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IP Montevideo research discovers immune cells that attack the motor system in ALS

MONTEVIDEO, Uruguay. An international team of researchers have discovered a previously unknown immune mechanism mediated by mast cells and neutrophils that appears to be closely linked to the progression of amyotrophic lateral sclerosis (ALS). The discovery could provide a new understanding of the disease mechanisms and alternative therapeutic approaches.

ALS is a progressive paralytic disease caused by degeneration of motor neurons and peripheral motor axons that command voluntary muscle activity. Degeneration of the distal motor nerve terminals is an early event in ALS. There is actually no curative treatment for this disease, and even a way to slow its progression would be a significant therapeutic advance, scientists say.

Findings were reported today in the Journal of Clinical Investigation Insight, by researchers from the Institut Pasteur de Montevideo, University of Alabama at Birmingham (UAB), Oregon State University (OSU) and Institut IMAGINE of Paris.

Scientists discovered that immune cells, known as mast cells and neutrophils, abnormally infiltrate into muscles of autopsied ALS patients and interact with neuromuscular junctions, the connection between motor neurons and muscle fibers that enables motion. “This finding was unexpected, it suggests a chronic inflammation process that could explain the failure of motor nerve fibers to correctly command the muscle”, said Dr. Luis Barbeito, principal investigator at Institut Pasteur of Montevideo, who has been working on ALS for more than 20 years.

The immune system has been shown to play an integral role in the acceleration of ALS, both in the central and peripheral motor systems. The neuroinflammatory response that occurs in this disease is created by reactive immune cells that invade the peripheral and central motor nerves and nerve terminals at the junction between nerve and muscle.

Using a rat model of ALS, scientists discovered that mast cells and neutrophils affected not only muscle nerve terminals but also nerves containing motor axons. More intriguing, immune cell number sharply increased after paralysis onset. “We believe that immune cell attack is driving paralysis progression of ALS; neutrophils seem to be noxious effectors because they destroy and engulf axons and myelin” said Emiliano Trias, an Uruguayan postdoctoral researcher at Institut Pasteur and leading author of the paper.

Of considerable interest, researchers said that mast cells and neutrophils seem to act in concert. Downregulation of mast cells in ALS rats by treatment with a tyrosine kinase inhibitor drug, masitinib, also prevented neutrophil infiltration and notably, progressive motor nerve degeneration and muscular denervation. “By blocking these different cell types in rodent models of ALS, we can begin to determine potential therapeutic effects in human ALS. This work emphasizes the importance of targeting therapy to the peripheral motor system including the junction between the muscle and nerve”, said the co-author Dr. Peter H. King, who has been involved in ALS clinical management for decades and oversees a multidisciplinary ALS clinic at the Birmingham Veterans Administration Medical Center in conjunction with the multidisciplinary clinic at UAB and a biorepository of tissue samples.

“This observation provides new therapeutic approaches towards treating the worst of the symptoms underlying ALS, the progressive and relentless loss of muscle wasting. The study also provides a stronger rationale for why Masitinib, a drug originally developed to treat mast cell tumors, might be protective in ALS. We look forward to seeing more results in clinical trials” said Dr. Joseph Beckman, co-author and leading ALS researcher at Linus Pauling Institute in OSU.

While tyrosine kinase inhibitors were used clinically in oncology for more than a decade, only masitinib has been tested in ALS clinical trials.

Slowing or stopping the progression of paralysis in ALS by means of specific drugs would be a critical first step on the road to working towards a cure, researchers said.

Current studies have been supported by research local agencies and participating institution grants. This study has been possible thanks to patients that generously committed to donate their bodies once they passed away to the biorepository Dr. King started 5 years ago.


JCI Insight. 2018;3(19):e123249.