Immunology

Cytokines contribute to the pathogenesis of T1D by upregulation of genes that activate immune cells, attract cells to the islets and prime beta cells for immune-mediated dysfunction and death. Many cytokines, acting through their receptors, cause the activation of receptor-associated Janus kinases (JAKs). Several JAK inhibitors are approved or in development for autoimmune diseases but have not yet been tested in T1D. Large clinical trials in rheumatological diseases have shown that the class of drugs is effective and well-tolerated. We have successfully employed JAK inhibitors to reverse established autoimmunity in NOD mice. JAK inhibitor exposure leads to down regulation of MHC class I on beta cells, prevention of beta-cell loss and reduced insulitis and diabetes. Thus, JAK inhibitors can act on T cells and beta cells making them highly attractive for T1D.

We have commenced a randomised, multicentre, double-blind, phase 2 clinical trial to test the JAK inhibitor baricitinib in participants who have been recently diagnosed with T1D. The aim is to slow the progressive, immune-mediated loss of beta-cell mass and function that occurs after clinical presentation. Success of this trial will meet an unmet patient need for immune intervention at the time of diagnosis.

Group Leaders: Prof Tom Kay and Prof Helen Thomas

Team Members: Dr Michaela Waibel, Dr Michell So, Dr Bala Krishnamurthy, A/Prof Stuart Mannering

Collaborators: A/Prof John Wentworth, Prof Fergus Cameron, Prof Richard MacIsaac, Prof Jenny Couper

Islet-specific CD8⁺ T cells expand just before diagnosis of diabetes and their quantity reflects the extent of pathology. However, how T-cell proliferation is regulated during spontaneous progression to T1D is poorly understood. Insight into this would provide valuable prognostic information in individuals at risk of developing T1D. We are studying mechanisms that regulate the number and effector function of antigen-specific CD8⁺ T cells close to diagnosis of diabetes. These include programmed death-1 and cytokine signalling pathways. We will cross reference mouse studies with those in human subjects who have developed T1D after checkpoint inhibitor therapy. We will also test therapeutic agents that target these pathways. Our preliminary data have revealed new insight into the action of inflammatory factors at the site of pathology that inhibit T-cell expansion and therefore control progression of type 1 diabetes.

Group leaders: Prof Tom Kay, Dr Bala Krishnamurthy

Team members: Prof Helen Thomas, Dr Gaurang Jhala, Dr Prerak Trivedi, Dr Tingting Ge, Evan Pappas, David de George

Identification of immune pathways that are critical for the autoimmune destruction of pancreatic islets in type 1 diabetes is likely to provide novel opportunities for therapeutic intervention to prevent or reverse type 1 diabetes in human patients. Type 17 immune responses are important pathogenic regulators in numerous autoimmune diseases such as multiple sclerosis, psoriasis and rheumatoid arthritis however their roles in type 1 diabetes are understudied to date. This project seeks to define the roles of key type 17 associated immune molecules such as IL-17, IL-23 and RORgt in preclinical models of type 1 diabetes and to test their therapeutic potential using inhibitors of these pathways.

Group Leaders: Dr Andrew Sutherland, Prof Tom Kay
Team Members: Mr Sangjong Yu, Ms Ashley Nowland, Mr Yohan Fernandopulle, Ms Stacey Fynch

Although immune interventions have shown great promise in type 1 diabetes mellitus (T1D) clinical trials, none are yet in routine clinical use or able to achieve insulin independence in patients. Also, the principles of T1D treatment remain essentially unchanged since the isolation of insulin, almost a century ago. Therapies that target beta-cell antigen-specific T cells are needed to prevent T1D. CD8+ T-cell exhaustion is an emerging area of research in chronic infection, cancer immunotherapy, and more recently, autoimmunity. Recent data suggest that exhausted T-cell populations are associated with improved markers of T1D. T-cell exhaustion is both characterized and mediated by inhibitory receptors. We aim to identify which inhibitory receptors may prove useful to induce T-cell exhaustion and identify how these may be used to treat T1D.

Group leaders: Dr Bala Krishnamurthy, Prof Tom Kay

Team members: Dr Gaurang Jhala, Dr Prerak Trivedi, Prof Helen Thomas, Stacey Fynch

Our long-term goal is to treat and prevent type 1 diabetes using antigen-specific therapy to restore immune tolerance without the risks of immunosuppression. We have been at the forefront of identifying pro-insulin as the best candidate auto-antigen for this. However, progress towards this goal in human diabetes has been slow, particularly because biomarkers that can indicate whether treatment has been effective are imperfect. Our current research is focused on exploring how antigen-specific therapy can be effective at a clinically relevant time. We have assembled a powerful suite of resources in the NOD mouse model including numerous transgenic strains and MHC class I and class II tetramers and are well placed to dissect the mechanisms of pro-insulin-specific immune tolerance by tracking, enumerating and phenotyping antigen-specific T cells.

Group Leaders: Dr Bala Krishnamurthy and Prof Tom Kay
Team Members: Dr Gaurang Jhala, Ms Stacey Fynch