Institute for Immunology and Allergy Research

The Institute for Immunology and Allergy Research (IIAR) was established to advance basic and clinical research in the fields of immunology and allergy.

Researchers are investigating the cellular and genetic basis for major diseases of the immune system, autoimmunity, immune deficiency, chronic viral infection and atopy, especially by dissecting the immunologic genes of the human genome and studying effects of genetic variation on immune function.

The Institute is also working on finding the genes responsible for autoimmune disease including:

• Multiple sclerosis
• diabetes and other allergic disease
• HIV and how genes influence the infection
• allergic disease and eh role of immune cells

We are also studying the molecular signals within T-cells in normal function and disease.

Clinical Professor Graeme Stewart is the founding head of the Department of Clinical Immunology and Allergy at Westmead Hospital and founding Director of the Institute for Immunology and Allergy Research (IIAR).

 

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Research Groups

The Centre has the following Research Groups.

Genetics of Multiple Sclerosis Research Group

Multiple sclerosis is the most common neurological disease in young adults, with millions affected world-wide, and many thousands in Australia. It is largely a genetic disease, and we expect that by finding the genes which cause MS susceptibility and affect its progression we will be able (by looking at the function of the genetic variants associated with disease) to determine the processes important in disease development. These processes could then be the targets for new drugs, provide tools for better patient management, and predict who will respond to which therapies. Our aims are to:

• discover Genes which affect MS susceptibility and progression.

• determine functional significance of SNPs associated with MS.

• devise therapeutic strategies based on genetic associations.

• develop patents associated with therapeutic strategies.

• improve patient management through development of techniques for analysis of drug response, using proteomics and genomics.

• provide a service to measure development of neutralising antibodies (NABs) to protein drugs for multiple sclerosis.

Molecular Genetics of Asthma and Atopic Dermatitis

Most asthmatics are allergic. This means they are highly sensitive to pollens, grasses, house dust mites, pet hair and so on. Collectively, these irritants are known as allergens. Allergy is due to cells of the immune system responding inappropriately to common allergens, triggering an asthma attack. Of course, in addition to the role of the immune system there are also important changes in the airways of asthmatics when compared to non-asthmatic individuals. However, the focus of our research is on the role of the immune system in allergic disorders.

It is well known that allergies can afflict several generations of a single family. This means there must exist a number of genes that are important in the development of allergy. Identifying the genes that are important in controlling the immune response in allergic individuals and understanding how these genes function is the cornerstone of our research program. To do this we study allergy in young children, in particular children with severe dermatitis. We have chosen dermatitis because it appears at a very early age and changes in the immune system associated with dermatitis are very similar to those occurring in asthma.

Using this group of children and their families we have identified several genes that regulate the activity of T-cells, a key cell in the immune response. Small genetic changes in these genes are more common in allergic children than in non-allergic children and we have evidence that these genetic changes affect the way a gene works.

The challenge facing scientists interested in understanding the genetics of allergy is to identify all the genes involved in asthma and other allergic disorders and to catalogue the number and function of genetic changes in these genes that could increase the risk of developing these disorders. In the future this will lead to new diagnostic tools for the earlier treatment of allergy and to the development of new therapies. To achieve all this we need the continued support of families with asthma or dermatitis to continue to expand our DNA database to help find the genetic basis of asthma and allergy.

Click here to hear Dr Graham Jones talk about Asthma and Dermatitis (FLV, 1,169Kb).

 

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Immunobiology and Apoptosis Research Group

The Immunobiology and Apoptosis Research group is working to elucidate the mechanisms by which cell death molecules control lymphocyte survival and cell death within the immune system and during virus infection. The immune system has an amazing capacity to continually produce millions of immune cells (specialized white blood cells called lymphocytes) within the body, every single day. In order to control the absolute number of these cells, molecules that induce cell death must constantly be at work. These "death molecules" (including cytokines Tumour Necrosis Factor (TNFα), TNFα-related apoptosis inducing ligand (TRAIL) and Fas ligand) act by binding to so-called "death-receptor" proteins that transmit a signal for the cell to die. However, these processes must be tightly regulated in order to avoid an imbalance – too much cell death or too little cell death. Too little cell death leads to increased numbers of lymphocytes, auto-immune disease, or an inability to dampen an immune response after an infection has been cleared. In contrast, too much cell death can result in organ failure.

The two main themes of our research are:

1. define the roles of death-inducing cytokines in the immune system and immune system disorders,
2. elucidate the mechanisms by which viruses utilize death cytokines and receptors, and/or inhibit their function.

To define the role of death cytokines in vivo, we are using mouse models in which specific death-genes are "knocked-out" or made non-functional. Using this approach we have demonstrated that cell death molecules TRAIL and Fas Ligand are absolutely essential for the normal maintenance of lymphocyte numbers in the immune system, because without these molecules, mice develop a severe lympho-proliferative and autoimmune diseases. This knowledge provides a better understanding of lymphocyte survival and function in vivo, and immune system mechanisms that guard against auto-immune diseases. In other words, our research seeks to identify the ways by which self-reactive lymphocytes develop in the first place and the processes that allow their survival and persistence in vivo. As such, we seek to identify the causes of lymphoproliferative and autoimmune diseases, not just ways to treat them.

More specifically, evidence has recently emerged suggesting that TRAIL is important in Multiple Sclerosis (MS). Indeed, high levels of serum TRAIL appear to define a favourable response to Interferon-β treatment in MS patients. Exactly what TRAIL does in MS disease is not yet clear, but we are seeking to understand the benefits and/or consequences of TRAIL protein expression in MS patients and normal individuals.

We are also studying how viruses evade death pathways. Poxviruses have captured TNFα receptor genes from the cells they infect, and incorporated them into their own genome, in order to specifically regulate the cell death process to their own advantage. By expressing a "decoy" death-receptor the virus protects itself from cell death and keeps the cell alive for long enough to enable the virus to replicate and spread within the infected host. Through this research we have identified a novel mechanism of viral subversion of cellular TNF receptor function, which has identified a region within viral and cellular TNF receptor proteins that is absolutely required for TNF-R function. One of the current most effective drugs used today in the treatment of Rheumatoid Arthritis is in fact a recombinant TNF receptor protein. Our discovery is likely to contribute to the development of the next-generation of TNF Receptor-based drugs for human inflammatory diseases, with potentially fewer side effects and greater efficacy. This discovery may also have therapeutic potential in human poxvirus infection, by limiting viral replication and dissemination in vivo.