the burden of disease through prevention. Firstly, it provides a potential avenue for more accurate prediction of disease. Secondly, as our preliminary data suggests, this could also be used to monitor the effect of interventions aimed at reducing allergic disease. Thirdly, exploring the role of this key intracellular signalling molecule could lead to a better understanding of disease pathogenesis, and fourthly this could ultimately provide a novel molecular target for future prevention strategies. Finally, understanding these aspects of early T cell development are also highly relevant to other important issues in early life such as susceptibility to infection, vaccine responsiveness and autoimmune propensity. This emphasizes the wide-ranging potential significance further studies planned in this area. 3. Identifying early influences that may promote or protect from allergic disease. Another key area of CAIR research has been in defining early influences in that may predispose or help prevent the development of asthma and allergic diseases. This includes a number of diverse projects including novel studies into the clinical immunologic effects of supplementation with probiotic bacterial 5-8 and omega-3 polyunsaturated fatty acids 9, 10 in very early life. We are also currently investigating the influence of antioxidant status on early immune development (in progress). The CAIR team have also investigated the potential effects of environmental pollutants on immune development, including novel exploratory studies on persistent organic pollutants (such as pesticides) 11, and novel studies on maternal smoking in pregnancy which have shown effects on key microbial recognition receptors (toll like receptors) 12. We are now exploring the role of early allergen exposure 13 (early feeding to induce tolerance) in a recently NHMRC funded ($2.2 million 2010-2013) DB-RCT in collaboration with Adelaide. Finally, we have provided evidence that interactions at the maternofetal interactions during pregnancy also have the potential to influence early fetal immune development 14. Our research in the area is ongoing with further important publications anticipated in the next 12 months. New directions: exploring epigenetic mechanisms in the Developmental Origins of Allergic Disease: We have just received new NHMRC funding (2010-2013) to explore how epigenetic modifications15 influence patterns of early gene expression and susceptibility to disease. This will help identify pathways through which environmental pressures are likely to be driving the epidemic rise in allergic disease. This novel study will identify genes differentially expressed during early development in relation to subsequent allergy (using whole genome microarray), and examine epigenetic regulation of these candidate pathways in relation to in utero influences. This study is as the cutting edge of research into allergy pathogenesis and directly addresses the recent call for human studies in this new field. University of Western Australia School of Paediatrics and Child Health W/Prof Susan Prescott A/Prof Meri Tulic

3. School of Paediatrics and Child Health Princess Margaret Hospital for Children VACCINE IMMUNOLOGY Assoc Prof Peter Richmond, Dr Andrew Currie, Dr Lea-Ann Kirkham and Dr Selma Wiertsema Immunological mechanisms involved in childhood vaccination Vaccine development Licensure of vaccine Policy & implementation Basic research: immunology, microbiology Clinical trials Surveillance and Epidemiology

4. School of Paediatrics and Child Health Princess Margaret Hospital for Children Paediatric Respiratory Research W/Prof Peter Le Souef Ingrid Laing Catherine Hayden Brad Zhang Immunogenetics of asthma, infectious disease and evolution of the immune system

5. School of Paediatrics and Child Health Princess Margaret Hospital for Children Paediatric Respiratory Research W/Prof Peter Le Souef Ingrid Laing Catherine Hayden Brad Zhang Immunogenetics of asthma, infectious disease and evolution of the immune system PAEDIATRIC RESPIRATORY RESEARCH Clin Prof Stephen Stick, Assoc Prof Graham Hall & Assoc Prof Peter Franklin Asthma and Cystic Fibrosis research Measurements of lung function and disease progression Environmental studies Bronchial epithelial cell cultures Therapeutic clinical trials

6. School of Paediatrics and Child Health Princess Margaret Hospital for Children Paediatric Respiratory Research W/Prof Peter Le Souef Ingrid Laing Catherine Hayden Brad Zhang Immunogenetics of asthma, infectious disease and evolution of the immune system PAEDIATRIC RESPIRATORY RESEARCH Clin Prof Stephen Stick, Assoc Prof Graham Hall & Assoc Prof Peter Franklin Asthma and Cystic Fibrosis research Measurements of lung function and disease progression Environmental studies Bronchial epithelial cell cultures Therapeutic clinical trials AEROSOL RESEARCH GROUP Assoc Prof Sunalene Devadason Effectiveness of therapeutic inhalers for children Development of new paediatric inhaler devices Effects of inhaled pollutants

7. School of Paediatrics and Child Health Princess Margaret Hospital for Children

8. School of Paediatrics and Child Health Princess Margaret Hospital for Children CHILDHOOD DIABETES AND OBESITY Clin Prof Tim Jones & Dr Liz Davis Epidemiology of Type 1 diabetes (T1DM) and hypoglycaemia in T1DM Studies into childhood obesity, insulin resistance and progression to Type 2 diabetes Research includes longitudinal observational studies, clinical assessments such as exercise tests, hypoglycaemic clamps and microvascular function, as well as cellular and genetic studies

9. School of Paediatrics and Child Health Princess Margaret Hospital for Children CHILDREN’S ONCOLOGY GROUP W/Prof Cathy Cole Phase II and II therapeutic clinical trials Lab-based mechanistic studies DEVELOPMENTAL NEUROSCIENCE GROUP Assoc Prof Jonathan Foster Profiling of hypothalamic-pituitary-adrenal (HPA) axis function in adolescents HPA axis function as a predictor of cognitive development Teaching and Learning Research Assoc Prof Pam Nicol Investigating the effectiveness of different teaching and learning techniques Teaching of paediatric cardiac auscultation skills Scenario based integrated resuscitation learning