The Worm-Specific Immune Response in Multiple Sclerosis Patients Receiving Controlled Trichuris suis Ova Immunotherapy

Abstract

Considering their potent immunomodulatory properties, therapeutic applications of Trichuris suis ova (TSO) are studied as potential alternative treatment of autoimmune disorders like multiple sclerosis (MS), rheumatoid arthritis (RA), or inflammatory bowel disease (IBD). Clinical phase 1 and 2 studies have demonstrated TSO treatment to be safe and well tolerated in MS patients, however, they reported only modest clinical efficacy. We therefore addressed the cellular and humoral immune responses directed against parasite antigens in individual MS patients receiving controlled TSO treatment (2500 TSO p.o. every 2 weeks for 12 month). Peripheral blood mononuclear cells (PBMC) of MS patients treated with TSO (n = 5) or placebo (n = 6) were analyzed. A continuous increase of serum IgG and IgE antibodies specific for T. suis excretory/secretory antigens was observed up to 12 months post-treatment. This was consistent with mass cytometry analysis identifying an increase of activated HLA-DRhigh plasmablast frequencies in TSO-treated patients. While stable and comparable frequencies of total CD4+ and CD8+ T cells were detected in placebo and TSO-treated patients over time, we observed an increase of activated HLA-DR+CD4+ T cells in TSO-treated patients only. Frequencies of Gata3+ Th2 cells and Th1/Th2 ratios remained stable during TSO treatment, while Foxp3+ Treg frequencies varied greatly between individuals. Using a T. suis antigen-specific T cell expansion assay, we also detected patient-to-patient variation of antigen-specific T cell recall responses and cytokine production. In summary, MS patients receiving TSO treatment established a T. suis-specific T- and B-cell response, however, with varying degrees of T cell responses and cellular functionality across individuals, which might account for the overall miscellaneous clinical efficacy in the studied patients.

The interplay between Trichuris and the microbiota

“…Harnessing how enteric parasites, such as whipworms, interact and modulate the gut microbiota will open new avenues for exploring anthelminthic treatments and addressing the growing concern of the ‘microbial diversity’ hypothesis regarding the dramatic increase in the incidence of allergic and autoimmune diseases in developed countries. Human trials using Trichuris eggs (specifically T. suis ) show promise as a probiotic agent, and has been used in trials as a treatment for multiple sclerosis (Fleming et al ., 2011 , 2019 ; Yordanova et al ., 2021 ; Williams et al ., 2017 ). More recently, clinical intervention trials using T. suis eggs against psoriasis and IBD are ongoing in North America, and it will be interesting to see how Trichuris can reduce symptoms mediated by an altered immune response and potentially by changes in gut microbial composition (Prosberg and Petersen, 2018 –2021).…”

A Helminth-Derived Chitinase Structurally Similar to Mammalian Chitinase Displays Immunomodulatory Properties in Inflammatory Lung Disease

“…Patients receiving TSO therapy, however, seem to not equally benefit from the worm therapy [ 22 , 26 – 28 ]. In this context, we observed a considerable degree of interindividual variability in the adaptive immune responses to this helminth treatment [ 29 ] suggesting that even how the anti-TSO response is formed depends on the environmental and inflammatory context of the individual treatment.…”

“…Early success stories of treatments of ulcerative colitis (UC) and Crohn's disease (CD) with TSO [ 23 – 25 ] were followed by larger trials with only modest results for various autoimmune diseases [ 22 , 26 – 28 ] and implicated the need for a greater understanding for the immunomodulatory mechanisms. In a rather small cohort of MS patients receiving controlled TSO treatment, we demonstrated varying degrees of parasite-specific T cell responses and cellular functionality across individuals receiving treatment, indicating the need to understand responders and nonresponders in order to develop more tailored treatment regimens [ 29 ].…”

Infection with Hymenolepis diminuta Blocks Colitis and Hastens Recovery While Colitis Has Minimal Impact on Expulsion of the Cestode from the Mouse Host

“…However, Crohn’s disease is a heterogeneous condition and with broad inclusion criteria for enrolling patients in the trial it is perhaps naïve to think that a single species of parasitic helminth could benefit all patients: There was also a high placebo effect in the trial [ 32 ]. Similarly, helminth therapy has been tested in multiple sclerosis and found to be safe; however, any beneficial “effect was modest” with considerable variation between subjects [ 33 , 34 ], with an inter-individual variability also seen in T. suis -specific T and B cell responses [ 35 ]. In addition, it is increasingly apparent that infection with enteric parasitic helminths affects the composition and activity of the gut microbiota [ 5 , 16 , 36 ], the production of short chain fatty acids by which has been implicated as a mediator of helminth-initiated anti-inflammatory effects [ 28 , 37 ].…”