Investigators and Projects
Both these papers take a mathematical modelling approach to investigate the importance of specific parameters in the development of autoimmune disease. In the first we use experimental data and show tha the dynamics of APC mobilisation play a key role in establishing rapid oscillations in target organ cell content. The second paper provides a model of autoimmunity that arises because of changes in the T Cell Receptor activation threshold following viral infection.Raveney, B. J. E., Copland, D. A., Calder, C.J., Dick, A. D., and Nicholson, L. B. (2010) TNFR1 signalling is a critical checkpoint for developing macrophages that control T-cell proliferation
Macrophages obtained from the eye profoundly suppress T cell proliferation. This paper shows that the development of this phenotype is dependent on signalling via TNFR1. Without this signal, macrophages support T cell proliferation. However, the suppressive function does not depend directly on signalling, since maturation in the presence of interferon gamma and prostaglandin E2 can turn a TNFR1 deficient macrophage into an efficient myeloid derived suppressor cell (MDSC) like phenotype.Wu WK, Llewellyn OP, Bates DO, Nicholson LB, Dick AD (2010) IL-10 regulation of macrophage VEGF production is dependent on macrophage polarisation and hypoxia
Macrophages integrate many signals from the environment and respond with a number of mediators that have profound effects on tissue remodelling. One of these is angiogenic growth factor VEGF. In these experiments, we investigated the role of IL-10 in regulating the angiogenic switch and showed that this was determined by other environmental factors. Consequently,therapies to suppress macrophage activation that as a result generate IL-10, or utilising IL-10 as a potential anti-angiogenic therapy, may result in a paradoxical support of neovascularisation and on-going tissue damage or aberrant repair.T. K. Khera, A. D. Dick and L. B. Nicholson (2010) Fragile-X-related protein FXR1 controls post-transcriptional suppression of lipopolysaccharide-induced tumour necrosis factor-alpha; production by transforming growth factor-beta1
Many cytokines are regulated through the action of mRNA binding proteins that interact with sequences in the 3'-UTR of their mRNA. TNF-alpha is a striking example of this and it is controlled by several different proteins. In this paper we show that an anti-inflammatory cytokine, TGF-beta1, induces the mRNA binding protein FXR1, implicating these two in negative feedback regulation. Such regulation might be exploited to reduce the over-expression of TNF-alpha that is a feature of uveitis.D. A. Copland, K. Hussain, S. Baalasubramanian, T. R. Hughes, B. P. Morgan, H. Xu, A. D. Dick and L. B. Nicholson (2010) Systemic and local anti-C5 therapy reduces the disease severity in experimental autoimmune uveoretinitis
The complement system is an ancient defence against infection and a pre-eminent example of the power of proteolytic cascades to amplify a small signal and produce a big response. In recent years there has been a lot of very interesting work identifying its role in modulating adaptive immune responses too. In the work described in this paper, which we carried out in collaboration with colleagues at Cardiff University, we found that inhibiting one step in this activation cascade dramatically reduced the severity of uveitis. Since the reagent has already been licensed for use in patients, this raises the possibility that its use could be translated quite rapidly to the clinic.Raveney, B. J. E., Copland, D. A., Dick, A. D., and Nicholson, L. B. (2009) TNFR1-Dependent Regulation of Myeloid Cell Function in Experimental Autoimmune Uveoretinitis
When inflammation develops in the retina, hundreds of thousands of white blood cells enter the eye as part of the autoimmune inflammatory response. Many of these are macrophages, and they cause extensive damage, because they are activated to fight infection by releasing mediators that kill cells. Activation also does some other interesting things to the macrophages. It produces cells that stimulate T cells to produce cytokines, but not to proliferate, and it leads to the expression of cell markers which are also found on macrophages that infiltrate tumours. In this paper, we investigate a key signalling molecule, TNFR1, and show that it plays an important role in inducing these functions and also in controlling the trafficking or accumulation of macrophages to within the eye.
A talk by Nobel laureate Sydney Brenner, got me thinking about the balance the immune system has to strike between preparing for the inevitable and expecting the unexpected .
I was in school recently, talking to some sixth formers about immune responses and how they can provoke autoimmunity. One story that struck a chord with the students was about the relationship between the search for a cure for rabies and autoimmune disease. I've put a summary of it here.
Copland, D. A., Wertheim, M. S., Armitage, W.J., Nicholson, L. B., Raveney, B.
J. E. and Dick, A. D. (2008).
The clinical time-course of experimental autoimmune uveoretinitis using topical endoscopic fundal imaging with histological and cellular infiltrate correlation
Invest. Ophthalmol. Vis. Sci. 49, 5458-5465 doi:10.1167/iovs.08-2348
Doctors need to be able to see into the eye to diagnose disease. When we study uveitis in mice, it's important to do this too, but until now visualizing the back of the mouse eye has been a challenge. By using a technique called Topical Endoscopic Fundal Imaging, (TEFI) that was described recently by Michel Paques and his colleagues, we can see more detail in the back of the mouse eye than ever before. We have used this new technique to capture high resolution images of the retina and study the clinical stages of ocular inflammation in mouse eyes over time. Until now, it has not been practical to monitor and correlate clinical changes with changes in the numbers and type of inflammatory cells within ocular tissues of living animals. Our application of this approach will allow us to assess more accurately new drugs, that are being tested to determine if they prevent sight loss, and expedite the translation of these drugs to patients in the clinic.
Kerr, E. C., Raveney, B. J. E., Copland, D. A., Dick, A. D., and Nicholson, L.
Analysis of Retinal Cellular Infiltrate in Experimental Autoimmune
Uveoretinitis Reveals Multiple Regulatory Cell Populations.
J. Autoimmunity 31, 354-361 DOI:dx.doi.org/10.1016/j.jaut.2008.08.006
The blinding condition uveitis depends on the movement of white cells of the immune system from the blood into the eye. Once in the eye, they damage the retina and disrupt sight. The drug FTY720 (fingolimod) inhibits the traffic of a subset of the white blood cells called T cells and is being tested in long term studies in multiple sclerosis. In a model of uveitis, we found that treatment with FTY720 led to a rapid and dramatic reduction in the traffic of white cells into the eye. We believe this type of approach will be useful in treating patients with uveitis. In the course of disease, these patients may have many numerous sudden attacks. A therapy that can terminate these rapidly, at an early stage, would be a significant therapeutic advance and prevent deterioration in vision.