Current Research Projects

Understanding the molecular control of dendritic cell function in tolerance

This project focuses on the function of the transcription factor RelB in the induction of tolerance by dendritic cells (DCs). Activity of the RelB subunit of NF-kappa B underlies the capacity of DCs to stimulate T cells after microbial signalling. Inhibition of RelB expression or function in DCs blocks their T cell stimulatory capacity. When antigen-exposed and adoptively transferred, these DCs induce antigen-specific regulatory T cells which suppress inflammatory disease in recipient mice. In this project we are defining the unique properties of RelB^lo DCs in migration, survival, interaction with effector cells, and generation of regulatory cells. RelB deficient mice develop spontaneous multi-organ autoimmune disease. We are identifying environmental factors which impact on RelB expression or function, and which therefore impact on maintenance of tolerance and predisposition to autoimmune disease.

Figure 1:  Uptake of liposomes by peritoneal macrophages and B-cells.

Pathogenesis of Rheumatoid Arthritis

In Humans: A variety of proteins become citrullinated in diseased joints. Citrullination is a physiological process of arginine deimination that occurs during apoptosis and inflammation. This process results in post-translational modification of arginine-containing proteins, which can give rise to sets of neo-self antigens in individuals bearing HLA susceptibility alleles which put them at risk of rheumatoid arthritis (RA). Citrullinated proteins have been demonstrated in inflamed tissues in RA, and at least two mouse models of inflammatory arthritis. Citrulline-specific autoantibodies are highly specific for RA and are associated with more severe joint damage and radiographic outcome. In this project, we are measuring peripheral blood T cell responses to citrullinated or unmodified native peptides derived from RA-autoantigens based on their predicted binding to disease-associated HLA-DR molecules. Measurement of these responses may be useful as a biomarker in RA patients and individuals at risk of disease. Moreover, these auto-reactive T cells may be future targets of antigen-specific immunotherapy in RA.

In Mice: Self-reactive T cells with a low signalling capacity through the T cell receptor have been observed in the SKG mouse model of rheumatoid arthritis, and have been linked to a spontaneous mutation in the ZAP-70 signal transduction molecule. In this project we are studying the role that antigen presenting dendritic cells play in the development of arthritis in this model, and whether dendritic cell immunotherapy can be used to treat arthritic mice.

Rheumatoid Arthritis Vaccine

Based on our discovery that RelB^lo dendritic cells induce antigen-specific tolerance, we have developed an autologous modified dendritic cell vaccine for testing in a phase I clinical trial in patients with rheumatoid arthritis (RA), known as Rheumavax. The vaccine consists of dendritic cells, grown in the laboratory from the blood of the patient to be immunised, and antigen relevant to the disease. Approximately 70% of patients with RA test positive to autoantibodies known as anti-CCP. These antibodies react against a component of proteins known as citrulline. RA patients who test positive to anti-CCP show evidence that their T lymphocytes respond abnormally to citrulline. We have formulated the vaccine to subdue T cells with citrulline reactivity in RA. Success in this trial would provide impetus to adapt the technology to other autoimmune diseases.

In mouse studies, we are analysing the survival and migration of injected dendritic cells in this vaccine to the lymph glands in models of rheumatoid arthritis and of type 1 diabetes. We formulated a cell-free technology deriving from this vaccine as microparticles. The microparticles contain a natural inhibitor, known as curcumin (from the spice turmeric), deliver antigen, and are taken up by dendritic cells in the lymph glands. They are a versatile platform technology, which can deliver different antigens or inhibitors.

If you are interested in further information on the RA vaccine trial, please email Helen Pahau at h.pahau"at" uq.edu.au or phone 07 3240 2170.

Type 1 (Juvenile) Diabetes

In Humans: We have developed a new diagnostic assay which identifies individuals with Type 1 diabetes (T1DM) and some of their relatives at risk of diabetes. Exposure of blood monocytes to the bacterial product lipopolysaccaharide led to an abnormally low level of activation of the protein, RelB. We are now extending these studies to determine the value of the assay for predicting whether otherwise healthy siblings of children with T1DM will develop diabetes in the future. This would allow us to identify those at risk from the so that they could be treated earlier or encouraged to make preventative changes to their lifestyle. We are studying a large cohort of families, drawn from an existing diabetes research project. We are looking at progression to autoantibody production, T1DM, and other autoimmune diseases, in otherwise healthy siblings with abnormal RelB response, as detected using our assay. The aim of the longitudinal study is to determine the sensitivity and specificity for predicting T1DM or possibly a predisposition to autoimmune disease, associated with cut-off points in the test– rather like a bone density test for predicting fractures.

If you have type 1 (juvenile) diabetes or your family has a member with the disease and you would like to participate in a study of a new blood test, please email Helen Pahau at h.pahau"at" uq.edu.au or phone 07 3240 2170.

In Mice: We have several models of spontaneous autoimmune disease of the pancreatic islets including NOD mice and RelB-deficient mice. We are testing the interaction of two innate immune factors – interleukin-1 and NF-kB activity on the development of adaptive autoimmunity. We are examining triggers for the excessive production of IL-1 in NOD mice, and how this production impacts on response to tolerising dendritic cell immunotherapy. We are particularly interested in the impact of autoimmunity in NOD and RelB-deficient mice on regulatory T cell numbers and function.

Figure 2: Mouse islet (red) with early inflammation, with infiltration by helper T cells (green).

A randomised, controlled double blind study to evaluate the effects of simvastatin in reducing atherosclerosis in early rheumatoid arthritis

The aims of this study are to examine the effectiveness of cholesterol-lowering medicine in atherosclerotic disease progression in rheumatoid arthritis. Patients with rheumatoid arthritis symptoms beginning within the past 12 months, and who have no history of cardiovascular or cerebrovascular disease are eligible. Sensitive ultrasound measures of the arteries, and blood tests are taken before and after treatment to assess the progression of disease. Patients are randomly allocated to receive cholesterol-lowering therapy with either simvastatin or no active substance (placebo) for 2 years. Ultrasound and blood measurements are taken yearly to assess progression of arthritis and atherosclerosis.

If you have recently been diagnosed with rheumatoid arthritis  and you would like to participate in this trial, please email Helen Pahau at h.pahau"at" uq.edu.au or phone 07 3240 2170.

Figure 3: High resolution imaging and automated measurement of IMT in the distal common carotid artery.

Professor Thomas is currently offering postgraduate projects in her laboratory. Click here for more information.