Using immunity to tackle obesity

February 26th 2019

Researchers at ULB’s immunobiology Laboratory have identified one of the mechanisms causing adipose tissue inflammation in obese subjects. This discovery may pave the way to obesity treatments based on immunotherapy.

In healthy subjects, adipose tissue contains a reserve of immune cells—especially type 2 innate lymphocytes—whose purpose is to fight inflammation. Among other things, these lymphocytes control the cells’ differentiation and functioning in adipose tissue (homeostasis).
In obese subjects, this feedback system is disrupted: their abdominal fat is infiltrated by (type 1) immune cells that do trigger an immune response. And chronic inflammation has been shown to play a major part in the onset of diabetes and other obesity-related cardiovascular comorbidities.?

Activating the PD-1/PD-L1 pathway
In collaboration with French and Dutch researchers, Guillaume Oldenhove and Muriel Moser—researchers at ULB’s immunobiology Laboratory—have highlighted one of the immune mechanisms that explain this inflammation. ‘When mice are fed a diet with high fat content, their type 2 lymphocytes express inhibitor receptor PD-1,’ explains Professor Muriel Moser, dean of ULB’s Faculty of Sciences. ‘In parallel, macrophages—which ordinarily ensure the proper functioning of adipose tissue—are activated by adipocytes that die by necrosis. They then become inflammatory, and start expressing ligand PD-L1. Once the PD-L1 “key” is linked with the PD-1 “lock”, the anti-inflammatory function of type 2 lymphocytes is inhibited. This allows type 1 immune cells to proliferate in abdominal fat, with the expected consequences.’

Therapeutic potential
This discovery was published in journal Cell Reports, and it opens up a number of potential avenues for treatment. ‘For instance, by blocking PD-1 using an anti-PD-1 antibody, we might reverse the process,’ explains Professor Moser. Using the same anti-PD-1 that are used in immuno-oncology? ‘In the case of obese subjects, this would be difficult due to the secondary effects that the drugs may produce. An ideal solution would be to identify an inhibitor that acts at an earlier stage, specific to adipose tissue and without the toxicity of immunotherapies used to fight cancer.’

Research prospects
First, however, we must learn more about the complex immune mechanisms involved. ‘We would like to identify the very first stages of the inhibition. What activates the macrophages and the inflammatory response? We have identified cytokine IL-33 as an activating factor, but there are likely others. And we still have to find out exactly why and how PD-1 works in the context of obesity.’?One thing is certain: immunotherapy is a promising approach to tackling this disorder!