Islet Biology

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 So

  Defining 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 George

  Islet 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 George

  New 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 Ge

  Effica 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