Myeloid cells with added ‘backpack’ may help halt MS inflammation

Novel treatment worked to ease motor symptoms in mouse model

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Attaching a kind of molecule backpack to myeloid cells — a type of immune cells involved in the inflammatory attack that drives multiple sclerosis (MS) — may help to halt inflammation and damage in the brain in MS by modulating immune cell activity, a study suggests.

The backpacks, loaded with anti-inflammatory molecules, helped modulate immune responses in the spinal cord of mice and reduced the amount of pro-inflammatory molecules circulating in the animals’ blood. This helped to halt neuronal damage and inflammation.

The treatment ultimately eased motor symptoms of MS in the mouse model.

“The results reported here demonstrate the possibility of myeloid cells as a therapy and drug target in MS,” the researchers wrote.

The study, “A backpack-based myeloid cell therapy for multiple sclerosis,” was published in PNAS.

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Creating a molecule backpack for myeloid cells

MS is marked by the body’s immune system going awry and launching an inflammatory attack that causes damage to the brain and the spinal cord, which make up the central nervous system (CNS).

While more than a dozen therapies are approved to treat MS, none represents a cure for the neurodegenerative condition — and many of these treatments have unwanted side effects.

Myeloid cells also play a role in MS inflammation, but no therapies to date target these cells directly or make use of their ability to swiftly change their status from pro-inflammatory to anti-inflammatory.

Now, a team at the Wyss Institute, in Boston, transformed these cells so they could be used as a potential MS therapy. In a novel approach, the investigators attached disc-shaped tiny particles, which they called backpacks, to the myeloid cells.

The backpacks contain molecules that help to turn the inflammatory response from myeloid cells, which also is expected to dampen the responses from other immune cells whose function is impacted by myeloid cells.

“Current MS therapies do not specifically target myeloid cells. These are very plastic cells that can toggle between different states and are thus hard to control,” Samir Mitragotri, PhD, study senior author and a core faculty member at the Wyss Institute, said in a press release.

“Our biomaterial-based backpack approach is a highly effective way to keep them locked into their anti-inflammatory state,” Mitragotri said.

Given that some of these backpack-carrying cells also can enter the central nervous system, they can travel to the areas with active inflammation and stop the inflammatory attack, the scientists noted. That, in turn, can prevent further damage.

“In many ways simpler than other cell therapies, myeloid cells can be easily obtained from patients’ peripheral blood, modified with backpacks in a short culture step, and reinfused back into the original donor, where they find their way to inflammatory lesions and affect the MS-specific immune response not only locally, but more broadly,” Mitragotri said.

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Treatment found to reduce inflammation in MS lesions

To test this in the lab, Mitragotri’s team turned to mice with experimental autoimmune encephalitis (EAE), an animal model that’s commonly used to mimic some of the symptoms of MS.

They attached the backpacks to monocytes, a type of myeloid cells that circulate in the bloodstream and can enter the CNS, where they develop into macrophages. Macrophages are a type of tissue-resident immune cells that can be found in areas of active inflammation in the brain of people with MS.

“Because of their ability to invade the CNS, infiltrate inflammatory lesions, and differentiate into macrophages, a backpack strategy allowing control over monocyte differentiation made extreme sense,” said Neha Kapate, a graduate student in Mitragotri’s lab and the study’s first author.

Monocytes from healthy mice were fitted with backpacks loaded with interleukin-4, an anti-inflammatory molecule, and dexamethasone, a glucocorticoid that’s sometimes used to treat acute relapses in people with MS.

“We decided on backpacks that contained interleukin-4 and dexamethasone, two molecules that we later found to provide a synergistic [cooperative] anti-inflammatory effect,” Kapate said.

The results showed that, after being infused into the bloodstream, backpack-carrying monocytes could more effectively enter the brain of EAE mice than control monocytes without the load.

Backpack-laden monocytes also elicited stronger effects on inflammation, modulating both infiltrating and resident myeloid cells, lowering the amount of inflammatory molecules, and also  tuning down Th1 and Th17 cells, two populations of immune cells that can drive inflammation in MS.

“They also reduced inflammation inside the lesions and shifted the local and systemic MS-associated immune response towards a therapeutic outcome,” Kapate said.

The ability of this team to convert a potentially pathogenic [disease-causing] type of immune cell into a therapeutic one for MS, which is extremely hard or impossible to treat, could open an entirely new path to treat patients with a variety of neurological diseases.

Some of the most common symptoms of MS include movement problems. While EAE mice given an infusion of unaltered control monocytes developed paralysis in their hind limbs, which means they lost the ability to move their legs, those who received the backpack-laden monocytes showed improved motor function and a limp tail only.

Animals treated with the backpack-carrying cells also lived for the whole duration of the study, while a significant number of mice infused with control monocytes died in the same period.

“The ability of this team to convert a potentially pathogenic [disease-causing] type of immune cell into a therapeutic one for MS, which is extremely hard or impossible to treat, could open an entirely new path to treat patients with a variety of neurological diseases,” said Donald Ingber, MD, PhD, the founding director of the Wyss Institute and a professor at Harvard Medical School and Boston Children’s Hospital.

Funding for the study came from the Wyss Institute, the School of Engineering and Applied Sciences at Harvard, and the National Science Foundation.

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