Prof Ian Wicks

Recipient: Prof Ian Wicks
Intended department: Inflammation Division- The Walter and Eliza Hall Institute of Medical Research Victoria


Exploring GM-CSF as a Regulator and Therapeutic Target in Vasculitis



Vasculitis is a disease characterised by inflammation of the blood vessels. Without treatment, this inflammation can cause the vessel to block or burst, which can be life threatening. We believe that understanding how inflammation develops during vasculitis will allow the development of new therapeutic targets aimed at limiting the progression of vasculitis and treating established disease.
In this grant, we have studied the inflammatory processes that drive two common vascular conditions – Kawasaki Disease (KD) and Giant Cell Arteritis (GCA). KD is caused by inflammation of blood vessels in the heart (coronary arteries). It affects young children (0-5 years) and can result in life threatening coronary aneurysms within the heart. GCA affects the elderly (50 years plus) and can result in blindness due to inflammation of the temporal arteries. Here, we performed multiple assays to measure
a wide panel of immune factors present in the blood of KD patients and the temporal arteries of patients with GCA. Our hypothesis was that through identifying the major immune factors that emerge in these disease (KD and GCA), we could design therapies that limit their pathogenic activity, which would in turn limit vascular inflammation. We successfully identified the unique immune signatures of KD and GCA. Specifically, we have found a family of mediators in KD patients; these include the cytokines CCL17 and CCL2, which are responsible for recruiting immune cells. Notably, these do not appear in GCA or in unrelated diseases such as pneumonia. Intriguingly, our earlier studies identified the pathway by which CCL17 and CCL2 are expressed and we have developed a therapeutic approach to block this process. Hence, our study supports the application of this therapy in KD. In contrast, for GCA we found that a different family of immune factors (notably IFN-gamma and CXCL9-10) were expressed in the inflamed temporal artery. This demonstrates that distinct types of immune responses drive pathology in these two diseases.

Our findings provide information on how these common inflammatory diseases develop and identify new biomarkers for diagnosis and potential therapeutic targets. Specifically, our findings demonstrate that for KD, therapies that target a pathway involving CCL2/17 (as well as GM-CSF, another immune mediator actively researched in our laboratory) may be effective, while therapies aimed at treating the IFNg-CXCL9-10 axis will be effective for GCA. These results were presented at a leading international conference on inflammation (Cold Spring Harbour in Asia, Suzhou, China, 2017) and will form the basis of future publications. Furthermore, we plan to assess the efficacy of targeting the above pathways in future pre-clinical trials Funding by the Australian Rheumatology Association and Arthritis Australia was
instrumental in achieving these goals and we gratefully acknowledge their support.