A Trinity scientist has discovered a 'brake' used by the body to shut down harmful inflammation, which could lead to important new drug therapies, writes Dick Ahlstrom
A Dublin researcher has discovered a way of shutting down inflammation, eliminating the risk of so called "friendly fire" that leads to diseases such as rheumatoid arthritis. The finding could help deliver entirely new drug therapies for many of today's intractable auto-immune diseases.
Our immune systems play a life-saving role in protecting us from bacterial and viral invaders. Sometimes, however, the immune system goes over the top, not only killing invaders but causing damage to otherwise healthy tissues.
Prof Luke O'Neill is the research professor of biochemistry in the department of biochemistry at Trinity College Dublin. He and colleagues today publish important new findings in Nature Immunology about how the body prevents runaway inflammation as a result of infection.
Prof O'Neill has done extensive research on the role of a collection of immune cell receptors or "switches" known as the Toll-Like Receptors (TLRs). "Tolls are good because you need these to fight infection," he says. "You need them to alert the immune system that an invasion is going on. The problem is they can be over activated." This in turn leads to auto-immune conditions where the immune cells either turn on healthy cells or cause unwanted damage because of the powerful substances the immune cells release.
Toxic shock as a result of runaway inflammation is a common example of what can occur, says Prof O'Neill. Between 1,500 and 2,000 people die in the Republic each year due to infections that lead to toxic shock and the current treatment options are limited.
"We now know that tolls are driving this specific response," Prof O'Neill says. He and his team have found a way to switch off the toll receptors. "We have discovered a brand new process that nobody has ever seen before."
Back in 1999 Prof O'Neill was on sabbatical at Millennium Pharmaceuticals in Cambridge, Massachusetts, where a team had discovered an immune cell protein called ST2. "They found it was highly expressed during inflammation," says Prof O'Neill. They also discovered that "when ST2 switches on, it switches off inflammation".
The company couldn't make headway with the discovery, however, because they didn't understand its action. The company shelved its research, but O'Neill continued looking at ST2 in the context of his ongoing examination of TLRs, work currently funded by Science Foundation Ireland.
"We tested tolls as a possible target for ST2 and it turns out ST2 turns off tolls. A brand new mechanism was found," he says.
When bacteria appear the TLRs are triggered into action, sending out messages that attract immune cells to the site of infection. This immediately causes local inflammation, desirable at that point to help overcome the bacteria.
However, the immune cells also begin producing a supply of ST2, the very substance that in time will halt the inflammatory process driven by TLRs. "Tolls get triggered by bacteria and then they induce the production of ST2, sowing the seeds of their own destruction," says Prof O'Neill.
Even as the immune cells begin to overcome the bacteria, the ST2 gradually begins to have an effect. Prof O'Neill and colleagues discovered that it mops up two essential proteins used by TLRs to sustain inflammation, MYD88 and MAL.
The ST2 sequesters these proteins, thereby interrupting the TLR signals and damping down inflammation. This blocks the "friendly fire" laid down by immune cells while trying to play their role in fighting infection. "Anything that inhibits tolls will have a role in controlling inflammation," says O'Neill, and for that reason he is now on the hunt for something that can mimic the action of ST2 in the body.
"There is a desperate need to come up with new drugs to treat sepsis and also inflammatory disease. We would like to come up with a mimic of ST2. We are looking at peptides (protein fragments) because the ST2 molecule is too large," says Prof O'Neill.