- New findings in people with amyotrophic lateral sclerosis suggest regulatory aspects of the immune system protect neurons from injury or degeneration in this disease.
- People with rapidly progressing ALS were found to have a lower percentage of regulatory T cells among their white blood cells than people with slowly progressing ALS. People who progressed rapidly also were found to have lower levels of the instructions for the FOXP3 protein in their blood cells.
- The researchers suggest that FOXP3 levels could be a useful marker of ALS progression, which could in turn influence treatment or clinical trial design.
- These results also may be relevant in other neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, researchers say.
Immune system cells known as regulatory T cells — T-regs for short — have been found to play a protective role in mice with a disorder that resembles human amyotrophic lateral sclerosis (ALS). They don't prevent the disease in genetically susceptible mice, but they do appear to slow it down, probably by putting a brake on inflammation in the central nervous system.
Now, investigators supported in part by MDA have found that T-regs appear to play the same protective role in people with the disease. The findings may lead to improved methods of predicting disease progression and influence treatment development for ALS.
The researchers, led by MDA research grantee Stan Appel at Methodist Neurological Institute in Houston, published the findings online Nov. 9, 2012, in EMBO Molecular Medicine. (The whole paper can be accessed, without charge.) Appel, a longtime MDA grantee, directs the MDA/ALS center at his institution, and serves as chairman of MDA's Medical Advisory Committee.
"These results support the importance of the immune system, and more specifically T-reg populations, in modulating the clinical course of a patient’s disease," Appel said. "Thus, enhancing the number of T-regs and their anti-inflammatory functions in ALS patients could have important therapeutic benefits in slowing the rate of disease progression and stabilizing ALS patients for longer periods of time than currently available therapies."
Fewer T-regs, less FOXP3 associated with faster progression
Appel, with colleagues at Methodist Neurological Institute and the Methodist Hospital in Houston, and at California Pacific Medical Center in San Francisco, first analyzed blood samples from 54 ALS patients who were at different stages of their disease, and compared them to blood samples from unaffected study participants (controls).
Using a standardized measure of ALS progression called the Appel ALS score, they divided participants with ALS into "slow progressers" and "rapid progressers". They found that the white blood cells of the rapid progressers contained 31 percent fewer T-regs than did the white blood cells of the slow progressers. (The slow progressers had about the same percentage of T-regs among their white blood cells as did the unaffected controls.)
Knowing that T-regs require a protein called FOXP3 to carry out their anti-inflammatory functions, the investigators also looked at FOXP3 levels in the blood samples. They found reduced levels of FOXP3 in the rapidly progressing patients compared to levels in controls or slow progressers.
In a second phase of the study, the researchers collected blood samples from 102 people with early-stage ALS and then evaluated their ALS symptoms every three months for three-and-a-half years, with the goal of seeing whether they could predict progression rates. They recorded survival time and the time it took for the Appel ALS score to drop by 100 points.
They found that low FOXP3 levels early in the disease predicted a rapidly progressive disease course and a short survival time. At the end of the three-and-a-half years, 35 percent of those who had low FOXP3 levels early in their disease had become ventilator-dependent or were deceased, while only 13 percent of those with high initial FOXP3 levels were in either of those categories.
Unfortunately, they did not find that high levels of FOXP3 early in the disease course ensured permanent slow progression. High levels only indicated that the study participant was in a slowly progressive phase of the disease at the time the sample was taken; some people converted to rapid progression later on.
The study's authors suggest that FOXP3, measured in a blood sample, could be a useful marker of ALS progression, which could in turn influence treatment or clinical trial design.
They say their results support the idea that T-regs and their associated FOXP3 protein suppress inflammation in the nervous system, which has implications for therapy development.
They also say the results may be relevant in other neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases.
For more information
Several experimental strategies now being considered in ALS research are based on modulation of the immune system. To learn more, read:
- ALS: Phase 2 Clinical Trial for NP001 Shows Possible Benefit (news story about a drug its developers hope will change immune cells from "attack" mode to "protective" mode, ALS News Online, Nov. 5, 2012);
- ALS TDI Webinar: TDI 132 Project Overview (summary of a webinar about TDI 132, Gilenya, a drug that is used to modulate the immune system in multiple sclerosis and is being considered for testing in ALS, ALS News Online, March 23, 2012); and
- Immunomodulator CTLA4-FC Being Tested in ALS Mouse Model (discusses how a compound that blocks activation of the immune system is being investigated as a possible ALS therapy, ALS News Online, Dec. 29, 2011).