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Overview of research program

Inflammatory arthritis

Rheumatoid arthritis (RA) is an auto-immune disease characterised by chronic inflammation in the joints that results in the destruction of cartilage and underlying bone.

The cartilage and bone destruction that occurs in rheumatoid arthritis (RA) results from its invasion by inflammatory tissue (pannus) which grows from the synovium (joint lining). The presence of degrading enzymes (proteases) and new blood vessels (angiogenesis) plays an important role in joint destruction. However, the factors which control protease activity or angiogenesis are poorly understood.

Our research will determine whether activated protein C (APC) reduces the severity of rheumatoid arthritis (RA) by preventing the abnormal immune response and subsequent inflammatory response. This approach is different to that used with the current range of "biological" therapy which targets the main inflammatory mediators, such as tumour necrosis factor alpha (TNF-α). By blocking the abnormal Th1 and Th17 immune events upstream of the inflammatory cascade, APC's actions would be more comprehensive than current biological treatments as it may subsequently block a range of inflammatory mediators, including TNF-α, interleukin (IL)-1 and IL-17. In addition, APC is known to have few side-effects. Thus, if our hypothesis proves to be correct, APC will provide a wide-ranging and safe therapy for RA with a novel mechanism of action.

There is no cure for arthritis and as the population ages, the burden of arthritis is increasing. The onset of arthritis is usually between the ages of 25 and 50, when people are active in the workplace and in family care roles, so has considerable social and economic costs. This is the International Bone and Joint Decade in which Commonwealth Government of Australia has made arthritis a national health priority. In response to this a National Action Plan has been developed, a key objective of which is to advance knowledge in RA, the most disabling form of arthritis. The knowledge gained from this project is likely to provide direction for new strategies to prevent joint destruction in arthritis. This new science will also provide insights into other diseases affected by similar mechanisms involving abnormal lymphocyte function including a large group of auto-immune and inflammatory diseases such as multiple sclerosis, inflammatory bowel disease and type 1 diabetes.

Wound healing

The healing of wounds is a complex process involving a number of stages, including coagulation, inflammation, remodeling and finally development of full strength skin. Impaired wound healing and/or skin ulcers occur in patients with peripheral arterial occlusive disease, deep vein thrombosis, diabetes, pressure sores and burns. Despite intense investigation, the precise mechanisms associated with impaired healing are poorly understood.

The Sutton team made a serendipitous finding when studying the anti-inflammatory role of the natural anticoagulant, activated protein C (APC). In addition to arthritis, APC proved to be beneficial to prevent type I diabetes and to heal chronic wounds. The wound healing study has progressed soundly through 2006-07. The study now involves collaboration of numerous RNSH staff from various departments including Dermatology, Rheumatology, Endocrinology, Severe Burns Unit, Vascular Surgery, Pharmacy and the Clinical Governance Unit.

Chronic leg ulcers are a major public health burden associated with high direct health-care costs and substantial negative impact on the quality of life of patients and carers. Despite recent advances in wound care many ulcers still fail to heal, leading to serious complications. In 2006-07, research in the Sutton laboratory has resolved mechanisms underlying APC's actions in wound healing. In addition, ethics approval to conduct an open-labelled pilot clinical trial in patients with chronic wounds was obtained. The preliminary results of this study conducted by Kaley Whitmont, Sara Tritton and Ian Reid are exciting, with patients showing dramatic improvement in healing and no adverse reactions were identified.

Our team was approved to run 3 randomised, double blind, placebo controlled clinical trials examining the efficacy of APC on i) split skin grafts, ii) burns, and iii) chronic leg ulcers. The trials are an essential step toward the validation of the therapeutic use of APC in wound healing. Topical application of APC is likely to emerge as a highly cost-effective treatment for this difficult health problem. The results have potential to make an enormous contribution to the international knowledge of wound healing as well as having a significant impact on the patients and the society as a whole with reduced public health burden.

Diabetes

Diabetes is a chronic, debilitating disease affecting all organ systems. In Australia, diabetes is a fastest-growing chronic disease; about 520,000 Australians are diagnosed with diabetes yearly. Type 1 diabetes represents 10 to 15% of all cases of diabetes and strikes children suddenly, makes them insulin dependent for life, and carries the constant threat of devastating complications including impaired wound healing, blindness, a high risk of infection, cardiovascular disease and kidney disease. Although the causes are not entirely understood, scientists believe the body's own immune system attacks and destroys insulin-producing cells in the pancreas. One group of cells found in human blood, known as white cells or leukocytes, includes neutrophils, monocytes and lymphocytes. These cells are major members of human cellular immune system. Abnormal behaviour of these cells is thought to be a principal cause of type 1 diabetes and its complications. We are isolating leucocytes from patients with type 1 diabetes and examining their function to test agents which can return these cells back to normal.

Our diabetes study is intriguing - cell culture and animal studies using non-obese diabetic mice (a model of human type 1 diabetes) from the Sutton lab have found that administration of activated protein C (APC), a naturally occurring clotting agent, prevents the onset of diabetes. Now that identification of children who are likely to become diabetic is possible, it is feasible that APC may become a therapeutic agent to prevent diabetes. The Juvenile Diabetes Research Foundation (JDRF) in the USA have recognised these interesting findings and have funded this project as an "innovative grant" in 2008.

APC is unique in that it not only targets the abnormal immune response but also directly inhibits inflammation, which is associated with insulitis. Thus, APC controls the two major processes implicated in the pathogenesis of type1 diabetes, inflammation and auto-immunity, which may explain how it substantially reduces blood glucose levels and prevents diabetes in non-obese diabetic mice.

An International (PCT) Patent Application was filed in January 2006 with priority from Australian Provisional Patent Application "Treatment for Autoimmune and Inflammatory Conditions" filed by Northern Sydney Central Coast Area Health Service in January, 2005. Update - The National Phase has been entered in July 2007 and we have taken out a patent application in Europe, the United States of America and Australia. Northern Sydney Central Coast Area Health Service is seeking to license this technology to a drug development company interested in taking the project to clinical trial stage.

Major funding sources

  • National Health and Medical Research Council (NHMRC)
  • Arthritis Australia
  • Rebecca Cooper Medical Research Foundation
  • Ulysses Club

Selected publications

Xue M, Jackson CJ. Autocrine actions of matrix metalloproteinase (MMP)-2 counter the effects of MMP-9 to promote survival and prevent terminal differentiation of cultured human keratinocytes. J Invest Dermatol. 2008 Nov;128(11):2676-85. Epub 2008 May 22. (IF 4.194) (No 1 in Dermatology).

Whitmont K, Reid I, Tritton S, March L, Xue M, Lee M, Fulcher G, Sambrook P, Slobedman E, Cooper A, Jackson C. Treatment of chronic leg ulcers with topical activated protein C. Arch Dermatol. 2008 Nov;144(11):1479-83. (IF 3.434) (No 2 in Dermatology)

Miriam Jackson, Margaret Smith, Meilang Xue, Chris Jackson, Chris Little. Activation of Cartilag Matrix Metalloproteinases by Activated Protein C, Arthr Rheum, in press (IF 7.621) (No 1 in Rheumatology)

Xue M, Smith M, Little C, Sambrook P, March L, Jackson CJ. Activated protein C mediates a healing phenotype in cultured tenocytes. J Cell Mol Med. 2008 May 2. [Epub ahead of print] (IF 6.2)

Jackson C, Whitmont K, Tritton S, March L, Sambrook P, Xue M. New therapeutic applications for the anticoagulant, activated protein C. Expert Opin Biol Ther. 2008 Aug;8(8):1109-22.(IF 3.8)

M Xue, D Campbell and C J Jackson, Activated protein C is an autocrine growth factor for human skin keratinocytes, J Biol Chem, 2007 May 4;282(18):13610-6. Epub 2007 Feb 9. PMID: 17293597 (IF 5.854)

M Xue, D Campbell, L March, P N Sambrook, and C J Jackson, Endothelial protein C receptor is over-expressed in rheumatoid arthritic (RA) synovium and mediates the anti-inflammatory effects of activated protein C in RA monocytes. Ann Rheum Dis, 2007 Dec;66(12):1574-80. Epub 2007 May 9. PMID: 17491095 (IF 5.767) (No 2 in Rheumatology)

M Xue, L March, P N Sambrook and C J Jackson, Differential regulation of matrix metalloproteinase (MMP)-2 and MMP-9 by activated protein C - relevance to inflammation in rheumatoid arthritis, Arthr Rheum, 2007 Sep;56(9):2864-74. PMID: 17763449 (IF 7.621) (No 1 in Rheumatology)

M Xue, D Campbell, P N Sambrook, K Fukudome and C Jackson. Endothelial protein C receptor and protease activated receptor-1 mediate induction of a wound healing phenotype in human keratinocytes by activated protein C, J Invest Derm, 2005, 125, 1279-85 (IF 4.194) (No 1 in Dermatology).

N. Buisson-Legendre, Sue Smith, Lyn March, and C. Jackson, Activated protein C (APC) is elevated in rheumatoid arthritic synovial joints and correlates with matrix metalloproteinase-2 (MMP-2), Arthr Rheum, 2004, 50 (7), 2151-2156 (IF 7.621) (No 1 in Rheumatology)

Major collaborations

  • Prof Kenji Fukudome, Department of Immunology, Saga Medical School, Nabeshima, Saga, Japan
  • A/Prof Shing Shung To, Department of Health Technology and Informatics, Hong Kong Polytechnic
  • Professor Stephen Hunyor, Department Cardiology, RNSH
  • Professor Alan Cooper, Department Dermatology, RNSH
  • Professor Greg Fulcher, Dr Rory Clifton-Bligh, Department Endocrinology, RNSH
  • Dr John Vandervord, Severe Burns Unit, RNSH
  • Dr Charles Fisher, Dr Vic Puttaswamy, Dept Vascular Surgery, RNSH