Tiny particles could provide big clue to taming inflammation

Particle affects immune responses

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Extremely small particles could provide a big clue to taming unwanted immune responses, such as in rheumatoid arthritis or organ transplants, researchers from Georgia Health Sciences University found.

In a study published today in the Journal of Immunology, the researchers looked at new ways of inducing indoleamine 2,3-dioxygenase, or IDO for short.

The enzyme was first attributed by GHSU researchers Dr. Andrew Mellor and Dr. David Munn as protection for a fetus from the mother’s immune system by locally reducing the activity of T cells.

The researchers have since tried to use it to increase the activity of the immune system against cancer and chronic infections by decreasing IDO and an IDO-inhibitor in phase II clinical trials in cancer, Mellor said.

But they have also sought to increase IDO to thwart hyperactive immune responses, to protect transplants and to reduce autoimmune diseases such as rheumatoid arthritis, type 1 diabetes and systemic lupus, he said.

“Those are very debilitating, long-term diseases and hard to treat,” said Mellor, the director of the Immunotherapy Center at GHSU.

The team was pursuing this immune-dampening strategy, working with nanoparticles designed to insert an IDO gene into a mouse’s cells to protect a transplant, when they made an unexpected finding, Mellor said.

Even without an IDO gene aboard, the nanoparticles stimulated the mouse to produce more protective IDO, he said. And a major consequence of that is the activation of regulatory T cells, which can dampen the hyperactivity of other immune cells.

It has proven difficult to activate regulatory T cells without activating other T cells that could prove harmful, he said.

“That is a major goal of clinical research at the moment, to try to figure out how to get human regulatory T cells to mediate their function of controlling the immune system,” Mellor said. While many laboratories are working on that, the GHSU approach is a little different, he said.

“We’re not targeting directly the regulatory T cells in this approach; we’re actually targeting the IDO mechanism, which is a pivotal mechanism to activate regulatory T cells,” Mellor said. “So by inducing the IDO, the regulatory T cells activate.”

The team is working with scientists at Georgia Tech and the Massachusetts Institute of Technology to try to enhance the effect and address a few problems.

One is that the nanoparticles are not biodegradable, which won’t fly with the Food and Drug Administration, Mellor said. A biodegradable polymer might already have been identified, he said.

Another challenge is to cut down on any toxicities associated with the therapy before potential clinical trials, Mellor said.

“Those are the directions in the future that we want to go in so that we can make these reagents much more acceptable for clinical applications to treat autoimmune syndromes or perhaps even transplant patients as well,” he said.


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