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New research from Dr Richard Williams’ group at the Kennedy Institute suggests a route for the development of more selective – and effective – therapies for immune-mediated inflammatory disease.

Dissecting tnf signalling in inflammatory disease
Artists representation of T lymphoyctes. Signalling through TNFR2 receptor maintains Foxp3 expression in suppressor T lymphocytes.

Anti-TNF therapy is used to treat millions of patients worldwide for rheumatoid arthritis and other immune-mediated inflammatory diseases (IMIDs). Current anti-TNF therapies block both receptors for TNF - TNFR1 and TNFR2. However, new work from Dr Richard Williams’ lab suggests the development of therapies that specifically block TNFR1 could be advantageous for treating IMIDs.

The Williams lab found that TNFR2 plays a role in limiting the severity and duration of arthritis in animal models. Signalling through TNFR2 prevented methylation of the gene encoding Foxp3, a key protein for maintaining suppressor T regulatory cells that promote immune homeostasis.  

Richard said: “This research has been a great team effort and the results exemplify the complexities of cytokine biology. Thus, one molecule, TNF, can have completely opposing effects, depending on which receptor it acts upon.”

Although biologics targeting TNF have improved the lives of millions of people living with IMIDs, not all patients respond adequately to therapy. The new work suggests an approach to develop more selective therapies to increase efficacy and reduce side effects. 

Richard explains, “This research is likely to further stimulate the clinical development of novel biologics for IMIDs that specifically target TNFR1, whilst sparing TNFR2 signalling. In addition, the finding that TNFR2 controls the activity of regulatory T cells may have implications for cancer therapy as these cells are thought to contribute to immunosuppression within the tumour microenvironment.” 

The work was supported by funding from the Chang Gung Memorial Hospital and the Ministry of Science and Technology, Taiwan.