New insights into Type 1 diabetes development and therapy

Event Abstract Back to Event New insights into Type 1 diabetes development and therapy Christopher R. Parish1*, Andrew Ziolkowski1, Zuopeng Wu1, Sarah Popp1, Craig Freeman1 and Charmaine J. Simeonovic1 1 John Curtin School of Medical Research, Australian National University, Department of Immunology, Australia Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing beta cells in the pancreas are destroyed by the immune system, although the molecular basis of this autoimmune destruction is unclear. We have recently reported that mouse islets express extraordinarily high levels of the glycosaminoglycan heparan sulfate (HS) intracellularly and are also surrounded by a basement membrane (BM) rich in HS. In fact, beta cells are exquisitely dependent on intracellular HS for their survival, with in vitro addition of HS or related molecules maintaining beta cell viability and rendering the cells highly resistant to damage by reactive oxygen species. Furthermore, we have found in vivo that destructive insulitis is associated with high level expression by leukocytes of enzymatically active heparanase, an endoglycosidase that degrades HS. In addition, in vivo treatment with several heparanase inhibitors significantly protected NOD mice from clinical diabetes. Based on these data we propose that initially leukocyte-derived heparanase degrades HS in the islet BM, allowing leukocyte entry into islets. Thereafter, heparanase-mediated degradation of beta cell-associated HS results in a novel mechanism of beta cell death. Recent studies using an acute T1D model in heparanase knock out mice has confirmed the importance of heparanase in T1D development, with heparanase expression by several different cell types being important. Thus heparanase inhibition, possibly combined with HS replacement in beta cells, has great therapeutic promise for treating T1D patients at an early stage of the disease and, potentially, for the prevention of T1D in “at risk” individuals. Acknowledgements JDRF, Diabetes Australia and National Health and Medical Research Council of Australia (NHMRC) for grant support References Ziolkowski, A., Popp, S., Freeman, C., Parish, C.R. and Simeonovic, C.J. (2012) Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes. J. Clin. Invest. 122, 132-141. Keywords: type 1 diabetes, Autoimmunity, Leukocyte migration, Heparan sulfate, Heparanase Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune-mediated disease pathogenesis Citation: Parish CR, Ziolkowski A, Wu Z, Popp S, Freeman C and Simeonovic CJ (2013). New insights into Type 1 diabetes development and therapy. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00770 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 18 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Prof. Christopher R Parish, John Curtin School of Medical Research, Australian National University, Department of Immunology, Canberra, ACT, 2601, Australia, christopher.parish@anu.edu.au Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Christopher R Parish Andrew Ziolkowski Zuopeng Wu Sarah Popp Craig Freeman Charmaine J Simeonovic Google Christopher R Parish Andrew Ziolkowski Zuopeng Wu Sarah Popp Craig Freeman Charmaine J Simeonovic Google Scholar Christopher R Parish Andrew Ziolkowski Zuopeng Wu Sarah Popp Craig Freeman Charmaine J Simeonovic PubMed Christopher R Parish Andrew Ziolkowski Zuopeng Wu Sarah Popp Craig Freeman Charmaine J Simeonovic Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.