One of the main foci of our research is to explore new avenues in MS treatment and toOne of the main foci of our research is to explore new avenues in MS treatment and togain a greater understanding of how best to use our current disease modifyingtherapies (DMTs). There are 9 approved DMTs in the UK and more are becomingavailable every year. All of them aid in decreasing inflammation and it is thought theymight even protect neurons. All DMTs work with the overall aim to improve the clinicaloutcome of people with MS.DMTs have been found to decrease the number and severity of relapse, slow thedevelopment and progression of brain and spinal cord lesions, and reducedisabilities. However, there is currently little to no evidence on which type of DMT isbest, for which patients, and when would be the most beneficial time to use them toget the best results.Stronger treatments are usually associated with riskier side effects. Therefore, thequestion is, can we find the right balance of effectiveness and side effects? Our aim,working with many other MS research teams across the world, is to provide thisevidence in order to find the best treatment for each patient.

  1. WIRMS (Worms for Immune Regulation in MS)

Epidemiological, experimental and limited clinical evidence indicates that gut helminths are protective in MS. Taking advantage of unique immunoparasitology experience at University of Nottingham and experience with therapeutic helminth trials, we conducted the largest randomised controlled trial on hookworm infection in relapsing MS. 71 patients received either hookworm larvae through the skin or placebo over 9 months, undergoing monthly MRI and immunology tests. We show that considerably more hookworm-treated MS patients had no new disease activity on MRI, and that hookworm increased regulatory cells that suppress inflammation. Follow up studies optimising the outcome measures, the target patient population, and hookworm dose are planned.

            Funder: MS Society; Bayer; Forman Hardy Charitable Trust

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  2. WIRMS – virology/EBV

Previous experimental evidence in mice shows that infection with gut parasites increases the risk of reactivation of gamma herpesvirus, the mouse equivalent EBV, the virus strongly associated with MS. We looked for EBV reactivation in MS during hookworm infection, and showed that there was no reactivation, and no differences from placebo. Dr Peter Maple, a virologist with interest in herpesviruses including EBV performed this research as part of his MRes in immunology. We found that a substantial proportion of MS patients, unlike healthy controls, have a continuous reactivation of EBV (regardless of treatment). Moreover, we found an inverse correlation between CMV infection and EBV responses, suggesting a protective action of CMV. Indeed, fewer patients with MS than controls were positive for CMV.

            Funder: MS Society through WIRMS; Forman Hardy Charitable Trust

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  3. WIRMS – microbiota

The gut microbiota is increasingly implicated in MS. Therapeutic helminths act in part by modifying the gut microbiota in a beneficial way. The WIRMS trial offered the opportunity to obtain one of the largest collections of gut microbiota samples in MS. The composition of the gut microbiome was investigated in collaboration with colleagues at Cambridge University. The placebo arm provided information about the composition and stability of the microbiota in untreated MS, while the helminth arm provided unique information on the effect of helminth treatment of MS on the gut microbiota. Changes associated with the treatment response, with relapses and with MRI activity were detected.

            Funder: MS Society through WIRMS

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  4. MSC MSC (mesenchymal stem cells in MS and controls)

Mesenchymal stem cells (MSC) have immunomodulatory and potential neuroregenerative capacity. There is almost no information on the effect of the interaction of MSC from people with MS with immune cells from the same donor, and how that differs from healthy volunteers. We have pioneered a study investigating these interactions and found that MSC from people with MS have diminished immunomodulatory activity on immune cells from the same donor, and in fact can enhance inflammatory responses. We have identified key factors involved in this faulty interaction. These factors can be targeted in the future, allowing MSC transplants to regain their immunomodulatory capacity.

            Funder: MS Society

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  5. GM-CSF in MS

Recent evidence implicates pro-inflammatory cytokine GM-CSF as a key factor in MS pathogenesis, likely to be more important than the traditional Th1 and Th2 cytokines. In a first trial of its kind, the safety, tolerability and immunogenicity of an anti-GMCSF antibody was tested in a phase I international trial led from Nottingham. The primary outcomes were reached, and there was suggestion an immunomodulatory action warranting further study.

            Funder: Morphosys

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  6. GM-CSF in MS – effect on oligodendrocytes

Radhika Patel completed a MRes investigating the effect of GM-CSF on human oligodendrocytes, the cells that produce myelin. GM-CSF suppressed production of myelin proteins, providing a mechanism for the demyelination seen during inflammation in MS, and suggesting that blocking GM-CSF for example through an antibody may facilitate remyelination.

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  7. THRIFT-MS (Tysabri High Resolution Imaging and Function of T cells in MS)

In this study, we investigated whether subtle changes in white and grey matter integrity still occur despite no new lesion development over 1 year of treatment with the potent DMT Tysabri. Reassuringly, even when imaging at ultra-high field (7 Tesla) we did not find such changes. Tysabri reduced some T cells subgroups that are damaging in MS more successfully than interferon beta.

            Funder: Biogen

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  8. Determining the Effectiveness of Early Intensive versus Escalation Approaches for the Treatment of Relapsing-Remitting Multiple Sclerosis - (DELIVER-MS)

DELIVER-MS is a study coordinated by Nottingham and the Cleveland Clinic in the USA is comparing two treatment strategies in 400 people with relapsing-remitting MS who have never taken a disease-modifying therapy. The study is recruiting at 30 centres in the United States and United Kingdom. One strategy is an “escalation” approach, in which individuals start taking a less-powerful therapy with the option of switching to a more potent one if disease activity continues. The other strategy involves starting with a strong therapy that is potentially more effective, but also carries greater risk for significant adverse effects.

Funder Patient-Centered Outcomes Research Institute (PCORI)

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  9. Interactive effects of Teriflunomide and repurposing molecules on a model of blood brain barrier

We study the effects and interactions of disease modifying treatments such as Teriflunomide, and molecules with potential of repurposing in MS, on transporter proteins and cytokine expression in a cultured primary human brain microvascular endothelium as a model of the human blood brain barrier. We aim to detect mechanisms of actions which can improve immunomodulation in MS.

Funder: Genzyme Pharma

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  10. Spinal cord, MS, & diabetes - The SpINDLE study

Our group has pioneered the measurement of spinal cord atrophy in MS and its use in longitudinal studies of MS DMT. In the SpINDLE study, we are applying our imaging techniques to diabetes with or without neuropathy, in an attempt to determine whether spinal cord area/volume can be used as markers of disease progression. This allows us to compare changes and rates of atrophy with those of people with MS.

            Funder: NUH Charity

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  11. Cardiff-Nottingham DMT analysis

Is the current treatment of MS significantly better than the one we used 10 years ago? There is an optimism in MS clinics that patients currently receive stronger treatments earlier and as a result the long-term outcomes are better. We set up a study with the University of Cardiff to explore if this is true and we plan to analyse clinical data from our clinics.

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