How obesity can switch the immune system and the response to immunotherapy – and how to change it

A team of researchers at the Gladstone Institutes, Salk Institute for Biological Studies and UC San Francisco discovered how obesity can alter the immune system and potentially how clinicians may be able to better treat allergies and asthma in obese people. Credit: Michael Short / Gladstone Institutes

When mice with atopic dermatitis – a common type of allergic dermatitis – are treated with drugs that target the immune system, their thickened, itchy skin generally heals quickly. But researchers have now discovered that the same treatment in obese mice makes their skin worse instead. This is because obesity alters the molecular basis of allergic inflammation, in both mice and humans.

For the new study, researchers from the Gladstone Institutes, the Salk Institute for Biological Studies and the UC San Francisco (UCSF) teamed up. Their results, reported in the journal Natureshed light on how obesity can alter the immune system and potentially how clinicians may be able to better treat allergies and asthma in obese people.

“We live in an era where the number of obesity is rising around the world,” said Alex Marson, MD, Ph.D., director of the Gladstone-UCSF Institute of Genomic Immunology and a senior author of the study. “Changes in diet and body composition can affect the immune system, so we need to think about how diseases involving the immune system can vary between individuals.”

“Our results show how differences in our individual metabolic states can have a major impact on inflammation, and how available drugs may be able to improve health outcomes,” said Ronald Evans, Ph.D., senior author of the study and director of the study. . Salk’s gene expression laboratory and the March of Dimes chair in molecular and evolutionary biology at Salk.

Different types of T cell responses

A recent study estimated that about half of adults in the United States will be classified as overweight by the year 2030. Researchers also know that obesity, sometimes classified as a chronic inflammatory condition, alters the immune system in countless ways. Clinicians have reported that people with obesity often appear to have different disease courses – from infections and allergies to cancer – and respond differently to some treatments.

During his master’s studies at Salk and subsequent research in the Marson laboratory, Sagar Bapat, MD, Ph.D. – now pathologist and faculty at UCSF – to know, at the molecular level, how obesity affected atopic dermatitis. He discovered that when mice were made overweight by eating a high-fat diet before the induction of dermatitis, they developed more serious disease than lean animals. To understand why, he and his colleagues analyzed the immune cells and molecules that were active in each group of mice.

“What we expected to see in the obese mice was just a greater degree of the same kind of inflammation,” says Bapat. “Instead, we saw a completely different kind of inflammation.”

The body’s T helper cells, which help protect against infection but also become overactive in autoimmune diseases or allergies, can be grouped into three classes: TH1, TH2, and TH17 cells. Researchers had considered atopic dermatitis as a TH2 disease; it means TH2 cells are those that cause dermatitis.

In lean mice with atopic dermatitis, Bapat and his colleagues actually found that TH2 cells were active. In obese mice with the same condition, TH17 cells were activated. At a molecular level, this meant that atopic dermatitis was completely different in the obese mice, raising the question of whether the drugs acting on lean animals would also be effective in obese animals.

Changing the effectiveness of a drug

In recent years, researchers have developed drugs aimed at treating atopic dermatitis by attenuating the response of TH2 cells. When Bapat and his colleagues treated obese mice with one of these drugs, it not only relieved their atopic dermatitis, it actually made the disease significantly worse.

“The treatment became a robust anti-treatment,” says Bapat. “This suggests that you may have identical twins appear in the hospital with the same disease, but if one is overweight and the other is slim, the same drug may not work on both.”

The researchers suspected that dysfunction in a protein called PPAR-gamma could mediate the link between obesity and inflammation. In 1995, Evans and his team discovered that PPAR-gamma was a master regulator of fat cells and a target for an approved drug for diabetes.

When the researchers treated obese mice with atopic dermatitis with one of these PPAR-gamma-activating drugs, called rosiglitazone, the animals’ skin was improved and the molecular profile of their disease shifted back from T.H17 to TH2 inflammation. In addition, the substances are directed at TH2 inflammation was then, almost as in lean mice, able to improve the atopic dermatitis of the obese animals.

“Basically, we have immunologically ‘defatted’ obese mice without changing their body weight,” says Bapat.

Back to the patients

The team also analyzed data from human patients with allergic disease, including 59 patients with atopic dermatitis as well as hundreds of people with asthma (another condition similarly involving a reaction from the immune system), enrolled in a large existing longitudinal study. They found that obese people were more likely to have indications of TH17 inflammation or decreased signs of the expected TH2 inflammation.

Although more studies in humans are needed, data suggest that in both humans and mice, obesity causes a change in inflammation that has implications for the pathology of allergic disease and the effectiveness of immunotherapies targeting T.H2-associated inflammation.

“What we want to know more about now is exactly how T cell switching happens,” says senior author Ye Zheng, Ph.D., an associate professor at the NOMIS Center for Immunobiology and Microbial Pathogenesis at Salk. “There are more details here to uncover that could be relevant to a wide range of diseases related to allergies and asthma.”

Already, however, the new study points to the usefulness of combining the therapy targeted at TH2 inflammation with a PPAR-gamma drug such as rosiglitazone for the treatment of obese patients with atopic dermatitis.

“This is a case where our scientific discovery could have a very safe and rapid application to therapy in humans,” Evans says. “Our preclinical results suggest that these already FDA-approved drugs may have a unique co-treatment benefit in certain patients.”

Atopic dermatitis associated with shorter stature in early childhood

More information:
Alexander Marson, Obesity changes pathology and treatment response in inflammatory disease, Nature (2022). DOI: 10.1038 / s41586-022-04536-0

Provided by the Gladstone Institutes

Citation: How Obesity Can Switch The Immune System And The Response To Immunotherapy – And How To Change It (2022, March 30) Retrieved March 31, 2022 from response -immunterapiog.html

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