Williams Group | Targeting Disease Pathways in Rheumatoid Arthritis

Kennedy

Our work is geared towards the development of new treatments and healthcare strategies for rheumatoid arthritis and other autoimmune diseases.

Context

Previous work from our group contributed to the successful development of anti-TNFα therapy and subsequent studies on combination therapy led to clinical trials of anti-TNFα plus methotrexate, which has set the gold standard for pharmacological management of moderate to severe rheumatoid arthritis.

Paradoxically, our most recent work has shown that anti-TNF treatment alone may be limited in its curative potential as it leads to an expansion of Th17 responses. We have also shown that this expanded population of Th17 cells is highly pathogenic when the anti-TNF therapy "brake" is withdrawn.

We hypothesise that the expansion of Th17 cells detracts from the therapeutic effect of TNF inhibitors and that their efficacy may be improved through the strategic use of combination therapy beyond methotrexate. We also hypothesise simultaneous targeting of immune and inflammatory pathways will interrupt the self-perpetuating cycle that drives chronicity.

Research objectives

Our core objective is the development of a combined therapeutic approach that will deliver long-term disease remission. We are also addressing questions which will help us understand the complex role played by tumour necrosis factors (TNF) in the immune system.

Specifically, our current research is focussed on understanding the regulatory pathways activated by TNF receptor signalling, including IRAK-M, which is a negative regulator of Toll-like receptor and IL-1 receptor signalling.

In addition, we are using next generation sequencing technologies to investigate the role of TNF receptor signalling in controlling the activity of regulatory T cells, which play a key role in maintaining a healthy immune system.

More recently, we have undertaken a new initiative, which aims to understand and exploit the indoleamine 2,3-dioxygenase pathway for the treatment of immune-mediated inflammation. As part of this research we are currently examining the potential of kynurenine pathway modulators to influence the activity of regulatory T cells Th17 cells.