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Immunology

In type 1 diabetes, insulin-producing beta cells (arranged in clusters called islets) are destroyed by immune mechanisms. The major immune cell type involved is the CD8+ cytotoxic T lymphocyte (CTL) that directly recognises short peptides derived from proteins like insulin presented by major histocompatibility complex class I proteins on the surface of beta cells. We study the precise mechanisms by which T cells destroy beta cells, and test ways to prevent this from happening. Much of our work is based on the NOD mouse model that develops diabetes in a similar manner to humans. We also have several transgenic mice that express particular T-cell receptors that are able to cause rapid diabetes. We use these mice, and our expertise in flow cytometry, immunohistochemistry and molecular biology, to study the role that cytokines, death-receptor molecules and perforin/granzymes play in the development of diabetes. The major questions we are studying are the use of immune tolerance to insulin as a way of arresting diabetes and also how CTL differentiate into fully effective cytotoxic T cells.

Research Themes

The BANDIT trial: using JAK inhibitors to treat type 1 diabetes

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

Factors that determine antigen-specific CD8+ T cell expansion

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

Defining the roles of type 17 immune responses and IL-17 family cytokines in type 1 diabetes

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

Inducing T-cell exhaustion to prevent type 1 diabetes

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

The effect of immune tolerance to proinsulin at different stages of autoimmune diabetes.

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

Student Projects

Staff

Publication Highlights

  1. Krishnamurthy B, Dudek NL, McKenzie MD, Purcell AW, Brooks AG, Gellert S, Colman PG, Harrison LC, Lew AM, Thomas HE, Kay TWH (2006) Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP. J Clin Invest 116:3258-65.
  2. Chong MM, Chen Y, Darwiche R, Dudek NL, Irawaty W, Santamaria P, Allison J, Kay TWH, Thomas HE (2004) Suppressor of cytokine signaling-1 overexpression protects pancreatic beta cells from CD8+ T cell-mediated autoimmune destruction. J Immunol 172:5714-21.
  3. 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)
  4. Chee J, Ko H-J, Skowera A, Jhala G, Catterall T, Graham KL, Sutherland RM, Thomas HE, Lew AM, Peakman M,  Kay TWH, Krishnamurthy B Effector memory T cells develop in islets and report islet pathology in type 1 diabetes. J. Immunol 192:572-80 (2014)
  5. Pathiraja V, Kuechlich JP, Campbell PD, Krishnamurthy B, Loudovaris T, Coates PTH, Brodnicki TC, O'Connell PJ, Kedzierska K, Rodda C, Bergman P, Hill E, Purcell AW, Dudek NL, Thomas HE, Kay TWH, Mannering SI Proinsulin specific, HLA-DQ8 and HLA-DQ8 transdimer restricted, CD4+ T cells infiltrate the islets in type 1 diabetes. Diabetes 64:172-82 (2015)
  6. Jhala G, Chee J, Trivedi PM, Selck C, Gurzov EN, Graham KL, Thomas HE, Kay TW, Krishnamurthy B Perinatal tolerance to proinsulin is sufficient to prevent autoimmune diabetes. JCI Insight 1:e86065 (2016)
  7. Trivedi PM, Graham KL, Scott NA, Jenkins MR, Majaw S, Sutherland RM, Fynch S, Lew AM, Burns CJ, Krishnamurthy B, Brodnicki TC, Mannering SI, Kay TW, Thomas HE. Repurposed JAK1/JAK2 inhibitor reverses established autoimmune insulitis in non-obese diabetic mice. Diabetes 66:1650-60 (2017)
  8. So M, Elso CM, Tresoldi E, Pakusch M, Pathiraja V, Wentworth JM, Harrison LC, Krishnamurthy B, Thomas HE, Rodda C, Cameron FJ, McMahon J, Kay TWH, Mannering SI Proinsulin C-peptide is an autoantigen in people with type 1 diabetes. Proc Natl Acad Sci USA 115:10732-7 (2018)
  9. Galligan A, Krishnamurthy B, Kay TW Comment on Trinh et al. Successful treatment of immune checkpoint inhibitor-induced diabetes with infliximab. Diabetes Care 43:e10 (2020)
  10. Jhala G, Selck C, Chee J, Kwong C-TJ, Pappas E, Thomas HE, Kay TW, Krishnamurthy B Tolerance to proinsulin-1 reduces autoimmune diabetes in NOD mice. Front Immunol, 12:645817 (2021)