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:
(i) 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.
(ii) 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.
(iii) HS is also lost from beta cells in Type 2 diabetes, due to an apparent defect in HS synthesis.
Prizes, Honours and awards
The Type I diabetes research on islet HS and heparanase, a collaborative project between the labs of Professsor Chris Parish and Associae 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.