New insight for developing more effective drugs to combat inflammatory bowel disease

December 21, 2016
David Lo is a distinguished professor of biomedical sciences in the School of Medicine at UC Riverside. Credit: I. Pittalwala, UC Riverside.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the intestine that includes Crohn's disease and ulcerative colitis. It is commonly treated with one of several available biological drugs that block an inflammatory molecule called Tumor Necrosis Factor Alpha (TNF-alpha), but not everybody is helped by this treatment.

New research by a team of biomedical scientists at the University of California, Riverside, led by David Lo, M.D., Ph.D., now offers a valuable tip that could help make these drugs more effective.

TNF-alpha is a protein produced by the body's . It signals other cells that then produce additional inflammatory factors. But Lo's lab discovered earlier this year that TNF-alpha also induces specialized immune surveillance cells, called M cells, which both promote inflammation and suppress it. In other words, TNF-alpha plays a role in the destruction and the healing of tissues - a double-edged sword.

"M cells normally help the immune system detect microbes in the gut, but in the case of IBD, these may also help bacteria enter tissues and worsen the inflammation," explained Lo, a distinguished professor of biomedical sciences in the School of Medicine.

His lab now reports that that while there are two receptors for TNF-alpha, only one receptor, TNFR2, induces M cells. Currently, TNF-alpha-targeted drugs block both TNFR1 and TNFR2.

"Newer therapies might be more effective by targeting only TNFR2," Lo said. "As an analogy, if a soldier knew her enemy was hiding in one of two caves, she would not debate which cave she should target; she might blow up both. But if she knows her enemy is in Cave A, then why would she waste ammunition and risk innocent bystanders by attacking Cave B as well?"

Study results appear online in the Journal of Crohn's and Colitis.

The body's intestinal lining has that form a barrier so that bacteria in the gut do not pass on into the rest of the body. During inflammation that occurs in IBD infection, TNF-alpha triggers an increase in the number of M cells along the colon. The M cells act like selective gates and serve as a conduit for pathogens to get across the barrier and into the body.

"The question is if you have more M cells, do you have better immune surveillance or do you have more bacteria getting across the barrier?" Lo said. "From a therapeutic point of view we might want to tamp M-cell production down just enough so that the immune system can do its job without having a whole lot of bacteria pass into the body from inside the gut."

Lo explained why not everybody with IBD benefits from anti-TNF drugs.

"These drugs target both TNRF-alpha receptors: TNFR1 and TNFR2," he said. "But our research identifies a distinct inflammation-inducible M-cell population that is dependent on TNFR2 signaling, but not TNFR1. If too many M cells are being produced, then the anti-TNF drug being used is not sufficiently blocking TNRF2, which induces the M cells, and is instead blocking the other receptor. If we understand why there are two receptors, then instead of drugs doing a global blockade, more focused therapeutic approaches could target only one of the receptors, resulting in a more efficient suppression of the inflammation we see in IBD."

An ongoing challenge for biomedical scientists doing IBD research is gaining a full understanding of the role M cells play in chronic inflammation. It remains unclear whether M cells help promote continuing inflammation or whether they are critical to initiating immuno-regulatory mechanisms.

"Knowing these roles should lead to more specifically targeted therapies that will promote the regulation and resolution of ," Lo said.

Explore further: Inflammatory protein involved in autoimmune diseases has healing potential

More information: Erinn A. Parnell et al. Inducible Colonic M Cells Are Dependent on TNFR2 but Not Ltβr, Identifying Distinct Signalling Requirements for Constitutive Versus Inducible M Cells, Journal of Crohn's and Colitis (2016). DOI: 10.1093/ecco-jcc/jjw212

Related Stories

Inflammatory protein involved in autoimmune diseases has healing potential

April 20, 2016
As its name suggests, inflammatory bowel disease, which afflicts more than 1.6 million Americans, involves chronic inflammation of all or some of the digestive tract. An autoimmune disease known to have a strong genetic component, ...

Tumor necrosis factor in colitis—bad actor or hero?

September 25, 2015
Investigators at Children's Hospital Los Angeles have found that a common therapeutic target for the treatment of inflammatory bowel disease (IBD) may actually protect against intestinal inflammation by inhibiting pathogenic ...

New impetus for treatment neurodegenerative diseases

October 10, 2016
Twenty years ago, tumor necrosis factor (TNF) seemed a promising target in the treatment of brain diseases like multiple sclerosis or Alzheimer's Disease. But clinical trials produced disappointing results. Now University ...

Target for new Rx class for inflammatory disorders discovered

October 3, 2013
Research led by Charles Nichols, PhD, Associate Professor of Pharmacology at LSU Health Sciences Center New Orleans, describes a powerful new anti-inflammatory mechanism that could lead to the development of new oral medications ...

Immune study offers treatment hope for arthritis patients

April 18, 2016
Arthritis and other inflammatory conditions could be helped by new insights into how the immune response is switched off.

Cytokine plays dual role in regulating inflammatory bowel disease, study finds

February 16, 2016
Small proteins that affect communication between cells play an important role in regulating inflammation that occurs during inflammatory bowel disease, according to researchers at Georgia State University, Emory University, ...

Recommended for you

New insights into protein's role in inflammatory response

July 28, 2017
A protein called POP2 inhibits a key inflammatory pathway, calming the body's inflammatory response before it can become destructive, Northwestern Medicine scientists have demonstrated in mouse models.

Targeting 'broken' metabolism in immune cells reduces inflammatory disease

July 12, 2017
The team, led by researchers at Imperial College London, Queen Mary University of London and Ergon Pharmaceuticals, believes the approach could offer new hope in the treatment of inflammatory conditions like arthritis, autoimmune ...

A perturbed skin microbiome can be 'contagious' and promote inflammation, study finds

June 29, 2017
Even in healthy individuals, the skin plays host to a menagerie of bacteria, fungi and viruses. Growing scientific evidence suggests that this lively community, collectively known as the skin microbiome, serves an important ...

Inflammatory bowel disease: Scientists zoom in on genetic culprits

June 28, 2017
Scientists have closed in on specific genes responsible for Inflammatory Bowel Disease (IBD) from a list of over 600 genes that were suspects for the disease. The team from the Wellcome Trust Sanger Institute and their collaborators ...

Trials show unique stem cells a potential asthma treatment

June 28, 2017
A study led by scientists at Monash University has shown that a new therapy developed through stem cell technology holds promise as a treatment for chronic asthma.

Researchers find piece in inflammatory disease puzzle

May 23, 2017
Inflammation is the process by which the body responds to injury or infection but when this process becomes out of control it can cause disease. Monash Biomedicine Discovery Institute (BDI) researchers, in collaboration with ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.