Therapy could reduce tissue damage following heart attack, infection, and in autoimmune diseases
By injecting mice with tiny, negatively charged particles following infection or damage to tissue, researchers were able to prevent additional harm to tissues, normally caused by excessive inflammation. The particles caused inflammatory monocytes—cells that secrete damaging proteins at the sites of injured or diseased tissue—to be diverted instead to the spleen, where they eventually died.
The researchers tested their novel technique in various mouse models of disease with inflammatory components including: West Nile virus encephalitis, multiple sclerosis, peritonitis and colitis, as well as in a mouse model of heart attack and kidney reperfusion. In all cases, the particles significantly reduced the extent of harmful inflammation caused by inflammatory monocytes. They published their findings in the January 15th issue of Science Translational Medicine.
“Secondary tissue damage as a result of inflammation is a huge problem in a very large number of diseases and conditions such as autoimmune disorders, infections, heart attack, stroke, and even following organ transplants,” said Jessica Tucker, Ph.D., Program Director of Gene and Drug Delivery Systems and Devices at NIBIB, which provided support for the research. “A therapy that can safely prevent harmful inflammation would have a major clinical impact.”
Inflammatory monocytes: A double-edged sword
Inflammatory monocytes (IMs) are a type of white blood cell that normally circulate in the blood, but enter tissues immediately following an infection or other types of damage. Once inside, they engulf dead or dying cells as well as pathogens via a receptor on their cell surface called the macrophage receptor with collagenous structure (MARCO). At the same time, IMs begin to secrete pro-inflammatory molecules that initiate the body’s inflammatory response but can also cause tissue damage. While this process is meant to rid the body of harmful pathogens and clear the way for tissue repair, its indiscriminate nature often leads to the destruction of healthy tissue.
Current treatments for reducing harmful inflammation involve the use of corticosteroids or non-steroidal anti-inflammatory drugs, both of which can cause serious side effects over the long term.
“At this time, there are no safe or effective therapies that specifically target inflammatory monocytes in a sustained manner,” said Tucker.
A biological detour
But a new therapy that involves the infusion of negatively charged microparticles—about 1/200th the diameter of a human hair—could provide a safe alternative to current anti-inflammatory drugs. Once inside the body, the microparticles are engulfed by circulating inflammatory monocytes via the MARCO receptor, which mistakes the particles for cellular debris. As a result, and for reasons not fully understood, the IMs are detoured to the spleen where they undergo cell death.
“Essentially what we’re doing with the microparticle injection is lessening the acute inflammatory response so that the initial destruction is kept to a minimal level,” said Stephen Miller, Ph.D., the Judy Gugenheim Research Professor at Feinberg School of Medicine and a researcher in the study.
A dramatic example of the damage caused by inflammatory monocytes is seen in patients following a heart attack. As blood flow begins to return to normal, inflammatory monocytes rush into the heart, resulting in a much larger area of damaged tissue than initially affected.
In their article, Miller and colleagues showed in a mouse model of heart attack that they could reduce the amount of heart inflammation by 20-25%, simply by infusing the mice with their microparticles within twelve hours of the heart attack and for three subsequent days. The reduction correlated with improved pumping action 30 days post-heart attack.
“It’s an exciting result because it shows how a fairly simple system can potentially be used to prevent further inflammatory damage by harnessing the body’s natural processes for removing dying cells,” said Tucker.
A healthy dose of negativity
The discovery that negatively charged microparticles could be used to divert inflammatory monocytes was initially made by Daniel Getts, Ph.D., lead author of the study, while working in the lab of Nicholas King, professor of viral immunopathology at the University of Sydney School of Medical Science. At the time, Getts was using microparticles tagged with fluorescent markers to visualize the influx of inflammatory monocytes into the brains of mice recently infected with West Nile virus.
“The model of West Nile virus we were using was 100% lethal, but one day after injecting the particles, some of the mice lived,” said Getts. “We didn’t know what was happening, but we repeated the experiment 10-15 times and kept getting the same result. Then we looked backwards and saw that there was a massive reduction in the number of inflammatory monocytes going to the brain, and this was causing the mice to survive.”
It turned out that the manufacturer that normally supplies Getts with his microparticles had accidentally sent some that were negatively charged. Because the MARCO receptor is positively charged, the inflammatory monocytes were highly attracted to these particles.
“We found that we could change many properties of the microparticles, but as long they had a negative charge, they would divert the inflammatory monocytes away from the brain,” said Getts.
Soon afterwards, Getts came to Northwestern to team up with Miller, an expert in immunoregulation of autoimmune diseases, and the pair began using microparticles that had antigens attached to them to induce selective repression (tolerance) of the immune system in mouse models of autoimmune diseases. At the same time, they began testing the effects of the negatively charged particles on various models of inflammatory disease.
The encouraging results from their recent studies have prompted Miller, Getts, and King, along with Lonnie Shea, a nanotechnology expert at Northwestern, to launch a biotech company called Cour Pharmaceutical Development Co. The company intends to test the microparticle injections in a clinical trial of heart attack patients within two years.
“We decided to try our therapy first in heart attack patients, because patients are usually in a hospital setting within 2-4 hours. This would allow us to give patients a microparticle infusion when it’s most likely to be effective,” said Miller.
One of the advantages of the microparticles is that they are made out of a biocompatible and biodegradable substance already approved by the FDA for use in re-absorbable sutures.
Tucker says using microparticles to modulate the immune system is an exciting new approach that holds considerable promise:
“There is a huge body of research using nano- or microparticles to deliver drugs to treat many different diseases. We’re just starting to understand how tiny modifications to these particles can have a huge impact on how the immune system reacts to them. It opens the door for researchers to manipulate the immune system in ways not previously possible.”
This work was funded in part by National Institutes of Health grants EB013198, NS026543, HL097021, and HL092357.