Maple, P.A.C.
(2018)
Human herpes virus antibody levels in helminth treated and placebo controlled multiple sclerosis patients.
MRes thesis, University of Nottingham.
Abstract
In the UK, multiple sclerosis (MS) is the leading cause of non-traumatic disability in young adults. MS most commonly presents in a relapsing-remitting form (RRMS); however, over time, a progressive, neurodegenerative pathology dominates, and the disease enters a secondary progressive phase. Approximately, 10-15% of MS cases are primary progressive, some with superimposed relapses. During RRMS an underlying autoimmune pathology presides which leads to nerve damage through inflammatory processes. Therapeutic modulation of these inflammatory processes is beneficial in reducing relapses and increasing the periods between them. A key approach is to induce a switch in immune system reactivity from a proinflammatory (T helper1) to a less inflammatory (T helper2) profile. Immune system regulation is faulty in MS and reconstitution of regulatory T and B cell activity is a goal of effective intervention strategies. There is evidence that Intestinal parasite (helminth) infection is protective for MS as it induces a T helper2 profile and promotes regulatory cell activity. Deliberate, controlled helminth infection may be a useful therapeutic intervention.
In 2012, the Nottingham University Hospitals Multiple Sclerosis Clinic commenced the Worms for immune regulation of multiple sclerosis (WIRMS) study (NCT 01470521), which was a randomized, double-blinded, placebo controlled study of hookworm treatment of multiple sclerosis. A total of 72 patients were enrolled, 36 were infected with 25 larvae of Necator americanus and 36 were given placebo. At the time of commencement, this was the largest study so far performed to assess the efficacy and safety of helminth therapy. Subsequently, concerns that helminth therapy might induce Epstein-Barr virus (EBV) reactivation have been raised and a key objective of the study presented in this thesis was to assess whether EBV reactivation is a complication of helminth therapy. Because a unique collection of serially collected samples was available together with relevant clinical information it has proven possible to investigate the time course of infection of EBV and other selected human herpesviruses (cytomegalovirus and varicella zoster virus) in helminth treated and placebo controlled patients.
Markers of EBV infection (early antigen IgG – EBV EA IgG, virus capsid antigen IgG and IgM – EBV VCA IgG and IgM, nuclear antigen-1 IgG – EBNA-1 IgG), cytomegalovirus infection (CMV IgG) and varicella- zoster virus infection (VZV IgG) were measured using commercially available enzyme-linked immunoassays (ELISAs). Samples from 51 patients (26 helminth infected and 25 placebo controlled) were available for testing and pre-treatment status was measured together with levels during the nine months of helminth infection and post infection/placebo status three months after the cessation of treatment. There was no evidence of treatment related herpesvirus reactivation in any of the patients sampled. Pre-treatment a total of 8 (30.7%) helminth treated patients were EBV EA IgG positive compared to 10 (40.0%) placebo controlled patients. The difference in the EBV EA IgG sero-positivity between the two groups was not significant and a state of constant reactivation was maintained throughout the study period. All patients (n = 51) were EBV VCA IgG and EBNA-1 IgG positive and antibody levels were stable throughout the study. One helminth treated patient was EBV VCA IgM positive and one placebo-controlled patient was EBV VCA IgM positive and in both cases, the pre-treatment serum samples were EBV VCA IgM positive. A total of 13 (50%) helminth treated patients and 4 (16.0%) placebo control patients were positive for CMV IgG. The difference in the CMV IgG sero-positivity between the two groups was significant. Generally, the CMV IgG levels were stable throughout the study period. All patients were VZV IgG positive and VZV IgG levels were constant over the study period in all but one case.
In conclusion, there was no evidence of EBV reactivation, or reactivation of other human herpesviruses, at the therapeutic dose of N. americanus used. The number of N. americanus larvae used to infect patients may prove critical as higher doses may prove deleterious to the patient and lower doses may fail to generate an adequate immune response. Generally, antibody levels of all IgG markers were stable throughout the study period. There was a significant mismatch of CMV seropositivity between the helminth treated and placebo control groups and the reasons for this sero-discordance are difficult to explain, particularly as patient recruitment was randomized. Cytomegalovirus serostatus may influence host immune responses and so prejudice the key principle that “like” is being compared with “like” apart from the treatment given. It would be most interesting to determine if other “randomized” clinical trials show CMV sero-discordances at the recruitment stage. Future clinical trials assessing the immunomodulatory effects of helminth infection may need to take account of patient CMV sero-status at the recruitment stage if the findings of this study are replicated. Finally, for this study the bulk of patient clinical data remains to be made available at the time of writing of this thesis, so any conclusions put forward should be viewed as preliminary.
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