Obesity can turn a helpful immunotherapy into a harmful one, mouse study shows

Researchers have long known that obesity rewires the immune system. Now a new study suggests these effects can be so profound they could turn a drug meant to treat a common inflammatory disease into one that makes things worse.

Scientists discovered that mice with atopic dermatitis, a painful and itchy skin rash often triggered by an allergic reaction, were worse off if they were obese. A closer look at their immune responses led to a surprise finding: Different immune cell types drove the disease in obese versus lean mice. That caused a standard treatment to exacerbate symptoms in heavier animals, but adding another drug that made the immune response of the obese mice resemble those of lean animals made the treatment regimen work again.

The authors found some preliminary evidence that obesity alters immune responses to allergic diseases similarly in people, too. But it’ll take additional work to show whether the findings, published Wednesday in the journal Nature, hold up in humans.

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These early-stage results aren’t cause for alarm among people concerned about whether their medications are working, cautions Alexander Marson, director of the Gladstone-UCSF Institute of Genomic Immunology, one of the study’s senior authors. But he added that the work raises the possibility that researchers may need to tailor treatments depending on a patient’s metabolism.

“This is now a major, major epidemic of metabolic disease and obesity around the world,” Marson said. “We have to start thinking about this as a particular variable that could influence the nature of inflammation and allergic disease.”

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More than 40% of U.S. adults have obesity, according to the Centers for Disease Control and Prevention, with some studies estimating that figure could jump to nearly 50% by 2030.

That’s likely to lead to a rise in all sorts of health conditions — and not just type 2 diabetes and heart disease. There’s growing evidence that obesity can worsen everything from asthma to various cancers to Covid-19. Part of the problem, researchers believe, is that obesity creates a low level of inflammation throughout the body.

To study the issue more closely, a team of researchers from the Salk Institute, Gladstone Institutes, and the University of California, San Francisco, zeroed in on atopic dermatitis. The inflammatory disease is the most common form of eczema and leads to dry and itchy patches of scaly skin across a person’s hands, feet, and eyelids, among other places.

Researchers triggered the disease in mice by injecting their ears with chemicals that sparked an inflammatory response in the skin. They found that disease was more severe in obese animals, whose ears swelled more than twice as much as lean mice.

Scientists then looked at exactly which immune cells were driving disease in both sets of mice. They discovered that obese mice didn’t simply have a higher level of inflammation — their disease was driven by a completely different set of cellular signals.

“That was the real surprise,” Marson said.

The unexpected finding came from looking at T helper cells. Like generals coordinating a military attack, they control the scale and strategy of an immune response. They do so by releasing chemicals known as cytokines, essentially marching orders for cells.

In lean mice, the authors found that disease was driven by a class of T helper cells known as Th2. That’s what they expected. But in obese mice, the response came from a distinct group known as Th17. Each subset of cells spits out different cytokines, and when scientists tried to treat obese mice with a pair of antibodies that blocks two key Th2 cytokines, they made things worse. The animals started to develop little pustules along their ears, a sign of severe disease.

Their next challenge? Understanding what happened, and whether they could reverse it. Researchers found that a protein called PPAR-gamma, which turns on key genes in Th2 cells, was less active in obese mice. So they treated these mice with rosiglitazone, a drug that revs up PPAR-gamma and is typically used to help people with type 2 diabetes respond to insulin, and the animals began responding to Th2-targeted treatment.

Turning an ineffective treatment back into a useful one was a key piece of this study, said Akiko Iwasaki, a Yale immunologist who wasn’t part of this effort. But she cautions that all the mice studied were male; in people, atopic dermatitis mainly affects women.

“It would have been good to see if there are any sex differences in the impact of obesity on atopic dermatitis disease and treatment,” said Iwasaki in an email to STAT.

The findings have potential real-world implications. Rosiglitazone has already been approved by the Food and Drug Administration and is sold under the name Avandia by U.K. pharma giant GlaxoSmithKline. And French drugmaker Sanofi markets Dupixent, a drug approved for eczema that blocks the same two Th2 cytokines Marson’s team went after in this study: IL-4 and IL-13.

Marson hasn’t spoken with any companies about the report, as there’s still plenty of follow-up work his team needs to do to see whether these results hold up in people. The authors looked back on previously collected data and found some signs of increased Th17 responses and decreased Th2 activity in obese patients with atopic dermatitis and asthma, respectively, but that evidence is preliminary.

He says a key next step would be to look at patients with many different types of allergic inflammation to see whether the immune signals driving disease are consistently different in people who have obesity. Marson adds that researchers could then sift through current data on how people respond to Th2-blocking treatments to see if the effectiveness of these drugs varies depending on a person’s body mass index. Those findings could potentially lead to future clinical trials that test the safety and effectiveness of therapies tweaked to better treat people with obesity.

“Do we have to think about different targets in the setting of altered metabolic states and obesity?” Marson said. “This hypothesis here is thought-provoking and changes the way that we see these things. But [it’s] not yet at a point where this could actually motivate specific treatment decisions.”