Temporal Changes in MRI Activity, Inflammation, Immunomodulation, and Gene Expression in Relapsing-Remitting Multiple Sclerosis Subjects Treated with Helminth Probiotic Trichuris Suis (S30.004)

Abstract

Objective: To define critical points at which immunological markers and gene expression patterns correlate with changes in brain MRI activity during treatment with Trichuris suis ova (TSO) in the HINT clinical trial for relapsing-remitting multiple sclerosis (RRMS). Background Despite extensive investigation in animal models and promising results in exploratory studies of helminth-induced immunomodulation for autoimmune diseases, including multiple sclerosis, at present the mechanism of action and key operative molecules are not well-understood. Design/Methods: Peripheral blood mononuclear cells (PBMC) and serum were obtained from RRMS subjects before, during, and after treatment with 2,500 live TSO given orally every 2 weeks. Serial determinations of inflammatory markers (CRP, eosinophils), immune responses (PBMC phenotypes),and gene expression (Affymetrix GeneChip 1.0 ST Array) were performed and compared with brain MRI scans read by masked neuroradiologists. Results: New enhancing MRI lesions (NEL) were significantly reduced in 5 of 6 subjects after TSO treatment. In individual subject 110, for whom frequent MRI studies at 2-4 week intervals were performed, a 91% relative reduction in NEL was observed after treatment. Markers of inflammation peaked at 1-2 months after treatment initiation and declined thereafter. CD8+/CD161hi T cells, which may be associated with IL-17 production, decreased in frequency in 2 out of 3 subjects. Gene expression tested in 3 subjects by enrichment analysis demonstrated significant changes (z-score > 4.0) in 17 Gene Ontology (GO) pathways after treatment, including GO:0034143, regulation of TLR-4 pathway; GO:0002684, positive regulation of immune system; GO:0002694, regulation of leukocyte activation; and GO:0004896, cytokine receptor activity. Conclusions: In exploratory studies of RRMS subjects treated with the probiotic helminth TSO, early inflammation, likely due to innate immunity, was followed by favorable adaptive immune responses temporally associated with reduction in brain MRI activity. Supported by: National Multiple Sclerosis Society research grant GR 3613A4/1 to JF. NIH research grant 1R56AI091462-01 to ZF. Disclosure: Dr. Fleming has received personal compensation for activities with Coronado Biosciences as a scientific advisory board member. Dr. Isaak has nothing to disclose. Dr. Hardin has nothing to disclose. Dr. Huston has nothing to disclose. Dr. Boland has nothing to disclose. Dr. Broman has nothing to disclose. Dr. Kendziorski has nothing to disclose. Dr. Field has nothing to disclose. Dr. Fabry has nothing to disclose.