Revolutionary Approach Harnesses Body Cells for Traumatic Brain Injury (TBI) Treatment

Knapsack-Mediated Anti-Inflammatory Macrophage Cell Therapy for the Treatment of Traumatic Brain Injury

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macrophages

Macrophages are a type of white blood cells of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, that do not have proteins specific to healthy cells in the body on their surface. This process is called phagocytosis and acts to defend the host against infection and injury. Macrophages are found in essentially all tissues, where they patrol for potential pathogens through amoeboid movement.

Main summary

Scientists have created a new treatment for traumatic brain injury (TBI) that reduced brain injuries by 56% and significantly reduced local inflammation levels in pigs. The new approach takes advantage of macrophages, a type of white blood cell that can increase or decrease inflammation in the body in response to infections and injuries. The team created disc-shaped microparticles called “backpacks” that contain anti-inflammatory molecules and then attached them directly to macrophages. These molecules kept the cells in an anti-inflammatory state when they reached the injury site in the brain, allowing them to reduce local inflammation and mitigate the damage caused.

“Every year, millions of people suffer a traumatic brain injury, but there is currently no treatment beyond symptom control. We have applied our cell backpack technology, which we previously used to enhance the inflammatory response of macrophages to cancerous tumors. “, to deliver localized anti-inflammatory treatment in the brain, which helps mitigate the cascade of uncontrolled inflammation that causes tissue damage and death in a human-relevant model,” said lead author Samir Mitragotri, Ph.D., in whose laboratory conducted the investigation.

Mitragotri is a senior faculty member at the Wyss Institute at Harvard University and the Hiller Professor of Bioengineering and the Hansjörg Wyss Professor of Biologically Inspired Engineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS).

Stopping a runaway inflammatory train

More than one million people in the U.S. suffer a traumatic brain injury (TBI) each year, about 230,000 of them are hospitalized, and nearly 70,000 die from TBI-related causes. There is currently no treatment for the damage caused to brain tissue during a traumatic brain injury, beyond managing the patient’s symptoms. One of the main drivers of damage caused by TBI is a runaway inflammatory cascade in the brain.

As the cells die from the impact, they release a cocktail of pro-inflammatory cytokine molecules that attract immune cells to clean up the damage. But the same cytokine molecules can also disrupt the blood-brain barrier, causing blood to leak into the brain. Blood pooling in the brain causes swelling, impaired oxygen supply, and increased inflammation, creating a vicious cycle of bleeding and damage that leads to even more cell death.

The Mitragotri laboratory saw an opportunity in this problem

“It is generally believed that anti-inflammatory therapies may be effective in treating TBI, but so far, none of them have been shown to be clinically effective. Our previous work with macrophages has shown us that we can use our backpack technology to effectively direct their behavior when they arrive at the site of injury. Since these cells are already active players in the body’s natural immune response to a traumatic brain injury, we had a hunch that we could augment that pre-existing biology to reduce the initial damage,” he said co-senior author Rick Liao, Ph.D. ., postdoctoral fellow at the Wyss Institute and SEAS.

Body, heal yourself

Macrophages are very malleable cells and can “switch” between pro-inflammatory and anti-inflammatory states. While the team’s previous work in cancer had focused on keeping macrophages in a pro-inflammatory state when they arrive in a tumor microenvironment that reduces inflammation, this new project would attempt to do the opposite: keep macrophages “calm” in the environment. plagued by inflammation from a brain injury.

To do this, they used a disc-shaped “backpack” that they had previously designed to treat multiple sclerosis and that contained layers of two anti-inflammatory molecules: dexamethasone, a steroid, and interleukin-4, a cytokine that stimulates macrophages to adopt a anti-inflammatory reaction. -Inflammatory state. They then incubated these microparticles with human and porcine macrophages in vitro and saw that the backpacks stably adhered to the cells without causing any negative effects. They also observed that the application of their backpacks decreased the expression of pro-inflammatory biomarkers and increased the expression of anti-inflammatory biomarkers, keeping the pigs’ macrophages in a healing state.

But to prove that this change would work in the body, they had to test backpack-carrying macrophages in vivo. They chose pigs as their model organism because their brain structures and responses to injury more closely resemble those of humans than those of mice.

“Probably our biggest challenge on this project was scaling up production to match what we needed to run the experiments. Our previous studies were done in rodents, requiring around two million macrophages and four million administered backpacks per subject. For the porcine study, we need 100 million macrophages and 200 million backpacks per subject (on the scale of what would be administered in humans) and a lot of helping hands,” said co-author Neha Kapate, Ph.D., a postdoctoral fellow at the Wyss Institute and MARES.

The final team consisted of more than 20 members from across the Wyss Institute, Harvard, MIT, and Mass General Hospital (MGH).

Once they generated enough backpack-carrying porcine macrophages, they infused them into the pigs’ bloodstream four hours after a traumatic brain injury. Seven days later, they analyzed the animals’ brains. The pigs that had received the macrophage treatment showed a high concentration of cells in the area immediately surrounding the injury site, their lesions were 56% smaller, and there was significantly less hemorrhage than in the untreated animals.

Local immune cells also showed a lower amount of a pro-inflammatory activation marker called CD80, indicating that macrophages had managed to control the damage by reducing inflammation in the brain. Corroborating those data, levels of two soluble biomarkers of inflammation in the blood and cerebrospinal fluid were lower in treated animals than in untreated ones. Treatment with macrophages also did not cause any negative effects.

The team plans to conduct future studies that focus on elucidating exactly how their anti-inflammatory macrophage therapy affects the integrity of the blood-brain barrier to prevent bleeding, which could also hold promise for treating other conditions such as hemorrhagic strokes.

“The susceptibility of macrophages to their local environment has historically prevented scientists from taking full advantage of their immune modulation capabilities. This impressive study describes a truly novel and potentially powerful macrophage-based therapy to treat the inflammation that is the root cause of so many human diseases. diseases in an effective, non-invasive way that works with biology rather than against it,” said Wyss founding director Donald Ingber, MD, Ph.D.

Ingber is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at SEAS.

Additional authors

Luke Sodemann, Tawny Stinson, Bryan Golemb, Alexander Hone and Andrea Slate of MGH; Supriya Prakash, Ninad Kumbhojkar, Vineeth Chandran Suja, Suyog Shaha, Kyung Soo Park, Michael Dunne and Kolade Adebowale of the Wyss Institute and SEAS; Lily Li-Wen Wang and Morgan James of the Wyss Institute, Harvard SEAS, and MIT; Mikayla Flanz, Rohan Rajeev, Dania Villafuerte and John Clegg of Harvard SEAS; Declan McGuone of Yale School of Medicine and Beth Costine-Bartell of MGH and Harvard Medical School.

The investigation

This research was supported by the U.S. Department of Defense under Grant No. W81XWH-19-2-0011, the National Science Foundation Graduate Research Fellowship under Grants Nos. 1122374 and 1745302, the Institute Eunice Kennedy Shriver National Health Service, the National Institute of Child Health and Human Development under Grant No. R01 HD099397, the Wyss Institute of Harvard University, and Harvard SEAS. The research is reported in PNAS Nexus.

Attribution/Source(s):

This peer-reviewed article related to our section on traumatic brain injury (TBI) was selected for publication by Disabled World editors because of its likely interest to our readers in the disability community. Although content may have been edited for style, clarity, or length, the article “A revolutionary approach harnesses the body’s cells to treat traumatic brain injuries (TBI)” was originally written by the Wyss Institute for Biologically Inspired Engineering at Harvard and published by Disabled-World.com on 01/04/2024. If you require further information or clarification, you can contact the Wyss Institute for Biologically Inspired Engineering at Harvard at wyss.harvard.edu. Disabled World makes no warranties or representations in connection therewith.

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