Hookworm Infection Seen to Boost T-cells That Regulate Immune System

A person infected through the skin by the hookworm Necator americanus shows a spike in  regulatory T-cells, specialized immune T-cells that work to limit inflammation, and a controlled infection by these generally safe worms may benefit some relapsing multiple sclerosis (MS) patients, research suggests.

“The findings of our study are encouraging. Whilst the results are modest in comparison to the current very potent and highly effective treatments available, some patients with milder disease or more inclined for natural treatments may consider this as an option,” Cris Constantinescu, a neurology professor at the School of Health Sciences, University of Nottingham and a study co-author, said in a press release.

The study, “Hookworm Treatment for Relapsing Multiple Sclerosis, A Randomized Double-Blinded Placebo-Controlled Trial,” was published in the journal JAMA Neurology.

In MS, a hyperactive immune system induces inflammation and demyelination — destruction of the myelin layer that protects nerves — leading to neuronal damage and loss. This also causes an unbalance between the pro- and anti-inflammatory molecules that control immune system activation.

Evidence suggests that MS is less prevalent in countries with a greater frequency of certain infections, like gut worms. This observation prompted researchers to speculate — in what they call the hygiene hypothesis — that certain parasitic infectious agents might protect against inflammatory diseases like MS.

These infectious agents are thought to induce a rise in the numbers of T-regulatory cells (Tregs), which are responsible for preventing the immune system from turning hyperactive.

Studies to date testing worm-based therapies in autoimmune diseases and MS have been of very short duration, with few patients, and without placebo controls. Still, the largest study conducted — which included 16 MS patients — showed moderately positive outcomes on MRI and immunological exams.

A team led by researchers at Nottingham conducted a large, placebo-controlled Phase 2 clinical trial in 71 MS patients, called WIRMS (NCT01470521), to assess whether exposure to a small number of hookworms would ease inflammation and disease activity.

They used the Necator americanus, a hookworm long present in human populations, and one that infects only people. These infections are typically benign, but a high number of worms can cause anemia. In a previous pilot study, these researchers showed that N. americanus infection in healthy volunteers with a small dose of larvae (10 to 50) was safe.

Small larvae were applied in a plaster to the skin, similarly to a natural infection. According to the researchers, this localized infection can last more than five years without the need for a repeat exposure.

Enrolled patients, ages 18 to 61, had never used a disease-modifying treatment. They were randomized to either hookworms (35 people, given 25 Necator americanus larvae via a plaster applied to an arm) or a sham plaster as a placebo group (36 people). The two groups were matched at the study’s start (baseline) in terms of MS clinical and MRI activity.

In total, 66 patients (93%) in the hookworm group and 34 (51.1%) in the placebo group finished the nine-month trial, and 61 in the hookworm group and 30 in the control group completed the three-month safety check that followed.

MRI scans were performed at baseline and throughout to evaluate MS brain lesions.

After nine months, the cumulative number of T2 lesions detected by MRI were 154 for the hookworm group and 164 for placebo group. This difference was not statistically significant. (T2 lesions are areas where inflammation has caused damage, regardless of whether there is ongoing inflammation at the time of the scan.)

However, 18 people (51%) in the hookworm group showed no detectable “new, enlarging or enhancing lesions,” as did 10 (28%) in the placebo group.

“This suggests that the HW [hookworm infection] had an anti-inflammatory effect,” the scientists wrote.

Researchers also observed a rise from study start in the percentage of Tregs in the blood of hookworm group patients, while the number of Tregs had fallen in those given a sham plaster. Four hookworm-treated patients (11.4%) had relapses, as did 10 (27.8%) in the placebo group.

A total of 305 adverse events (AE) were reported — 153 in the hookworm group and 152 in the placebo group. The most frequent AE were diarrhea, skin reactions at plaster site, and infections. But the only “apparent difference” between the two groups were common “plaster-site reaction in the HW arm,” the study noted, and no one withdrew because of adverse effects.

“Treatment with hookworm was safe and well tolerated,” and “increased T regulatory cells, suggesting an immunobiological effect of hookworm. It appears that a living organism can precipitate immunoregulatory changes that may affect MS disease activity,” the researchers wrote.

“Clearly, this study has set the scene for follow up trials, where I would envisage booster infections being given to enhance the immune modulation already recorded,” said David Idris Pritchard, a professor of parasite immunology in the University of Nottingham’s School of Pharmacy and a study author.

“The dosage used in the current study (25 larvae) was the maximum permitted under regulatory guidelines, therefore boosting with this dose would be preferable to increasing the level of primary exposure,” Pritchard added.

Additional studies are necessary to better understand the potential benefits of hookworm infection in relapsing MS, and how they might be improved.

“Further studies are now needed to establish whether different protocols can enhance this benefit. For instance, would a booster infection in around nine months enhance the regulatory T cells responses and enhance the clinical/radiological benefit?” Constantinescu asked.