Islet biology

Group Leader: A/Prof Helen Thomas

Team Members: Prof Tom Kay, Dr Stuart Mannering, Dr Michaela Waibel, Dr Gaurang Jhala, Dr Satoru Akazawa. Dr Sara Litwak, Ms Stacey Fynch, Ms Marie Christensen, Mr Jonathan Bebbington

Collaborators: Dr John Wentworth, Dr Chris Burns, pharmaceutical companies (Eli Lilly, AbbVie, Gilead Sciences and Incyte Corporation), Dr Davis McCarthy, Dr Mark Chong

Our goal is to prevent the immune-mediated destruction of insulin-producing pancreatic beta cells that leads to type 1 diabetes. The JAK-STAT signalling pathway is critical for immune-mediated pancreatic beta cell destruction. We have exciting new data showing that inhibitors of JAK1/JAK2 prevent diabetes and also reverse newly diagnosed diabetes in the non-obese diabetic (NOD) mouse model of type 1 diabetes. These results provide a compelling rationale to apply JAK1/JAK2 inhibitors, some of which are approved for human use, to the prevention and treatment of type 1 diabetes in humans. The goal of this project is to investigate the use of JAK inhibitors for the treatment of type 1 diabetes. We propose to take several steps towards achieving this goal. One of these is to determine which of the many JAK inhibitor drugs in development is the best to use in type 1 diabetes. Another step is to identify the best way to test that JAK inhibitors are affecting type 1 diabetes pathogenesis in patients. We will then conduct a clinical trial with a JAK inhibitor in patients with type 1 diabetes. Finally, we propose a discovery approach in which we will identify molecules that are affected by inhibition of JAK/STAT signalling, to give us a better understanding of the mechanisms by which JAK inhibitors work.

Group Leaders: A/Prof Helen Thomas and Dr Bala Krishnamurthy

Team Members: Prof Tom Kay, Dr Gaurang Jhala, Ms Claudia Selck, Ms Marie Christensen, Mr Justin Kwong, Ms Tara Catterall

Collaborators: Prof Matthias von Herrath

Effective antigen-specific therapies that prevent type 1 diabetes have not yet been developed, and data suggest that antigen-specific therapy on its own may not be effective if autoimmunity is already established. We hypothesise that islet inflammation fuels the development of effector memory T cells, and that if this is controlled by immunotherapy, such as JAK inhibitors, antigen-specific therapy will be successful. To test this, we have used mice generated in the lab that have inducible expression of proinsulin in antigen presenting cells under control of the MHC class II promoter, combined with JAK1/JAK2 inhibitor treatment to block cytokine signalling. Preliminary experiments show that short-term JAK inhibitor treatment between 2 and 4 weeks of age, combined with proinsulin tolerance induced at 4 weeks, led to a significant reduction in insulitis that was not observed with either treatment alone. Based on this finding we are now working to confirm this result and test the potential for using the combination therapy as a treatment for established autoimmunity.

Group Leaders: A/Prof Helen Thomas and Dr Tom Brodnicki

Team Members: Prof Tom Kay, Dr Satoru Akazawa, Dr Bala Krishnamurthy, Dr Gaurang Jhala, Ms Stacey Fynch

Collaborators: Prof Phil Bird, Prof Joe Trapani, Dr Scott Lieberman.

Cytokines, including interferons, play important roles in the autoimmune T cell responses against beta cells. There is a significant gap in our knowledge of the events leading to initiation of autoimmune diabetes, and interferons have been implicated in this process. Interferons induce a transcriptional signature in the islets and promote immune cell activation and survival in humans and mouse models of type 1 diabetes. We hypothesise that interferons create an environment conducive to the breakdown of immune tolerance. We are studying whether interferons have overlapping roles in the pathogenesis of diabetes using NOD mice with deficiency in all three of the interferon receptors, made using CRISPR. In addition, we are studying the role of type 1 interferon in initiation of autoimmunity. We have identified an important role for granzyme A, a protease implicated in the degradation of intracellular DNA, in regulating autoimmunity. We are using NOD mice lacking granzyme A, and the DNA sensor stimulator of interferon genes (STING), generated using CRISPR in our lab, to understand how granzyme A maintains immune tolerance.

Group Leader: A/Prof Helen Thomas
Team Members: Dr Jingjing Ge, Mr William Stanley, Dr Sara Litwak
Collaborators:  Prof Andreas Strasser, Dr Sean McGee, Dr Ian Smyth, A/Prof Ross Laybutt

In type 2 diabetes evidence suggests that loss of beta-cell mass is due to apoptosis, and hyperglycaemia has been suggested as a potential cause of beta-cell death. We showed that beta cell apoptosis induced by high glucose concentrations occurs through activation of the pro-apoptotic BH3-only proteins BIM and PUMA. To test whether blocking BIM is able to prevent islet cell death in vivo, we generated leptin receptor deficient db/db mice that lack BIM. These mice have larger islets than wild-type db/db mice and improved glycaemic control, suggesting that protection of beta cells from apoptosis may reduce type 2 diabetes. We plan to study db/db mice with beta cell-specific deletion of BIM. We also generated unexpected but exciting results that indicate BIM has a much broader role in mitochondrial function in vivo. We plan to define whether there is an interaction between apoptosis and metabolism and to determine whether the mitochondrial function of BIM could influence the development of type 2 diabetes. These studies have implications for regulation of metabolism in obesity and type 2 diabetes.