11 Oct 2016

Thinking outside the box pays dividends for research on obesity and immune function

Immune system function is impaired in obese mice.
by Anne Crawford

In 2010, the Department of Immunology at Monash University held a competition encouraging post-doctoral researchers to “think outside the square”, challenging them to design a project outside conventional thinking and their usual area of expertise. That competition, with a prize of $10,000, mushroomed into an NHMRC-funded project employing two post-doctoral researchers and two honours students. It culminated in 2016 with a paper reporting on the influence of obesity on allergic asthma – and some unexpected findings.

The competition, conceived by then department head, Professor Fabienne Mackay, was won by Drs Sara Prickett and Charles Hardy, who proposed using mouse models to investigate the possible effect of obesity and a high-fat diet on allergic asthma. While non-allergic asthma is a well-established co-morbidity of obesity, the influence of obesity on allergic asthma is still debated.

The project set out to test whether the effect of obesity would disrupt induction of what’s called respiratory tolerance – the normal process in healthy people that prevents them from becoming allergic to all sorts of airborne allergens present in the environment. Allergic asthma is thought to result from impaired respiratory tolerance.

“It was very exciting,” recalls Dr Hardy. “You had to do something that addressed a big problem – which obesity and asthma are – which was attractive to funding and was feasible. The immunology we were looking at was reasonably cutting-edge but our project was feasible – it clearly outlined a series of experiments.”

After winning the challenge, Dr Hardy and Honours student Suzanne Luong worked through the experiments, which successfully supported their hypothesis that respiratory tolerance would be defective in obese mice, leading to exacerbated allergic airway inflammation or allergic asthma.

Dr Hardy gained NHMRC funding to expand on the studies conducted in the pilot program, which helped employ two post-doctoral researchers, Dr Angela Pizzolla and Dr Ding Oh, and an Honours student. The team carried out three solid years of detailed experiments focussing on two important cell types that regulate the immune response leading to allergy; T cells and the dendritic cells.

Dr Pizzolla says they fed the mice a high-fat diet rendering them obese, and used as a control group mice that were fed a normal diet and remained lean. The high-fat mice had changes in their metabolism compared to the lean ones – like obese individuals. The researchers also observed changes in gut microbiota (gut bacteria) of mice fed the high-fat diet.

The study had some exciting results but some of the findings surprised the researchers.

While the pilot study suggested that obesity and a high-fat diet prevented the mice from being able to mount a normal tolerance, this result was not confirmed by the larger study. However, the study demonstrated that some functions of the immune system were impaired in obese mice, which had a lower immune response to allergens.

Moreover, high-fat diet inhibited the response of T cells and dendritic cells after the induction of respiratory tolerance. This observation fitted with data about the effects of obesity in other areas of research, such as infection, adding to the bigger picture of obesity and impaired immune response.

“It reinforced the idea that diet really does affect aspects of your immune function,” Dr Hardy says.

He says the project successfully showed how far a concept could go that looked at a big picture problem and new ways of tackling it, gaining seed funding and an NHMRC grant. “The evolution of the project shows the value of thinking outside the square and identifying new ways of thinking about an old problem.”

Significantly, the study found – for the first time – that mice had the same changes in some gut microbiota as did humans. It found obesity increased certain bacterial populations and decreased others with similarities in some species thought to be important to gut health.

“It was interesting to see that one bacteria group which is increased in obese individuals is also increased in obese mice,” says Dr Pizzolla, who is now continuing her postdoctoral studies at the University of Melbourne.

Pizzolla A, Oh DY, Luong S, Prickett SR, Henstridge DC, Febbraio MA, O'Hehir RE, Rolland JM, Hardy CL. High Fat Diet Inhibits Dendritic Cell and T Cell Response to Allergens but Does Not Impair Inhalational Respiratory Tolerance. PLoS One. 2016 Aug 2;11(8):e0160407. doi: 10.1371/journal.pone.0160407. eCollection 2016.

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