Type 1 diabetes is caused by an autoimmune T cell response that destroys the cells that produce insulin, called beta cells. The focus of the Islet Biology Laboratory is to protect these beta cells from immune-mediated destruction.
Our vision is to prevent insulin dependence in type 1 diabetes with therapies that target the immune system. We aim to understand how different effector mechanisms participate in diabetes development, and how these can be prevented. We do this by studying interactions between the immune system and beta cells. In particular, we are interested in preventing CD8+ T cells from killing beta cells, and in understanding how blocking the action of cytokines with JAK inhibitors prevents type 1 diabetes.
Our work is currently being applied in:
- the transplantation of human islets from organ donors to treat severe and unstable type 1 diabetes
- a clinical trial to test the JAK inhibitor baricitinib in participants with newly diagnosed type 1 diabetes
Current research projects
Molecular changes induced by JAK inhibitors in type 1 diabetes (T1D)
JAK inhibitors potentially have direct beneficial effects on both pancreatic beta cells and immune cells by affecting the signalling from several cytokine receptors. We are evaluating the impact of the JAK inhibitor baricitinib on T1D-associated immune responses and investigating the mechanisms by which this drug impacts the progression of T1D. We are undertaking this work with samples from the BANDIT clinical trial, using phenotypic and genomic analyses of islet antigen-specific T cells from trial participants.
Tetramer-based magnetic bead enrichment of T cells is used to phenotype cells by flow cytometry. Simultaneous cell surface protein and transcriptome analysis (CITE-seq) is performed to identify gene signatures in antigen-specific T cells. Complementary studies are being done in NOD mice after treatment with JAK inhibitors in combination with antigen-specific tolerance. Our studies are important for design of future human studies for robust, drug-free prevention of T1D.
Group leaders: Professor Helen Thomas, Prof Tom Kay
Team members: Associate Professor Bala Krishnamurthy, Associate Professor Stuart Mannering, Dr Prerak Trivedi, Dr Davis McCarthy, Laura Sanz-Villanueva, Tara Catterall, Dr Sara Litwak, Dr Michelle SoDefining the role of interferons in autoimmune diabetes
Cytokines, including interferons, play important roles in the autoimmune T cell responses against beta cells. Interferons have been implicated in the pathogenesis of type 1 diabetes. Interferons induce a transcriptional signature in pancreatic 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. By studying the action of interferons on beta cells and on immune cells (including T cells and antigen presenting cells) within the islet, we aim to better understand the role of this cytokine family in antigen-specific immune responses.
Group Leaders: Professor Helen Thomas, Professor Tom Kay
Team Members: Dr Bala Krishnamurthy, Dr Gaurang Jhala, David De GeorgeIslet biology in human type 1 diabetes
While much is known about the pathogenesis of T1D in NOD mice, far less is known of human type 1 diabetes. The Tom Mandel Islet Transplant Program occasionally receives pancreases from organ donors with type 1 diabetes and it is of enormous value to study these.
Recently, we have isolated islets from three donors who had T1D. Pancreas sections reveal a range of pathologies, ranging from islets infiltrated with T cells in a donor with recent onset T1D to islets with no insulin staining in a donor who had diabetes for 30 years. We have been able to sort CD4+ and CD8+ T cells from donor islets and have performed single cell RNA sequencing. We will investigate this data to better understand the immune system in T1D in humans, comparing to similar data from NOD mice.
Group Leaders: Professor Helen Thomas, Professor Tom Kay, Associate Professor Stuart Mannering
Team Members: Associate Professor Bala Krishnamurthy, Dr Tom Loudovaris, Dr Pushpak Bhattacharjee, Associate Professor Mark Chong, David De GeorgeNew ways to treat checkpoint inhibitor induced type 1 diabetes
Immune checkpoint inhibitors targeting PD-1 and its ligand PD-L1 have been widely prescribed for cancer treatment with clinical success. However, immune-related adverse events, including T1D, can occur as a side-effect.
We have investigated the mechanisms of diabetes after anti-PD-L1 therapy in a mouse model to identify methods for treatment. Our data show that T cell proliferation and upregulation of MHC class I on beta cells (which are both dependent on cytokine signalling) are hallmarks of T1D induced by anti-PD-L1. We have recently shown that JAK inhibitors, which block cytokine signalling, can prevent checkpoint inhibitor induced diabetes in NOD mice. Our next step is to look in more detail at the mechanism of action by examining the effect of anti-PD-L1 on islet and immune cells.
Group Leader: Professor Helen Thomas, Prof Tom Kay
Team Members: Associate Professor Bala Krishnamurthy, Dr Tingting GeEffica Biolabs – a preclinical testing service
Our preclinical testing service, Effica Biolabs, addresses unmet needs for a service platform to assist industry and academic labs in testing candidate therapies for type 1 diabetes. Our main objective is to assist pharma and biotech companies to reveal hidden value in their drug pipelines by expanding their indications and accelerating development of therapies.
Group leaders: Professor Helen Thomas, Dr Tom Brodnicki
Team members: Dr Michalea Waibel, Dr Chris Meoli, Dr Tom Loudovaris and members of the lab
- Leanne Mackin, Research assistant
- Tara Catterall, Research assistant
- Jarrod Skinner, Research assistant
- Lina Mariana, Islet isolation coordinator
- Cameron Kos, Islet production officer
- Lorraine Elkerbout, Laboratory assistant
- Dhruv Balasubramanian, Laboratory assistant
- David De George, PhD student
- Laura Sanz-Villanueva, PhD student
- Anthony Jarmache, honours student
Ge T, Phung A-L, Jhala G, Trivedi P, Principe N, De George DJ, Pappas EG, Litwak S, Sanz-Villanueva L, Catterall T, Fynch S, Boon L, Kay TW, Chee J, Krishnamurthy B, Thomas HE Diabetes induced by checkpoint inhibition in nonobese diabetic mice can be prevented or reversed by a JAK1/JAK2 inhibitor. Clin Transl Immunol, 2022, e1425, doi: 10.1002/cti2.1425
Jhala G, Krishnamurthy B, Brodnicki TC, Ge T, Akazawa S, Selck C, Trivedi PM, Pappas EG, Mackin L, Principe N, Brémaud E, De George DJ, Boon L, Smyth I, Chee J, Kay TWH, Thomas HE. Interferons limit autoantigen-specific CD8+ T-cell expansion in the non-obese diabetic mouse. Cell Rep. 2022 Apr 26;39(4):110747. doi: 10.1016/j.celrep.2022.110747.
Akazawa S, Mackin L, Jhala G, Fynch S, Catterall T, Selck C, Graham KL, Krishnamurthy B, Pappas EG, Kwong CJ, Sutherland APR, Kay TWH, Brodnicki TC, Thomas HE. Deficiency of the innate immune adaptor STING promotes autoreactive T cell expansion in NOD mice. Diabetologia. 2021 Apr;64(4):878-889. doi: 10.1007/s00125-020-05378-z.
Ge T, Jhala G, Fynch S, Akazawa S, Litwak S, Pappas EG, Catterall T, Vakil I, Long AJ, Olson LM, Krishnamurthy B, Kay TW, Thomas HE. The JAK1 Selective Inhibitor ABT 317 Blocks Signaling Through Interferon-γ and Common γ Chain Cytokine Receptors to Reverse Autoimmune Diabetes in NOD Mice. Front Immunol. 2020;11:588543. doi: 10.3389/fimmu.2020.588543.
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 proapoptotic 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. 2014 Mar 13;5:e1124. doi: 10.1038/cddis.2014.88.
Thomas HE, Parker JL, Schreiber RD, Kay TW. IFN-gamma action on pancreatic beta cells causes class I MHC upregulation but not diabetes. J Clin Invest. 1998 Sep 15;102(6):1249-57. doi: 10.1172/JCI2899.
ORCID profile: https://orcid.org/0000-0001-6604-6640
Google Scholar profile: https://scholar.google.com.au/citations?user=p7L8c3YAAAAJ&hl=en