Feldmann Group | Unravelling the Role of Cytokines in Disease
My research over the past 30 years has focused on understanding the pathogenesis of autoimmune diseases. In 1983 I published a new hypothesis linking HLA expression, antigen presentation cytokines and autoimmunity (1).
Testing this hypothesis led to the discovery in 1989 of the pivotal role of TNF in rheumatoid arthritis (RA) synovial cultures (2). Testing this concept clinically has shown TNF blockade as both effective and relatively safe, which has dramatically changed therapy for this disease (3) as well as other chronic inflammatory diseases such as Crohn’s disease, ankylosing spondylitis and psoriasis (4). Anti-TNF drugs (antibodies or TNF receptor fusion protein) are now since 2012 the biggest parmaceutical drug class with sales exceeding $25 billion per annum.
But much remains to be done, as only about 60% of RA patients respond well to anti-TNF, and so we need to understand how to get closer to a cure. Some of the work of the Kennedy Institute is focused on testing various approaches to ‘getting closer to a cure’. A new approach is to use the ‘CytoF’ machine which permits multi-parameter analysis (35+) without any auto-fluorescence, to unravel signalling pathways which are still active in patients not responding well to treatment.
My group has extensive links with the biotech and Pharmaceutical industries, much of this in collaboration with the structural Genomics Consortium next door.
Anti-cytokine therapy in a wider context
I have also been very interested to use the understanding we gained about the importance of cytokines in rheumatoid arthritis to gain insights into other important unmet medical needs, using evaluation of cytokines and human tissue as a probe.
It is paradoxical that currently cytokines, acute response mediators are used as therapeutic targets for chronic but not acute diseases. It is likely that this is due to the fact that clinical trials are easier in chronic diseases, and research is easier in chronic diseases. So a long term goal is to help usher in appropriate anti-cytokine therapy in acute diseases. There are many clues that this might work, despite the costly and reputational damaging failure of anti-TNF blockade in severe sepsis of 20 years ago. For example, Prof. Tracey Hussell and Prof. Peter Openshaw have reported that anti-TNF is protective in severe influenza in mice, without reducing the CD8+ immune response, so TNF blockade might work in acute respiratory distress.
Post-Operative Cognitive Dysfunction (POCD)
Together with Prof. Mervyn Maze and other colleagues there has been exploration of new uses for cytokine blockade, in cognitive dysfunction following major surgery: post-operative cognitive dysfunction occurs in more than 10% of older patients with major joint surgery, and even more often in patients after open heart surgery. In an animal model it was shown that blocking IL-1 or TNF (5) were capable of preventing POCD.
Improving the response in inflammatory arthritis
While I am very proud of the part I played in the discovery of anti-TNF therapy, this is not a cure, and more needs to be done to improve therapy in RA and other inflammatory arthritic diseases (6, 7, 8).
There are many projects running to explore novel therapeutic targets, these projects also involve other scientists at the Kennedy Institute, such as Dr Lynn Williams for synovial studies, and Dr Richard Williams and Fiona McCann for animal models.
Coordination of a network of research in Inflammatory Mechanisms and Inflammatory Diseases
Anti-TNF is approved for use in 7 diseases, used in others ‘off label’. So it makes sense to view inflammatory diseases as a group and look for research synergies both in the laboratory and clinically. To help these networks progress, there was a Vice-Chancellor’s Symposium on October 6th, 2011 in the Richard Doll building. And since 1984, we have had a series of translational research meetings, held at Trinity College, to promote research in this field.