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People with negative responses to a tuberculin skin test a few years after being vaccinated against tuberculosis had a significant, 25% lower risk of developing <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in their lifetime, according to a study in Norway.
Because a positive reaction is linked to the recruitment of T cells — a type of immune cell involved in memory immunity and responses to vaccines — these findings may support the role of T-cell responses in the development of ALS, its researchers said.
The study, “<a href="https://www.sciencedirect.com/science/article/pii/S2666354623001187">Tuberculin responses after BCG vaccination predict amyotrophic lateral sclerosis risk</a>,” was published in the journal <a href="https://www.sciencedirect.com/journal/brain-behavior-and-immunity-health">Brain, Behavior, &amp; Immunity – Health</a>.
[recommended-reading id=88406]
<h3>Immune system response to motor neuron damage known in ALS</h3>
In people with ALS, inflammatory cells such as T-cells and microglia are known to locate in brain and spinal cord regions where motor neurons are damaged. However, it remains unknown if this immune cell infiltration is an actual contributor to disease onset and progression, or if it is a consequence of other disease processes.
“If T cells play a primary role, one would expect to find evidence of altered regulation of T cell responses before ALS development,” the researchers wrote.
To better understand T-cells&#8217; role in ALS, researchers at the University of Oslo and Akershus University Hospital used data from a compulsory screening program of people in a Bacillus Calmette–Guerin (BCG) vaccine drive to prevent tuberculosis. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis bacteria that mainly affects the lungs.
Individuals were monitored regularly to determine if they had a positive immunological response to the vaccination and remained protected from tuberculosis, which was widespread in Norway in the early 20th century.
Monitoring was done using the tuberculin skin test, or TST, in which a small amount of tuberculin — a protein from the bacteria that causes tuberculosis — is injected into the skin. The skin reaction was evaluated for size, hard area, or swelling after a few days.
Usually, BCG vaccination results in a positive TST test, but some vaccinated people fail to develop an immune response against tuberculin, meaning their immune system is not equipped to fight the tuberculosis bacteria in case of an infection.
While seemingly unrelated, immune mechanisms involved in a TST response are relevant to ALS because both involve the recruitment of T-cells, enabling researchers to compare T-cell responses in people who later ended up developing ALS with those who didn&#8217;t.
From the screening program data, the scientists identified nearly 325,000 people, born between 1910 and 1955, who received a BCG vaccination and had a TST examination one to 15 years afterwards.
Over a median of 40 years of follow-up, 496 of them developed ALS.
<h3>Negative skin test results indicate a weaker adaptive immune response</h3>
People with a negative TST result had a 25% lower risk of ALS, compared with those with a positive TST reaction, results showed. This association was observed throughout the follow-up, and it was still present four decades later.
Notably, the association between a negative TST test result and reduced ALS risk was even greater as the time between vaccination and TST decreased. For example, patients with a negative TST result within 10 years of vaccination were 33% less likely to develop the disease, and those with a negative test within five years of getting the vaccine were 43% less likely.
In a subgroup of 228,900 people who were vaccinated during adolescence (ages 12 to 17), researchers identified 275 cases of ALS over a median follow-up of 43 years. Regardless of the interval between vaccination and screening, patients in this group with a negative TST reaction had a 33% lower risk of developing ALS.
“We conclude that on population level, a weak secondary adaptive immune response, as measured by TST following BCG vaccination, is associated with low ALS risk several decades later. These results support a primary role for immune regulation in ALS development,” the researchers wrote.
The inability to exclude possible confounding factors that could impact the risk for ALS was noted as a study limitation.

Tuberculosis vaccine screening links T-cell response to ALS risk

Rapamycin, an approved medication used to prevent organ rejection after a kidney transplant, didn&#8217;t increase the number of <a href="https://alsnewstoday.com/tregs/">regulatory T-cells</a> in adults with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) who are taking part in a Phase 2 clinical trial.
Along with not meeting its primary goal, <a href="https://clinicaltrials.gov/study/NCT03359538">RAP-ALS (NCT03359538)</a> also failed to meet a number of secondary measures. The findings may have been impacted by the COVID-19 pandemic, which prevented many blood samples from being collected, and more trials may be needed to support the effectiveness of rapamycin, which was deemed generally safe and well tolerated.
“Rapamycin treatment is well tolerated and provides reassuring safety findings in ALS patients, but further trials are necessary to understand the biological and clinical effects of this drug in ALS,” the researchers wrote in “<a href="https://www.nature.com/articles/s41467-023-40734-8">Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis</a>,” which was published in <a href="https://www.nature.com/ncomms/">Nature Communications</a>. The study was funded in part by <a href="https://www.pfizer.com">Pfizer</a>, which markets an approved version of rapamycin called <a href="https://www.pfizer.com/products/product-detail/rapamune">Rapamune</a> (sirolimus).
While the exact <a href="https://alsnewstoday.com/causes-of-als/">causes behind ALS</a> are not clear, several disease processes are common to most patients. For example, most have an abnormal accumulation of proteins such as TDP-43 or SOD1 that form clumps outside the nucleus of nerve cells, triggering inflammation and damage.
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<h3>What does rapamycin do in ALS?</h3>
Rapamycin is believed to help nerve cells eliminate these toxic clumps by activating something called autophagy, a process cells use to recycle abnormal components or molecules that are no longer needed.
It also may increase the production of regulatory T-cells (Tregs), immune cells that regulate the excess activity of the immune system. These are often reduced and poorly active in ALS, and disease progression actually tends to occur faster in ALS patients with fewer Tregs, so increasing their amount has been an important consideration for new treatments.
To see if rapamycin could indeed impact the number of Tregs and other disease processes in ALS patients, researchers launched the RAP-ALS trial, which enrolled 63 participants across seven centers in Italy. They were randomly assigned to receive one of two doses of rapamycin — 1 or 2 mg per square meter of body surface area (mg/m2) — or a placebo, given daily for 18 weeks (about four months).
All continued to receive a stable dose of riluzole (sold as <a href="https://alsnewstoday.com/als-treatment/rilutek-riluzole/">Rilutek</a>, <a href="https://alsnewstoday.com/tiglutik-riluzole-oral-suspension/">Tiglutik</a>, and <a href="https://alsnewstoday.com/exservan-riluzole-oral-film/">Exservan</a>) during the trial, the main goal of which was to determine if more patients on rapamycin than a placebo saw a positive response — defined as an increase of at least 30% in the number of Tregs from the trial’s start (baseline) to week 18.
The proportion of patients showing a positive response was higher among those who received rapamycin at 1 or 2 mg/m2 versus a placebo (28 and 20% vs. 12%), but the difference wasn&#8217;t significantly different. Similar observations were made after correcting the results for sex, disease duration, rate of decline, and previous treatment with <a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava</a> (edaravone).
Patients in all three groups saw a decline in the ALS Functional Rating Scale Revised (ALSFRS-R), a measure of disease severity where lower scores indicate more severe disease, for up to 54 weeks (about one year). The placebo group tended to progress at a faster rate than patients given the active treatment, but the differences between the groups weren&#8217;t significant.
<h3>Changes in inflammatory molecules, immune cells</h3>
Other secondary efficacy outcomes included changes in inflammatory molecules and in the activation and traveling ability of various immune cells.
The inflammatory cytokine interleukin (IL)-18 was significantly reduced with rapamycin compared with a placebo at week 18, indicating less inflammation, but the effect was lost after treatment stopped.
Rapamycin also significantly increased the numbers of certain immune cells such as monocytes and switch memory B-cells, a type of immune that may produce antibodies upon reactivation, suggesting “a compensatory mechanism of controlling inflammation by B cells,” wrote the researchers, who noted the findings “should be interpreted cautiously and require confirmation in larger studies, considering&#8221; corrections for multiple tests weren&#8217;t applied.
While the lower dose of rapamycin reached stable levels in the blood throughout the 18 weeks, the higher dose peaked at higher than desired levels, which required the next doses to be adjusted.
At week 18, rapamycin wasn&#8217;t detected in samples of the liquid that flows in and around the brain and spinal cord, called the cerebrospinal fluid, indicating it can&#8217;t enter the brain and reach the affected nerve cells.
The proportion of patients who had one or more side effects was similar in the rapamycin and placebo groups (55% vs. 52%), as was the proportion of those with serious side effects (19% for both).
Side effects related to the skin, such as redness, itching, and rash, were about five times as common with rapamycin than with the placebo. A case of acute hepatitis (liver inflammation) was reported in one patient and was likely related to the higher dose, but no lasting consequences were reported.
“In conclusion, this trial demonstrated that treatment with a low dose of rapamycin is safe in patients with ALS, but it failed to demonstrate an effect of the drug on Treg cells,” the researchers wrote.

Rapamycin fails to raise regulatory T-cell levels in RAP-ALS trial

Treatment with <a href="https://alsnewstoday.com/tregs/">regulatory T-cells</a> (Tregs), a type of anti-inflammatory immune cell, reduced biomarker levels of inflammation and oxidative stress in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), a study shows.
The experimental approach may help curb these contributions to nerve cell damage in ALS, the findings suggest, and routinely measuring the biomarkers could aid in monitoring responses to Treg treatment.
&#8220;The simultaneously assessed levels of immunological and oxidative factors are candidates to monitor disease progression and to properly target clinical trial endpoints response to [Treg] therapy in ALS,&#8221; the researchers wrote in “<a href="https://ageneudisjournal.com/article/view/6047?utm_source=sendgrid.com&amp;utm_medium=email&amp;utm_campaign=website">Immunological, oxidative, and structural factors and their responses to regulatory t lymphocyte therapy in amyotrophic lateral sclerosis</a>,” which was published in <a href="https://ageneudisjournal.com/">Ageing and Neurodegenerative Diseases</a>.
In ALS, motor neurons, the nerve cells that control voluntary movements, become damaged and die. As a result, the brain progressively loses control of movement, triggering <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms</a> such as muscle weakness, atrophy (shrinking), and stiffness.
Biological hallmarks associated with motor neuron loss include an overactive inflammatory response and <a href="https://alsnewstoday.com/news/oxidative-stress-may-be-therapy-target-in-als-study-of-skin-cells-suggests/">oxidative stress</a>, a type of cell damage caused by highly reactive oxygen-containing molecules generated from normal metabolism. Oxidative stress is increased in ALS and likely contributes to disease progression.
“Our pre-clinical studies have suggested that oxidative stress results from and promotes neuroinflammation and neuronal injury in ALS,” Stanley Appel, MD, scientific advisory board chairman of <a href="https://coyatherapeutics.com/">Coya Therapeutics</a> said in a <a href="https://www.businesswire.com/news/home/20230831425850/en/Coya-Therapeutics-Announces-Publication-of-Potential-Novel-Blood-Biomarker-Data-in-Amyotrophic-Lateral-Sclerosis-ALS-Patients-That-Accurately-Reflect-Therapeutic-Responses-When-Treated-with-Regulatory-T-Cell-Treg-Enhancing-Therapies">company press release</a>. Coya is developing two investigational anti-inflammatory treatments for ALS that boost Treg function.
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<h3>Treg therapy&#8217;s effect on inflammation, oxidative stress</h3>
In the new study, Appel and his colleagues at Houston Methodist Hospital, Texas examined the levels of various blood-based biomarkers associated with inflammation, oxidative stress, and nerve cell structural integrity in 30 people with sporadic ALS (63.3% male). The samples were compared to those from 10 age-matched healthy people (controls).
Blood tests revealed significantly elevated levels of CCL2, an immune signaling molecule associated with inflammatory responses, compared with healthy people. CCL2 levels were particularly increased in patients with rapid ALS progression over those progressing more slowly, although this group&#8217;s levels were still significantly higher than the controls&#8217;.
Similarly, the pro-inflammatory signaling protein interleukin-18 (IL-18) was significantly elevated in patients versus controls and in patients whose disease was progressing rapidly compared with those progressing slowly.
4-HNE, an oxidative stress marker, was also significantly increased in ALS patients with rapidly progressive disease, but slower progressors had levels similar to controls. MDA, another oxidative stress marker, was elevated in both patient groups versus controls, indicating it didn&#8217;t correlate with disease progression.
Levels of NfL and pNfH, two markers of nerve cell damage were examined too. NfL was elevated in rapidly progressing patients compared with slow progressors, but the patient groups didn&#8217;t differ significantly from healthy people. pNfH was reduced in rapidly progressing patients compared with controls, but no other group differences were observed.
<h3>Biomarkers of treatment response</h3>
To validate the biomarkers as indicators of treatment response, the researchers tested samples from ALS patients who participated in one of two clinical trials.
A <a href="https://clinicaltrials.gov/ct2/show/NCT03241784">Phase 1 pilot trial (NCT03241784)</a> enrolled three people with ALS and treated them with a Treg therapy called COYA 101 (formerly ALS001). Tregs are white blood cells that suppress immune responses and prevent unnecessary inflammation.
The cells were isolated, grown to greater numbers in a laboratory, and then infused back into the same patient. The participants also received interleukin-2, an immune signaling protein that boosts Treg function. Data, published in 2018, showed it <a href="https://alsnewstoday.com/news-posts/2021/02/05/coya-therapeutics-als001-treg-off-shelf-therapy-als-progression-phase-2-trial/">slowed progression rates</a> during the early and later stages of the disease.
The Treg/IL-2 combination therapy also suppressed CCL2, IL-18, and 4-HNE, and stabilized clinical status, as assessed with the Appel ALS (AALS) scoring system. During a “washout” period without Treg therapy, the biomarker levels increased and clinical status deteriorated.
A <a href="https://clinicaltrials.gov/ct2/show/NCT04055623">Phase 2a study (NCT04055623)</a> investigated COYA 101 in ALS patients given monthly infusions for six months. A six-month, open-label extension followed.
In this trial, the combination therapy suppressed CCL2 levels in five of the eight patients and IL-18 levels in six. 4-HNE levels were elevated in two patients, but remained low in six. As <a href="https://alsnewstoday.com/news/coya-treg-therapy-als001-als-reduces-inflammation-early-trial/">previously reported</a>, COYA 101 reduced ox-LDL, another marker of oxidative stress, in both the Phase 1 and Phase 2a study patients.
“It is gratifying that biomarkers of oxidative stress — 4-HNE and ox-LDL — correlated with responsiveness to therapy in 2 ALS clinical trials of Treg-enhancing therapies, and may provide an objective confirmation of clinical benefit in forthcoming trials,” Appel said.
“Immunological and oxidative pathological factors accurately reflected therapeutic responses in these pathways and are candidates to target clinical trial endpoints,” the researchers said.
The biomarkers will help assess the effectiveness of COYA 302, a combination of IL-2 and a fusion protein known as CTLA4-Ig or abatacept, Coya maintains. This therapy is designed to further increase Treg activity, reduce inflammation, and slow disease progression.
So far, in a small proof-of-concept clinical trial, four ALS patients saw a <a href="https://alsnewstoday.com/news/mda-2023-coya-302-therapy-slows-als-progression-early-trial/">marked slowing in disease progression</a> with COYA 302. The company plans to <a href="https://alsnewstoday.com/news/coya-meet-fda-about-phase-2-trial-coya-302-als/">file a request</a> with U.S. regulators to continue testing COYA 302 in a Phase 2 clinical trial.

Tag: regulatory T-cells (Tregs)

Tuberculosis vaccine screening links T-cell response to ALS risk

Rapamycin fails to raise regulatory T-cell levels in RAP-ALS trial

ALS biomarkers are lowered with Coya’s Treg therapy: Study