A cell therapy using myeloid cells attached to drug delivery microparticles reduces disease burden in a preclinical model of multiple sclerosis. — Daily Science

A key factor in MS is sudden inflammation of the nerves caused by so-called myeloid cells of the “innate” immune system in vulnerable regions of the brain and spinal cord, which together form the central nervous system (CNS). These “acute inflammatory lesions” then attract other myeloid cells, as well as autoreactive T and B cells that belong to the second arm of the immune system, known as the “adaptive immune system,” and directly attack the myelin sheath. While there is no available cure for MS, existing disease-modifying therapies in the form of small-molecule drugs and proteins directly target autoreactive immune cells or broadly dampen inflammation. However, many of these therapies cause serious side effects in different parts of the body, including the immune system itself, and therefore carry significant health risks.

Now, a research team from the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) has developed a cell therapy as a strong alternative to protein therapies and existing small molecules that the myeloid takes advantage of. cells, the same type of immune cells that cause the nerve inflammation that triggers MS in patients.

To transform potentially inflammatory myeloid cells into therapeutic cells, they isolated and cultured monocytes (a type of myeloid cell) from the bone marrow of donor mice and stably attached tiny microparticles, called “backpacks,” to the cell surfaces. These backpacks are loaded with anti-inflammatory molecules that direct the differentiation of carrier cells into anti-inflammatory cells. live. When reinfused into a mouse model of MS, the backpack-loaded monocytes were able to affect MS-specific immune responses and partially reverse hindlimb paralysis and improve motor functions. The results are published in the Proceedings of the National Academy of Sciences (PNA).

“Current MS therapies do not specifically target myeloid cells. These are very plastic cells that can switch between different states and are therefore difficult to control. Our biomaterials-based backpack approach is a very effective way to to keep them locked into their anti-inflammatory state,” said lead author Samir Mitragotri, Ph.D., who is a core faculty member at the Wyss Institute. “In many ways simpler than other cell therapies, myeloid cells can be easily obtained from patients’ peripheral blood, backpack-modified in a short culture step, and reinfused back into the original donor, where they find their way into lesions.” inflammatory and affect the MS-specific immune response not only locally, but more broadly.” Mitragotri is also the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering in MARES.

Many cell therapies, such as the famous CAR-T cell therapies, require the mobilization of immune cells from specific tissue compartments in the body with drugs, genetic modification, and then amplification for weeks outside the body. Myeloid cells can be directly recovered using established methods and modified with backpacks in a matter of hours, making the therapy easier to translate. In addition, some types of myeloid cells possess the ability to cross the blood-brain barrier, making them especially suitable for the treatment of CNS diseases.

New twist for cellphone backpacks

Mitragotri’s group had previously found that when they attached small disk-shaped backpacks to cells of the myeloid lineage, they remained stably exposed on the cell surface, while many other cells would easily internalize and inactivate them. Adding certain molecules to the backpacks allowed the team to keep a check on the behavior of the cells. They made use of this finding in a tumor-fighting cell therapy consisting of backpack-laden macrophages, which is a specific type of myeloid cell. In their new study, they focused on monocytes, which also belong to the myeloid differentiation lineage and are precursors to macrophages. Monocytes can effectively infiltrate the brain and then differentiate into macrophages, which are one of the predominant inflammatory cell types in active MS lesions.

“Because of their ability to invade the CNS, infiltrate inflammatory lesions, and differentiate into macrophages, a backpack strategy that would control monocyte differentiation made a lot of sense,” said first author Neha Kapate, a graduate student working with Mitragotri. “We decided on backpacks that contained interleukin-4 [IL-4] and dexamethasone, two molecules that we later discovered provide a synergistic anti-inflammatory effect.”

The team made their backpacks the size of a micrometer through a process known as serial “spin coating,” in which thin films composed of a PLGA polymer and other biocompatible substances, and containing anti-inflammatory molecules, are superimposed like layers of an onion. As a final step, the outer surface of the backpack was equipped with an antibody fragment to allow it to adhere to monocytes.

Cellular backpacks put on legs

To test the therapeutic efficacy of the backpack-loaded monocytes, the researchers isolated monocytes from healthy donor mice and, in a short cell culture step, attached the backpacks to them. They then infused the modified cells into a mouse model of MS, known to researchers as the experimental autoimmune encephalomyelitis (EAE) model. “When we infused backpack-carrying monocytes and, in parallel, unaltered control monocytes into EAE mice with ongoing nerve inflammation, backpack-carrying monocytes more effectively infiltrated inflamed CNS lesions. They also reduced inflammation within cells. lesions and changed the local and systemic MS-immune response associated with a therapeutic outcome,” Kapate said. “The resulting anti-inflammatory monocytes also elicited cross-effects with other immune cell populations, such as specific T helper cells that are linked to the self-directed adaptive autoimmune response.”

Disease symptoms in EAE mice treated with backpack-laden monocytes were significantly improved and, at the end of the study, the animals simply exhibited a limp tail, compared to complete hindlimb paralysis in control animals. The treatment also prolonged the survival of the animals: all the mice that received backpack monocytes survived until the end of the study, whereas a significant number of control mice had died. Importantly, the magnitude of the therapeutic benefit the team observed is on par with reported therapeutic treatments that had been tested in other studies using the same model. Since the EAE model primarily mimics the progressive form of MS and not the more prevalent “relapsing-remitting” form, with which the disease begins in approximately 85% of MS patients, and which in later stages can also become progressive, the team plans to investigate their approach in relapsing-remitting MS models as well. Being able to suppress inflammation early on could have huge benefits for patients.

“This team’s ability to convert a potentially pathogenic immune cell type into a therapeutic for MS, which is extremely difficult or impossible to treat, could open up a whole new avenue for treating patients with a variety of neurological diseases,” he said. Wyss. Founding Director Donald Ingber, MD, Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Children’s Hospital Boston, and the Hansjörg Wyss Professor of Bioinspired Engineering in MARES.

Other study authors include Michael Dunne, Ninad Kumbhojkar, Supriya Prakash, Lily Li-Wen Wang, Amanda Graveline, Kyung Soo Park, Vineeth Chandran Suja, Juhee Goyal, and John Clegg. The study was supported by the Wyss Institute at Harvard University, SEAS, National Science Foundation (under award #ECCS-2025158 and 1122374).