Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study

Abstract

Background: Probiotic treatment strategy based on the hygiene hypothesis, such as administration of ova from the non-pathogenic helminth, Trichuris suis, (TSO) has proven safe and effective in autoimmune inflammatory bowel disease.

Objective: To study the safety and effects of TSO in a second autoimmune disease, multiple sclerosis (MS), we conducted the phase 1 Helminth-induced Immunomodulatory Therapy (HINT 1) study.

Methods: Five subjects with newly diagnosed, treatment-naive relapsing-remitting multiple sclerosis (RRMS) were given 2500 TSO orally every 2 weeks for 3 months in a baseline versus treatment control exploratory trial.

Results: The mean number of new gadolinium-enhancing magnetic resonance imaging (MRI) lesions (n-Gd+) fell from 6.6 at baseline to 2.0 at the end of TSO administration, and 2 months after TSO was discontinued, the mean number of n-Gd+ rose to 5.8. No significant adverse effects were observed. In preliminary immunological investigations, increases in the serum level of the cytokines IL-4 and IL-10 were noted in four of the five subjects.

Conclusion: TSO was well tolerated in the first human study of this novel probiotic in RRMS, and favorable trends were observed in exploratory MRI and immunological assessments. Further investigations will be required to fully explore the safety, effects, and mechanism of action of this immunomodulatory treatment.

Trial registration: ClinicalTrials.gov NCT00645749.

Figure 1

MRI Results. Masked reading of the number of new (unique to each scan) enhancing lesions after double-dose gadolinium (0.2 mmol/kg body weight) administration on a 3-Tesla MRI brain scan by study day, with study day 1 being the first day of Trichuris suis ova (TSO) administration. Shown in the figure are the screening period (1 month), TSO treatment period (3 months), and the post-treatment observation period (2 months). Subjects are designated by the symbols shown in the insert box.

Figure 2

Systemic acute-phase reactants. (A) Serum high-sensitivity C-reactive protein (hs-CRP) levels in mg/l. (B) Blood eosinophil levels in cells/μl. (C) Specific IgG1 for Trichuris suis in optical density units (OD 465nm). (D) Specific IgA for T. suis in optical density units (OD 465nm).

Figure 3

Serum cytokine determinations. The cytokines shown were measured by ELISA and reported in pg/ml.

Figure 4

Frequency of alternatively activated monocytes (AAM). After isolation of peripheral blood mononuclear cells by Ficoll density gradient and staining for CD14+ (monocytes), cells were stained with markers characteristic of AAM (Panel (A) CD23+; Panel (B) CD 124+). Representative results are shown for a control healthy donor subject and two of the study subjects, 001 and 002. Data are shown for timepoints at screening and after 1, 2, or 3 months of TSO treatment, and the frequency of doubly stained, AAM phenotypic cells is indicated by the insert box and the percent enumerations shown. No significant increases in AAM frequency were noted during TSO treatment.

Figure 5

Frequency of CD4+CD25+FoxP3+T regulatory cells. After isolation of peripheral blood mononuclear cells by Ficoll density gradient, cells were stained for CD4 and CD25, fixed and permeabilized, and then stained for Foxp3 expression. The frequency of FoxP3+ cells as a percentage of total CD4+ cells for all subjects during the study is shown.