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Islet biology

Our research is focused on preventing pancreatic beta cell destruction to preserve beta cell mass in diabetes. We have identified pathways of beta cell death in type 1 and 2 diabetes. We aim to understand how different effector mechanisms participate in diabetes development, and how they can be prevented. The pathogenesis of type 1 and 2 diabetes is complex, with immune abnormalities in type 1 and insulin resistance in type 2 diabetes. However, beta cell deficiencies are required for both diseases, and this is the focus of the Islet Biology Laboratory. In type 1 diabetes, we study the interaction between the immune system and beta cells. In particular, we are interested in preventing beta cell killing by CD8+ T cells, and in understanding the mechanisms by which CD4+ T cells kill beta cells. We are studying the stress, inflammatory and cell death pathways activated by high glucose concentrations in beta cells in type 2 diabetes, and we are testing the role of these pathways in vivo. Our work is being applied to humans through the transplantation of human islets from organ donors to reverse diabetes in severe cases.

Research Themes

The use of small molecule inhibitors to prevent beta cell destruction in type 1 diabetes

Group Leader: A/Prof Helen Thomas
Team Members: Dr Kate Graham, Mr Prerak Trivedi, Dr Stuart Mannering, Prof Tom Kay
Collaborators: Dr Chris Burns, Prof Andrew Wilks, Prof Joe Trapani

Over the past 10 years, our team has been able to delineate the functions of molecules and pathways that both prevent and promote T cell-mediated beta cell destruction leading to type 1 diabetes. Our work has focused on new targets of therapeutic intervention. These include the cytotoxic molecule perforin, with our demonstration that CD8+ T-cell mediated beta cell killing is dependent on perforin. We have also shown that beta cells respond to inflammatory signals using the JAK/STAT pathway, making them susceptible to CD8+ T-cell mediated killing. Our current goal is to develop and validate compounds that block these processes, which are essential for beta cell destruction. Our collaborator Prof Trapani has generated highly specific small molecule inhibitors of perforin that we will test in mouse models of type 1 diabetes. We also propose to use drugs that inhibit JAK1/JAK2, the kinases downstream of interferons, to prevent activation of inflammatory pathways in beta cells. These compounds of interest are either approved for clinical use for other diseases (JAK inhibitors), or are being developed for clinical use (perforin inhibitors). We will be the first to investigate the applications of these compounds in autoimmune diabetes.

Activation of innate immunity and type 1 interferon production in initiation of type 1 diabetes

Group Leader: Dr Helen Thomas
Team Members: Dr Kate Graham, Dr Zia Mollah, Mr Hong Quah Sheng, Prof Tom Kay
Collaborators: Prof Joe Trapani, Dr Tom Brodnicki, Dr Alan Baxter

Sensing of nucleic acids by innate immune pathways is essential for normal immunity against viruses, and defects in this process lead to autoimmune diseases such as type 1 diabetes. Cleavage of intracellular DNA is mediated by molecules of the SET complex, and this complex can be activated by the serine protease granzyme A. Mutations in molecules in the SET complex, such as the 3’ endonuclease Trex1, result in autoimmunity in mice and humans that is driven by excessive production of type 1 IFN. Type I interferons (IFN) have been implicated in initiation of islet autoimmunity and development of type 1 diabetes. While studying cytotoxic T cell-mediated b cell death in type 1 diabetes, we discovered that non-obese diabetic (NOD) mice lacking granzyme A have accelerated diabetes, and a 6-fold increase in islet expression of genes regulated by type I IFN. Our data indicate a crucial role for granzyme A in controlling activation of innate immunity. While type 1 IFN in NOD mice is not required for diabetes development, excessive activation on a genetic background that is prone to autoimmunity results in accelerated disease. We are continuing our work in this area to identify the mechanism by which granzyme A contributes to accelerated diabetes development.

Intracellular pathways of beta-cell death in type 2 diabetes

Group Leader: A/Prof Helen Thomas
Team Members: Dr Jibran Wali, Dr Jingjing Ge, Dr Esteban Gurzov
Collaborators:  Prof Andreas Strasser, Prof Sof Andrikopoulos, Dr Ross Laybutt, Dr Ian Smyth

Type 2 diabetes is an enormous global health problem affecting nearly 350 million individuals world-wide. It occurs as a result of declining beta-cell function in insulin-resistant subjects together with a decrease in beta cell mass. Evidence suggests that loss of beta cell mass is due to apoptosis, with hyperglycaemia as a potential cause. Inhibition of apoptosis may be able to prevent beta cell loss. Increasing functional beta cell mass would reduce insulin requirements, improve glucose control and reduce complications of diabetes. However, drugs to inhibit apoptosis have not been implemented in diabetes.

Using very well characterized mouse models, we were the first to identify that the pro-apoptotic molecules Bim and Puma are required for glucose-induced apoptosis of islet cells. We have generated exciting results that suggest Bim deficiency protects leptin receptor mutant Leprdb/db mice from development of fasting hyperglycaemia and increases beta cell mass. It is unclear whether this is an intrinsic beta cell effect or due to improved insulin sensitivity. We aim to study how Bim contributes to type 2 diabetes development using conditionally targeted mouse models. We will also examine how beta cell mass is increased in Bim-deficient mice.

Activation of islet inflammation by cytokine signaling in pancreatic beta cells

Group Leader: Dr Esteban Gurzov
Team members: Dr Sara Litwak, Mr Hamdi Saadi, Mr William Stanley, Mr Evan Pappas, A/Prof Helen Thomas
Collaborators: Prof Decio Eizirik

Type 1 diabetes is the result of autoimmune assault against the insulin-producing pancreatic b cells, where chronic local inflammation (insulitis) leads to b cell destruction. T cells and macrophages infiltrate into islets early in type 1 diabetes pathogenesis. These immune cells secrete cytokines that lead to the production of reactive oxygen species (ROS) and T cell invasion and activation. Cytokine signaling pathways are very tightly regulated to prevent excessive signaling. Two molecules that inhibit cytokine signaling include the suppressor of cytokine signaling (SOCS)-1 and T cell protein tyrosine phosphatase (TCPTP). These molecules are expressed in b cells, and their inactivation sensitizes b cells to cytokine signaling. Protein tyrosine phosphatases such as TCPTP are highly susceptible to oxidation by ROS, which occurs during pathological inflammation. The gene for TCPTP, PTPN2, has also been associated with type 1 diabetes in genome-wide association studies, and the genetic susceptibility is linked with reduced expression of TCPTP. ROS-mediated inactivation of TCPTP, together with its reduced expression in genetically susceptible individuals, provides a mechanism by which excessive cytokine signaling in b cells results in increased expression of inflammatory genes (e.g. chemokines) and exacerbated insulitis. In this project we will utilize mice that lack TCPTP or SOCS1 specifically in b cells to test the hypothesis that b cells contribute to their own demise by activating inflammatory signals driven by local ROS and cytokine production.

Honours and PhD Projects

Staff

Publication Highlights

  1. Thomas HE, Parker JL, Schreiber RD, Kay TWH. IFN- action on pancreatic beta cells causes class I MHC upregulation but not diabetes. J. Clin. Invest. 102:1249-1257 (1998)
  2. Chong MM, Chen Y, Darwiche R, Dudek NL, Irawaty W, Santamaria P, Allison J, Kay TW, Thomas HE. Suppressor of cytokine signaling-1 overexpression protects pancreatic cells from CD8+ T cell-mediated autoimmune destruction. J. Immunol, 172:5714-5721 (2004)
  3. Campbell PD, Estella E, Dudek NL, Jhala G, Thomas HE, Kay TW, and Mannering SI. Cytotoxic T-lymphocyte mediated killing of human pancreatic islet cells in vitro. Human Immunology 69: 543-51 (2008)
  4. Thomas HE, McKenzie MD, Angstetra E, Campbell PD, Kay TW. Beta cell apoptosis in diabetes. Apoptosis 14:1389-1404 (2009)
  5. Thomas HE, Trapani, JA, Kay TW The role of perforin and granzymes in diabetes. Cell Death Differ, 17:577-85 (2010)
  6. O’Connell PJ, Holmes-Walker JD, Goodman D, Hawthorne WJ, Loudovaris T, Gunton JE, Thomas HE, Grey ST, Drogemuller CJ, Ward GM, Torpy DJ, Coates PT, Kay TW, On behalf of the Australian Islet Transplant Consortium. Multicenter Australian Trial of Islet Transplantation: Improving Accessibility and Outcomes. Am. J. Transplant., 13:1850-8 (2013)
  7. Quah HS, Miranda-Hernandez S, Khoo A, Harding A, Fynch S, Elkerbout L, Brodnicki TC, Baxter AG, Kay TWH, Thomas HE*, Graham KL* Deficiency in type I interferon signaling prevents the early interferon-gene signature in pancreatic islets but not type 1 diabetes in non-obese diabetic mice. Diabetes 63:1032-40 (2014)
  8. Wali JA, Rondas D, McKenzie MD, Zhao Y, Elkerbout L, Fynch S, Gurzov EN, Akira S, Mathieu C, Kay TW, Overbergh L, Strasser A, Thomas HE The pro-apoptotic BH3-only proteins Bim and Puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity. Cell Death Dis. 5:e1124 (2014)
  9. Stanley WJ, Litwak SA, Quah HS, Tan SM, Kay TWH, Tiganis T, de Haan JB, Thomas HE, Gurzov EN Inactivation of protein tyrosine phosphatases enhances interferon signalling in pancreatic islets. Diabetes 64:2489-96 (2015)
  10. Zhao Y, Scott NA, Fynch S, Elkerbout L, Wong WW-L, Mason KD, Strasser A, Huang DC, Kay TWH, Thomas HE Autoreactive T cells induce necrosis and not BCL-2-regulated or death receptor-mediated apoptosis or RIPK3-dependent necroptosis of transplanted islets in a mouse model of type 1 diabetes. Diabetologia 58:140-8 (2015)
  11. Zhao Y, Scott NA, Quah HS, Krishnamurthy B, Bond F, Loudovaris T, Mannering SI, Kay TW, Thomas HE Mouse pancreatic beta cells express MHC class II and stimulate CD4+ T cells to proliferate. Eur J Immunol 45:2494-503 (2015)
  12. Krishnamurthy B, Chee J, Jhala G, Trivedi P, Catterall T, Selck C, Gurzov EN, Brodnicki TC, Graham KL, Wali JA, Zhan Y, Gray D, Strasser A, Allison J, Thomas HE, Kay TW Bim deficiency protects NOD mice from diabetes by diverting thymocytes to regulatory T cells. Diabetes 64:3229-38 (2015)