New Research Grants Announced

Professor Miriam Wittmann, University of Leeds

We now have a range of medicines available to treat psoriasis. These therapies work in many but not all patients and some patients have to stop medication due to side effects. Unfortunately, we still do not have tests available to tell us which therapy works best for which patients. The answer to this question is of high importance. At present, many patients experience a phase of “trial and error” before a good therapy is identified. Failure to respond to treatment leads to frustration, depression and potential side effects from ineffective drugs.

Our project aims to predict therapy response to the commonly used drugs methotrexate and adalimumab. Our approach is different from already existing ones. Along with clinical data we also will collect information from affected skin but will not need biopsies. Instead we use a non-invasive tape stripping. We have used this method before and have optimised it so we can now detect thousands of proteins from each sample.

Due to the large amount of data collected it is impossible to analyse this information manually. We will therefore input all of the different and complex data into a “machine learning” computer program. Machine learning can be very powerful. Through many millions of calculations the computer is able to find “patterns” within very complex data. In our case we will look for the best “pattern” to predict response to methotrexate and adalimumab. We will share the program that we develop so that other researchers can use it to predict response to other drugs.

Professor Silvia Bulfone-Paus, University of Manchester

Psoriasis is a common, chronic, and as yet incurable inflammatory skin disease. Our project seeks to investigate the contribution of specific skin immune cells, namely mast cells and CD8 T lymphocytes (CD8 T cells), to the development of psoriasis. The latter have long been known to play a critical role in psoriasis, while the former cells have mainly been studied in the context of psoriasis-associated itch. Instead, here we explore whether mast cell-CD8 T cells interactions actually can drive the disease and are thus an important, new therapeutic target.

In psoriasis plaques, both mast cells and CD8 T cells are higher in number than in normal, healthy skin and appear to interact closely with each other. Furthermore, by isolating mast cells from skin biopsies and comparing their gene expression in healthy skin and in psoriasis plaques we have identified a number of secreted products or mediators of mast cells whose expression is increased in psoriasis and can regulate CD8 T cell activities.

Therefore, the overall goal of our project is to characterize the biological significance of mast cells-CD8 T cell interactions and how these may contribute to the development of psoriasis and their response to treatment. We also study how their activities are affected by biologic therapy targeting a key immune system molecule – interleukin (IL) 17. This knowledge will suggest novel strategies for therapeutic intervention, e.g. by manipulating mast cell mediators in psoriatic plaques so as to block the activation of CD8 T cell and thus reduce skin inflammation.

Dr Francesca Capon, King’s College London

Several studies have demonstrated that smokers are at increased risk of psoriasis. At the same time, it is not clear whether giving up cigarettes can improve disease symptoms. Our study will address this important question by:

- Identifying the changes that occur in the skin of smokers affected by psoriasis

- Demonstrating that these alterations can be reversed by quitting smoking

Thus, our specific objectives will be:

- To identify changes in chromosome conformation in psoriatic skin. Smoke can affect the way that genes and proteins are packaged together into chromosomes. As this can influence the activity of genes that contribute to inflammation, we will compare chromosome conformation in individuals with psoriasis and healthy volunteers.

- To demonstrate that the chromosome changes observed in psoriatic skin are linked to smoke. We will grow skin cells in a dish, in the presence of chemical substances that are found in cigarette smoke. We will then determine whether these chemicals can induce the same changes we observed in the skin of affected individuals.

- To show that giving up cigarettes can reverse the chromosome changes induced by tobacco. We will obtain skin biopsies from psoriasis sufferers who have agreed to stop smoking. We will determine whether their chromosomes are reverting to a normal conformation and whether this correlates with an improvement in disease symptoms.

Taken together, these experiments are expected to provide a scientific rationale for introducing stop-smoking programmes in the treatment of psoriasis.

Dr Alison Havelin, Royal Victoria Infirmary, Newcastle

Psoriasis is a chronic skin disease affecting 2% of the UK population. It is a visible, often stigmatising disease and can have a significant impact on patients’ quality of life. UVB (ultraviolet B light) is one of the few psoriatic treatments that can lead to complete psoriasis clearance and a period completely free of psoriasis (remission) after treatment has stopped. For patients, this means living a life without the burden of applying messy topical therapies or taking potentially harmful medications to control their disease. The achievement of improved clinical remission with UVB is therefore highly attractive.

UVB is more effective in some patients than others, with 2/3 of patients achieving good clearance. The response to UVB is variable and currently there is no accurate way of predicting which patients will do better than others.

A typical UVB treatment course requires patients to attend hospital 3 times weekly for 6-10 weeks. Our recent study identified a subgroup of patients who were less likely to achieve clearance of their psoriasis, by analysing their response after just 3 weeks of treatment.

We hypothesis that by identifying these “slow-responders” early and changing their phototherapy regimens from three times per week to five times per week, they will have a better chance of clearing. To the best of our knowledge, this has never been studied before.

The optimisation of UVB treatments based on individual responses allows us to develop personalised treatment plans. This would benefit patients by reducing the need for potentially toxic systemic treatments and would result in better utilisation of NHS resources.

Dr David Hill, the University of Sunderland

Psoriasis is a chronic skin complaint characterised by raised red patches of skin called plaques. These plaques are caused by the over-production of skin cells, which in contrast to normal skin cells that die and become replaced by healthy cells from below, fail to die off correctly leading to thickened skin and impaired skin barrier function. As a result, psoriatic plaques can often become inflamed and painful. Unfortunately, despite the development of new immuno-therapies there remains no cure. Therefore, to develop more effective therapies for psoriasis we need a better understanding of the underlying causes of the disease.

Our preliminary data and results from previous studies suggest that psoriasis skin has increased expression of a protein called fatty acid binding protein 5 (FABP5), which is responsible for controlling the breakdown of a class of growth-regulators called endocannabinoids, and has been linked to increased growth of several cancers. We propose that endocannabinoids, which suppress the growth of normal skin cells, are degraded in the skin of psoriasis patients leading to increased cell production and defective skin barrier formation. Our research aims to investigate how frequently levels of FABP5 are increased in psoriasis by staining a small cohort of affected and unaffected skin biopsies with antibodies that detect FABP5. We will also reconstruct full-thickness skin in the lab from normal skin cells that we have genetically modified to increase levels of FABP5, which will tell us whether high FABP5 is sufficient to cause psoriasis. Finally, because psoriasis skin likely has reduced levels of endocannabinoids, we will investigate the effect of cannabinoid treatment (and specific FABP inhibition) on the growth and behaviour of FABP5-expressing skin cells.

Patients and health practitioners are increasingly looking at cannabis and cannabis-derived compounds as realistic and viable sources of medicine due to their excellent safety profile and changing legal status. However, the lack of preclinical evidence regarding disease-specific mechanisms and efficacy is a cause for concern. This study will allow us to better understand the role of cannabinoid signalling in psoriasis, which will form a rational basis for conducting future in-patient clinical trials.