"The most critical next steps would to explore the therapeutic approach in non-human primates, where the immune response is stronger and similar to humans," Dr. Ronald Evans of The Salk Institute for Biological Studies in La Jolla told Reuters Health by email. "Secondly, to explore patients who take peroxisome proliferator-activated receptor-gamma (PPARg) therapy to see if there is a lower incidence for atopic dermatitis (AD)."
"While PPARg drugs are approved for diabetes, they have long-ter side effects, such as weight gain and some bone loss," he said. "However, if the study can be done with a short-term intervention, a pilot study might be helpful."
One implication of the current study, he said, "is that (since) obesity makes the situation worse, clinicians should encourage their patients to improve their diets, get exercise and lose weight."
As reported in Nature, Dr. Evans and colleagues studied two mouse models of AD, and found that obese mice mount markedly different immune responses from lean ones. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation.
They also observed different responses to AD biologic therapies targeting TH2 cytokines; the drugs protected lean mice but exacerbated disease in obese mice.
Yet, when the team treated the obese mice with rosiglitazone, a PPARg-activating drug, the animals' skin improved and their molecular profile switched from TH17 back to TH2. At that point, therapies aimed at TH2 inflammation were almost as effective as in lean mice.
The authors conclude, "These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity."
Dr. Jonathan Silverberg, Director of Clinical Research and of Patch Testing at George Washington University School of Medicine and Health Sciences in Washington, DC, commented on the study in an email to Reuters Health. "The results are interesting," he said. "However, many experts in the field have noted that mouse models of AD are more similar to psoriasis in humans."
"Psoriasis is a Th17-mediated disorder that is strongly associated with obesity and metabolic syndrome, whereas AD is associated with Th2 and less Th17," he noted. "These results suggest that obesity skews the immune system toward Th17."
"Some AD patient subsets were found in previous studies to have increased Th17 activation, particularly patients of Asian descent," said. "However, these were, if anything, lighter weight patients."
"I am not sure if any of these results are generalizable to humans," he added. "Nevertheless, I think future studies are certainly warranted."
SOURCE: https://go.nature.com/3v2n19V Nature, online March 30, 2022.
By Marilynn Larkin
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