Welcome to the next installment of our regular update where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past few weeks.
RAEPing the benefits of immune regulation in the fight against cancer and autoimmunity
The immune system is constantly performing a careful balancing act. An overactive immune system can result in autoimmune conditions such as Crohn’s disease or rheumatoid arthritis (RA), whereas an underactive immune system could give way to the development of infections or cancer. One way that immune cells regulate their activity is by signalling through the receptor PD-1. In T cells, PD-1 promotes their anti-inflammatory function, and current drugs which block PD-1 activity are used to activate the immune system against cancer cells.
Scientists at Newcastle University, led by BSI member Dr Shoba Amarnath, have shown that PD-1 also prevents the activity of an enzyme called AEP. From studies in mice, the group showed that AEP activity promotes the inflammatory functions of T cells and enables them to attack tumour cells, whereas a lack of AEP function – either through drugs or in mice engineered to lack AEP – prevented graft versus host disease (GvHD), an immune reaction which leads to transplant rejection. This finding could, in the future, lead to new and improved treatments for immune-mediated diseases such as Crohn’s and RA, as well as GvHD.
Of the work, published in the journal Immunity, Dr Amarnath said: “What we have found in our lab studies is that AEP enhances the effect of these checkpoint inhibitor drugs in advanced melanoma. When found in higher levels in the T cells of the immune system, the supporting AEP worked in combination with the checkpoint inhibitory drug in numerous diseases. It was successful in attacking tumours in skin cancer, by switching on the immune system and in preventing graft versus host disease, by switching off the immune system”.
Read the press release here.
Read the full article here: Stathapoulou et al. DOI: https://doi.org/10/1016/j.immuni.2018.05.006
Cabbage vs. cancer
With many of us being told to ‘eat your greens’ since childhood, we know that consuming plenty of vegetables is central to a healthy diet. This week, a team of scientists at the Francis Crick Institute, led by BSI members Professor Gitta Stockinger and Dr Chris Schiering, have shown that the humble vegetable may go one step further and prevent the development of colon cancer.
Cancer, defined as the uncontrolled growth of abnormal cells, has historically been associated with long-term inflammation. During inflammation in the colon, or intestine – for example during an infection – its lining, or epithelium, becomes damaged. To repair itself, the intestine must grow new epithelial cells (IECs). Importantly, this process must be regulated to ensure that the cells become functional IECs and that new cell growth is controlled and does not lead to cancer.
Using mice infected with C. rodentium (similar to E. coli infection in humans), the team showed that activity of the aryl hydrocarbon receptor (AhR) is important in the prevention of cancer development following inflammation, as mice that lacked activity of this receptor developed tumours after infection. The team then fed the same type of mice a diet rich in the chemical indole-3-carbinol (I3C), which binds to and activates AhR. This chemical is found in high concentrations in cruciferous vegetables such as cabbage, broccoli and kale. These mice were protected from cancer development and any tumours which were present stopped growing. Thus, this study suggests that chemicals in our diet can have profound effects on the development of intestinal cancer. Of the study, published in the journal Immunity, Professor Stockinger said:
"We found that AhR-promoting chemicals in the diet can correct defects caused by insufficient AhR stimulation. This can restore epithelial cell differentiation, offering resistance to intestinal infections and preventing colon cancer. These findings are a cause for optimism; while we can’t change the genetic factors that increase our risk of cancer, we can probably mitigate these risks by adopting an appropriate diet with plenty of vegetables.”
Read the press release here.
Read the full article here: Metidji et al. 2018 Immunity DOI: https://doi.org/10/1016/j.immuni.2018.07.010
Endocannabinoids: putting an end to intestinal hostility
The intestine is a unique immune site, as it treads a fine line between being able to mount an aggressive immune response to harmful bacteria such as Salmonella while ignoring, or remaining ‘tolerant’ to, commensal bacteria and food. A disruption in this balance can lead to inflammatory bowel diseases (IBD) such as Crohn’s disease.
Although there is no current cure for IBD, marijuana users have historically reported that the drug has positive effects on IBD symptoms. Scientists from the University of Bath and the University of Massachusetts have published an article in the Journal of Clinical Investigation which shows a potential biological mechanism behind these reports.
During inflammation, activated immune cells called neutrophils enter the gut to kill harmful bacteria. However, neutrophils can be inappropriately activated and damage the intestine, leading to the development of IBD. In a study published this week, Professor Randy Mrsny and his team showed that, in mice, naturally-produced molecules called endocannabinoids – which are very similar to cannabinoids found in marijuana – halted the influx of neutrophils to the intestine and reduced intestinal inflammation.
Remaining cautious about the findings, Professor Mrsny said: “We need to be clear that while this is a plausible explanation for why marijuana users have reported cannabis relieves symptoms of IBD we have only worked in mice and have not proven this experimentally in humans.
“However, our results may provide a mechanistic explanation for anecdotal data that cannabinoid exposure benefits some colitis patients. For the first time we have identified a counterbalance to the inflammation response in the intestine and we hope that these findings will help us develop new ways to treat bowel diseases.”
Read the press release here.
Read the full article here: Szabady et al. 2018 Journal of Clinical Investigation DOI: https://doi.org/10/1172/JCI96817