Inflammatory bowel disease (IBD) is miserable for anyone, but when it strikes a child under age 5, it’s much more severe, usually causing bloody diarrhea, wrenching abdominal pain and stunted growth. Early-onset IBD is rare, but on the rise: For reasons unknown, its incidence is increasing by about 5 percent per year in some parts of the world.
A recently identified form of early-onset IBD shows up within months of birth, causing severe inflammation in the large intestine and abscesses around the anus. Recently linked to genetic mutations in the cellular receptor for a signaling protein, interleukin-10 (IL-10), it can also lead to lymphoma later in life.
As with all early-onset IBD, IL-10-receptor deficiency has no good treatment. A bone marrow transplant is actually curative, but carries many risks, especially in infants.
“We’ve been trying to understand why IBD in these children is so severe and presents so early,” says Dror Shouval, MD, a pediatric gastroenterologist at Boston Children’s Hospital and a fellow in the lab of Scott Snapper, MD, PhD. The beginnings of such an understanding—detailed recently in the journalImmunity—could lead to a new treatment approach for this and perhaps other kinds of early-onset IBD.
Of mice and macrophages
Working through its receptor, IL-10 quiets inflammatory immune responses when they’re not needed to protect against infection. Working with mouse models, Shouval, Snapper and colleagues showed that when innate immune cells near the intestine didn’t receive IL-10 signals, the mice developed rapid, severe intestinal inflammation and weight loss.
Delving further, they showed that without the ability to sense IL-10, the mice could not produce the kinds of immune cells that tend to temper inflammation. They churned out plenty of pro-inflammatory macrophages, but far fewer macrophages with anti-inflammatory properties, and those they made didn’t work well. As a result, they also produced fewer T-regulatory cells, another type of “calming” immune cell; again, those they did make functioned poorly.
Simply put, their intestinal immune responses were out of whack.
“Loss of IL-10 signaling disrupts the delicate balance in the intestine between pathogenic and regulatory immune cells,” says Snapper, who directs theInflammatory Bowel Disease Center at Boston Children’s
The researchers then tapped a worldwide patient cohort study of early-onset IBD, known as NEOPICS, which serves as a clearinghouse for research and on which Snapper is a co-principal investigator. “We get an email or phone call at least once a week from physicians around the world who are struggling with the work-up and management of patients who developed IBD very early in life,” says Shouval. “Based on the clinical presentation, we tailor a specific diagnostic plan to try to find the cause.”
Using the NEOPICS database, Shouval and Snapper identified seven children from the U.S., Canada, Israel, Saudi Arabia, Brazil, Germany and the Netherlands—all with IBD and IL-10-receptor mutations—and studied their disease in a dish.
“Like in the mice, their macrophages are much more aggressive and lead to an exaggerated immune response,” says Shouval. “The generation and function of anti-inflammatory macrophages are also decreased.”
Bench to bedside?
The mouse studies had another, more hopeful finding. By transferring anti-inflammatory macrophages into the IL-10-receptor-deficient mice, the researchers were able to ameliorate their IBD.
“If you can modulate macrophage function, it could be a new avenue for IBD treatment,” says Shouval. “This is very preliminary, but what we hope to do is take monocytes from the patient’s blood, stimulate them in the lab, create more anti-inflammatory macrophages, and give them to the patient.”
This type of cell transplant would be milder than a full bone marrow transplant, which requires immunosuppressive medications that can have severe side effects in young children, including cancer.
And, Shouval and Snapper believe, it could potentially work for children with early-onset IBD who don’t have an IL-10-receptor deficiency. “Many pathways may converge to this IL-10 signaling pathway, and other patients might have blunted responses to anti-inflammatory signals like IL-10, so we think it might be possible to use this in a broader way,” Shouval says. “There is a great need to develop new therapies for IBD, and we hope that the knowledge gained by these experiments will lead to drug discovery and improved treatment options.”