Investigators and Projects
I often wonder when my interest in immunology first took root. It was probably when I was studying pathology. As part of the course, we had a short series of lectures on the immune response. I don’t think I realised it at the time, but I came away hooked. About a year later I persuaded the same department to give me £50 to go to a meeting organised by Nature magazine in London. To earn the money, I gave a lunch-time seminar at which I spilled over with enthusiasm for the elegant molecular approaches that Michael Neuberger and Greg Winter were using to produce chimeric antibodies. At the end of the presentation I took questions, and one came from a crusty looking gentleman sitting at the back. ‘But what use,’ he asked, ‘will monoclonal antibodies ever be to me?’
Although his question left me speechless, it did not dull my enthusiasm. Eventually this propelled me to London where I worked on thyroid autoimmune disease, (or Grave’s disease), with Paul Banga and Alan McGregor. During my time as a PhD student, I developed a longstanding interest in the mechanisms of T cell recognition and activation. For anyone interested in autoimmune disease, this issue of how pathogenic cells get activated is key.
Trying to answer this question took me, eventually, from London to Boston to Vijay Kuchroo’s laboratory. Here we spent several happy years focussing on how peptides with single amino acid substitutions (altered peptide ligands) influence the type of autoimmune response that in people causes multiple sclerosis. Quite early in my time with Vijay, we published a paper in this area, showing that altered peptide ligands (APLs) could modulate experimental autoimmune encephalomyelitis (Immunity 3: 397-405 1995), which I am proud to say continues to be highly cited. In work with Ana Anderson, we found that certain MHC molecules could be associated with large populations of autoantigen specific T cells (Journal Of Experimental Medicine 191:761-770 2000). This led us to a novel hypothesis that explained the well known association between specific MHC haplotypes and autoimmune disease; specifically that some MHC molecules selected a more potentially dangerous repertoire of T cells than others.
I also continued to work on cross-reactive T cell responses, studying one T cell receptor, called 1B6, in some detail. One of the important conclusions from this work was that the immune response incorporated mechanisms for modifying the responses potentially dangerous T cells in a way that could preserve their usefulness but minimise their danger. Much of this work was covered in a review that Vijay, other members of his lab and I wrote (Annual Review of Immunology 20:101-123 2002). In 2003 I moved to Bristol University where I extended my interest in organ specific autoimmune disease to the eye. One early project focussed on the control of nitric oxide secretion by macrophages lacking the TNFreceptor 1. This work, with Claudia Calder and Andrew Dick, was recognised and the most significant contribution to basic uveitis research of 2005, by the Deutche Uveitis Arbeitsgemeinschaft.
The work in my lab in Bristol continues my long term interest in how autoimmune inflammation is initiated and regulated. Over the years I have moved to trying to examine the whole response, and so we now expend a lot of effort in understanding the contribution of antigen presenting cell activation. But the main goal remains unchanged. To control autoimmune inflammation safely and specifically, to treat the chronic debilitating conditions it causes.