Study level

  • Master of Philosophy
  • Honours

Faculty/School

Faculty of Health

School of Biomedical Sciences

Topic status

We're looking for students to study this topic.

Research centre

Supervisors

Dr Stephen Daley
Position
Senior Lecturer in Immunology
Division / Faculty
Faculty of Health
Professor Tony Kenna
Position
Professor
Division / Faculty
Faculty of Health

External supervisors

  • Dr Siok Tey (QIMR)

Overview

Autoimmune diseases affect approximately 5% of Australians. Well known examples include type I diabetes, multiple sclerosis and rheumatoid arthritis. These diseases have unpleasant, and sometimes tragic, consequences for the affected person and are a costly burden on our health system. As treatment is often limited to managing symptoms, new therapies for autoimmune diseases are much desired.

Many autoimmune diseases are tightly associated with inheritance of a particular allele at the major histocompatibility complex (MHC, also called human leucocyte antigen or HLA). MHC genes encode cell-surface proteins that present antigens to T cells. The main antigens presented by MHC molecules are peptides derived from the incomplete breakdown of proteins. The current paradigm is that autoimmune diseases are mediated by pro-inflammatory T cells that co-recognise self-peptides presented by disease-associated MHC alleles. There is no reason to doubt this concept, but many people who have disease-associated MHC alleles do not develop autoimmune disease, implying that progression to disease requires some additional trigger(s).  Recent research showed that an “upstream” step in pathogenesis is a defect in antigen-specific FOXP3+ T-regulatory cells (Treg) that would otherwise prevent autoimmune disease [Ooi et al., Nature. 2017 May 11;545(7653):243-247].

Treg prevent autoimmune disease in nature but their therapeutic potential has yet to be harnessed. In this project, we will engineer T cell receptor-modified Treg (TCR-Treg) specific for a self-peptide autoantigen presented by an autoimmunity-prone human MHC molecule. We will also create high-affinity TCR-Treg using a confidential approach. The effects of conventional and high-affinity TCR-Treg therapy will be tested in vitro (Honours) and in vivo (Masters or PhD) in a humanised mouse model of Goodpasture disease, an autoimmune disease that affects the kidney (Ooi et al., ibid).

Approaches/skills and techniques

  • Transformation of plasmids into bacteria.
  • Transduction of plasmids into mammalian cells.
  • Retroviral transduction of mouse cells.
  • Tissue culture.
  • Flow cytometry and single-cell sorting.
  • DNA sequence analysis.
  • Handling, anaesthesia and immunisation of mice.
  • Data management and presentation.
  • Statistical analysis.
  • Written and oral communication skills.

Outcomes

We will obtain preclinical data on the efficacy of TCR-Treg therapy in Goodpasture disease and on whether TCR-Treg self-affinity affects the outcome of therapy.

Keywords

Contact

Contact Dr Stephen Daley for more information.