Researchers Explore Targeted Therapies for Autoimmune Diseases

Study findings may help determine why inflammatory bowel disease patients have a chronic type of inflammation.

A recent finding involving a proinflammatory molecule and a protein that promotes immune system regulatory response could lead to new targeted drug therapies for autoimmune diseases.

A study published in The American Journal of Pathology used mice to focus on the gut. TNF-alpha has already been known to cause inflammation, but the results of the study suggest that TNF-alpha also promotes immune system regulatory responses by first inducing M cells, immune surveillance cells.

According to researchers, the induction of M cells suggest the body may have a built-in system that promotes both inflammation and regulation, leading to the suppression of the immune response.

“If we don't know what triggers the disease then the best we can do is treat the disease by suppressing inflammation,” said lead researcher David Lo. “Currently, the main drug therapeutics being used to manage IBD are anti-inflammatory treatments. One of the newest is a series of biologicals, basically antibodies that absorb the inflammatory molecules that promote the inflammatory response. There are half a dozen of these biologicals specifically targeting the cytokine TNF-alpha. They don't work in all patients, resulting often in some patients having to try one biological after another to find out what works.”

Although TNF-alpha promotes the destruction of tissues, cytokine promotes tissue healing.

“Cytokines are regulators of host responses to infection and inflammation,” Lo said. “Some make disease worse because they are proinflammatory. Others reduce inflammation and promote healing because they are anti-inflammatory. TNF-alpha plays a dual role in that it does both. If we had a more focused way of dealing with the undesired inflammatory aspects of TNF-alpha, we could still retain the healing, restorative aspects of this cytokine.”

They study revealed that TNF-alpha triggers can increase in number of M cells in the colon of IBD infection and the M cells act as selective gates.

“They show up in the colon where they didn't exist before, alerting the immune system that something is up,” Lo said. “Through the M cells and their selective gatekeeping, the immune system is able to do some sampling of the gut, both more frequently and along the whole intestine.

“The colon is not normally a place where you have this sort of sampling going on. To significantly ramp up the sampling process by these M cells this way can help us figure out how the immune response will gear up its ability to either deliver a more powerful immune response or, alternatively, regulate and suppress the inflammation, and thus restore normal homeostasis in the intestine.”

Although these findings can lead to the development of more targeted drug therapies, it can also help scientists better understand why inflammatory bowel disease patients have a chronic type of inflammation to begin with.

“Advanced immune surveillance is a clue into how the immune system is attempting to restore balance and calm in the tissues,” Lo said. “If M cell production is a critical part of this restoration process, then it means we can develop more targeted therapies that don't block this restoration. Many of the biologicals being used today absorb and wipe out TNF-alpha, but in the long run this may be harmful to the patient because removing TNF-alpha altogether also blocks its ability to produce restorative mechanisms.”

The next step for researchers will focus on different receptors in the body that receive signals, causing the start of inflammation and tissue restoration.

More specifically, Lo hopes to learn which receptors are responsible for what; which ones create undesired inflammatory effects; which promote restorative effects; and how does it trigger a sequence of events that leads to restoration of calm and inflammation removal.

“The ultimate goal would be to have drug therapies that are more targeted so it's no longer like throwing a sponge at the infection and hoping something will work,” Lo said.