The Simeonovic Group - Diabetes/Transplantation Immunology
The Simeonovic Group is currently accepting applications from potential Honours and PhD Students. The available project opportunities are listed on this page. Please contact us.
Our research
Type 1 diabetes (T1D) is an “autoimmune” disease in which an individual’s immune system destroys the body’s insulin-producing beta cells present in specialised tissue compartments in the pancreas, called “islets”. Although T cells, a type of white blood cell, plays a critical role in beta cell destruction, recent clinical trials blocking T cell activation and function in patients recently diagnosed with T1D, have revealed only a modest benefit, suggesting that other components of the immune system are important in T1D disease progression.
Recently, other white blood cells called “neutrophils” (belonging to the quick-acting “innate” immune system) have been implicated in T1D development. In various other autoimmune diseases, activated neutrophils expel their DNA and associated proteins called “histones” into the surrounding environment. This network of DNA/histones is called an “extracellular trap” or “NET”. NETs/histones can damage and kill other cells in the body’s tissues. Recently diagnosed T1D (recent-onset) patients have shown increased levels of NETs and markers of neutrophil activation in their blood (circulation). Of significance, circulating platelets (another blood component), like neutrophils, are also activated in children and adolescents with T1D. Neutrophils are activated by platelets and platelets are also activated by neutrophil NETs/histones, creating a “vicious cycle” of platelet-neutrophil activation. Drugs, newly developed by our team, block this platelet-neutrophil activation cycle, inhibit platelet activation by histones and prevent NET/histone toxicity and tissue injury in other disease models.
We propose that during T1D development, neutrophils are activated by platelets to release NETs/histones inside blood vessels and within islets, resulting in initial or early beta cell damage. Such damage could promote the activation and expansion of autoreactive T cells, conventionally recognised as being responsible for T1D disease. Our studies will potentially identify a novel therapeutic for targeting platelet-neutrophil driven islet/beta cell damage in T1D and as an aid for preventing on-going disease progression in new-onset patients and/or children identified to be at a high risk of developing clinical T1D.
Recent research findings
- Pancreatic islets are surrounded by a conventional basement membrane (BM) containing the heparan sulfate proteoglycan (HSPG) perlecan, a BM component which functions as a barrier to leukocyte migration. This discovery provided an explanation for the initial peri-islet accumulation of inflammatory leukocytes (insulitis) in T1D in NOD mice, a characteristic feature of T1D histopathology.
- Both mouse and human pancreatic islets contain high levels of heparin sulphate (HS) which is essential for the survival of insulin-producing beta cells and is lost from beta cells (before insulin) during T1D development. We further demonstrated that (a) HS protected beta cells by acting as an antioxidant and (b) T1D could be prevented in NOD mice by drugs that functioned as heparanase inhibitors and HS replacers. These findings marked the discovery of a new T1D therapeutic.
- HS is also lost from beta cells in Type 2 diabetes, due to an apparent defect in HS synthesis.
Prizes, Honours and awards
- Congratulations to Sarita Dhounchak, PhD student who has received a travel award of 1500 EURO to present her PhD data at the European Association for the Study of Diabetes (EASD) Annual Meeting in Lisbon, Portugal in September this year.
- The Type I diabetes research on islet HS and heparanase, a collaborative project between the labs of Professor Chris Parish and Associate Professor Charmaine Simeonovic was selected by NHMRC for the 2014 edition of the NHMRC’s Ten of the Best Research Projects publication.
- Ms Fui Jiun Choong, Young Investigator Award for her oral presentation entitled "The role of heparanase in the rejection of islet allografts" at the 2012 Annual Scientific Meeting of the Transplantation Society of Australia and New Zealand held in Canberra, 27-29 June 2012.
- Dr Zuopeng Wu, Travel Award to present his poster entitled "Heparanase is indispensable for islet infiltration by autoreactive T cells in Type 1 diabetes" at the 2012 Annual Scientific Meeting of the Australian Diabetes Society and the Australian Diabetes Educators Association, held at the Gold Coast, Qld, 29-31 August 2012.
- Dr Andrew Ziolkowski, Poster prize for his poster entitled " Preventing beta cell demise in db/db mice with heparan sulfate mimetics" at the 5th Australian Islet Study Group 2012 meeting, held in Melbourne, 25 October 2012.
- Congratulations to Sarita Dhounchak, who has received a travel award of 1500EURO to present her PhD data at the European Association for the Study of Diabetes (EASD) Annual Meeting in Lisbon, Portugal in September this year.
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- Kopprasch, S, Dheban, S, Schuhmann, K et al 2016, 'Detection of independent associations of plasma lipidomic parameters with insulin sensitivity indices using data mining methodology', PLOS ONE (Public Library of Science), vol. 11, no. 10, pp. 16pp.
- Bogdani, M, Simeonovic, C, Nagy, N et al 2015, 'The Detection of Glycosaminoglycans in Pancreatic Islets and Lymphoid Tissues', Methods in Molecular Biology, vol. 1229, pp. 413-430.
- Choong, F, Freeman, C, Parish, C, Simeonovic CJ 2015, 'Islet Heparan Sulfate but Not Heparan Sulfate Proteoglycan Core Protein Is Lost During Islet Isolation and Undergoes Recovery Post-Islet Transplantation', American Journal of Transplantation, vol. 15, pp. 2861-2864.
- Bogdani, M, Korpos, E, Simeonovic, C et al 2014, 'Extracellular Matrix Components in the Pathogenesis of Type 1 Diabetes', Current Diabetes Reports, vol. 14, no. 12, pp. 1-11.
- Delghingaro-Augusto, V, Madad, L, Chandra, A et al 2014, 'Islet inflammation, hemosiderosis, and fibrosis in intrauterine growth-restricted and high fat-fed sprague-dawley rats', American Journal of Pathology, vol. 184, no. 5, pp. 1446-1457.
- Irving-Rodgers, H, Choong, F, Hummitzsch, K et al 2014, 'Pancreatic Islet basement membrane loss and remodeling after mouse islet isolation and transplantation: Impact for allograft rejection', Cell Transplantation, vol. 23, no. 1, pp. 59-72.
- Simeonovic, C & Parish, C 2013, 'Comment on: Korpos et al. The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human. Diabetes 2013;62:531-542', Diabetes, vol. 62, no. 8, pp. e13.
- Parish, C, Freeman, C, Ziolkowski, A, He YQ, Sutcliffe EL, Zafar A, Rao S, Simeonovic CJ. 2013, 'Unexpected new roles for heparanase in Type 1 diabetes and immune gene regulation', Matrix Biology, vol. 32, no. 5, pp. 228-233.
- Simeonovic, C, Ziolkowski, A, Wu, Z, Choong FJ, Freeman C, Parish CR. 2013, 'Heparanase and autoimmune diabetes', Frontiers in Immunology, vol. 4, pp. 1-7.
- Tait, B, Simeonovic, C & McCullagh, P 2012, 'Contributions of Australasians to the Study of Immune Responses to Allogeneic Transplanted Tissue', in Brian D Tait (ed.), More than a Footnote, Australian Scholarly Publishing Pty Ltd, Melbourne, pp. 465-489.
- Ziolkowski AF, Popp SK, Freeman C, Parish CR, Simeonovic CJ. 2012, 'Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes', Journal of Clinical Investigation, vol. 122, pp. 132-141.
- Schmid, J, Ludwig, B, Schally, A et al 2011, 'Modulation of pancreatic islets-stress axis by hypothalamic releasing hormones and 11 beta-hydroxysteroid dehydrogenase', PNAS - Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 33, pp. 13722-13727.
- Schmid, J, Ludwig, B, Schally, A et al 2011, 'Reply to Liu et al.: Hypothalamic control of islets', PNAS - Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 51, pp. E1391-E1391.
- Hodgson R, Christiansen D, Ziolkowski A, Mouhtouris E, Simeonovic CJ, Ierino FL, Sandrin MS 2011, 'Prolonged xenograft survival induced by inducible costimulator-Ig Is associated with increased Forkhead Box P3+ Cells', Transplantation, vol. 91, no. 10, pp. 1090-1097.
- Mulley, W, Li, Y, Wee, J et al 2008, 'Local expression of IDO, either alone or in combination with CD40Ig, IL10 or CTLA4Ig,inhibits indirect xenorejection responses', Xenotransplantation, vol. 15, no. 3, pp. 174-183.
- Irving-Rodgers, H, Ziolkowski, A, Parish, C et al 2008, 'Molecular composition of the peri-islet basement membrane in NOD mice: a barrier against destructive insulitis', Diabetologia, vol. 51, pp. 1680-1688.
- Popp, S, Mann, D, Milburn, P et al 2007, 'Transient transmission of porcine endogenous retrovirus to fetal lambs after pig islet tissue xenotransplantation', Immunology and Cell Biology, vol. 85, pp. 238-248.
- Solomon, M, Ramshaw, I & Simeonovic, C 2005, 'Recombinant fowlpox virus for in vitro gene delivery to pancreatic islet tissue', Immunology and Cell Biology, vol. 83, pp. 615-625.
- Simeonovic, C, Ziolkowski, A, Popp, S et al 2005, 'Porcine endogenous retrovirus encodes xenoantigens involved in porcine cellular xenograft rejection by mice', Transplantation, vol. 79, no. 12, pp. 1674-1682.
- Solomon, M, Kuziel, W & Simeonovic, C 2004, 'The contribution of chemokines and chemokine receptors to the rejection of fetal proislet allografts', Cell Transplantation, vol. 13, pp. 503-514.
- Solomon, M, Kuziel, W, Mann, D et al 2003, 'The role of chemokines and their receptors in the rejection of pig islet tissue xenografts', Xenotransplantation, vol. 10, pp. 164-177.
- Simeonovic, C, Cordery, D, Van Leeuwen, B et al 2002, 'Host systemic and local nitric oxide levels do not correlate with rejection of pig proislet xenografts in mice', Xenotransplantation, vol. 9, pp. 169-182.
- Lidbury, B, Simeonovic, C, Maxwell, G et al 2000, 'Macrophage-induced muscle pathology results in morbidity and mortality for Ross River virus-infected mice', Journal of Infectious Diseases, vol. 181, no. 1, pp. 27-34.
- Paule, M, Ramshaw, I & Simeonovic, C 2000, 'Avipox virus vectors for gene delivery to fetal mouse and pig proislets', Transplantation Proceedings, vol. 32, no. 5, p. 1067.
- Paule, M, McColl, S & Simeonovic, C 2000, 'Murine chemokine gene expression in rejecting pig proislet xenografts', Transplantation Proceedings, vol. 32, no. 5, pp. 1062..
- Simeonovic, C, Townsend, M, Morris, C et al 1999, 'Immune mechanisms associated with the rejection of fetal murine proislet allografts and pig proislet xenografts: comparison of intragraft cytokine mRNA profiles', Cell Transplantation, vol. 67, no. 7, pp. 963-971.
- Simeonovic, C 1999, 'Xenogeneic islet transplantation', Xenotransplantation, vol. 6, no. 1, pp. 1-5.
- Simeonovic, C, Townsend, M, Karupiah, G et al 1999, 'Analysis of the Th1/Th2 paradigm in transplantation: interferon-gamma deficiency converts Th1-type proislet allograft rejection to a Th2-type xenograft-like response', Cell Transplantation, vol. 8, no. 4, pp. 365-373.