Inhibition of the signals triggered by a molecule called PD-L2 may prevent activation of autoimmunity in the gut and the progression of Crohn’s disease, a preliminary study suggests.
“This study is another important step in our understanding of Crohn’s disease and opens up a new area to investigate,” Graham Radford-Smith, who is a deputy director at the Royal Brisbane and Women’s Hospital department of gastroenterology and co-author of the study, said in a press release.
“If we can understand why inflammation occurs in Crohn’s patients, then we can work out strategies to treat, and possibly in the future, prevent the disease.”
The study, “Crohn’s disease is facilitated by a disturbance of programmed death‐1 ligand 2 on blood dendritic cells,” was published in the journal Clinical & Translational Immunology.
Crohn’s disease is a common form of inflammatory bowel disease (IBD) that is triggered by the over-activation of the immune cells in the small intestines and colon.
Inhibition of pro-inflammatory signaling molecules has been shown to help manage Crohn’s symptoms. However, available therapies are only effective in 20–50% of patients, highlighting the continuing need for better understanding of the disease and new therapeutic strategies.
Prior studies have suggested that the interaction between dendritic cells and reactive T-cells — two subsets of immune cells — is critical for managing autoimmunity. This process is mediated by a receptor in dendritic cells called PD-L1 and its ligand, PD-1, in T-cells.
In fact, administration of PD-L1 has been shown to reduce colon inflammation in mice, further supporting the idea that PD-L1 signals have an important role in autoimmunity in IBD.
Besides PD-L1, dendritic cells can also produce another molecule — called PD-L2 — that works as the natural inhibitor of PD-L1 signals. However, to date, it remains unclear what the role of PD-L2 is in IBD and Crohn’s disease.
To shed light on this, researchers from the QIMR Berghofer Medical Research Institute in Australia conducted a pilot study.
They started by analyzing samples of non-inflamed and inflamed tissue from the intestines of patients with diagnosed Crohn’s disease, and non-inflamed biopsies from control volunteers.
Approximately 1.25% and 2.5% of the cells in the inﬂamed and non-inflamed areas of patients’ biopsies were dendritic cells, whereas dendritic cells represented about 9.5% of all cells in control samples. Still, the percentage of dendritic cells that were positive for PD-L1 and PD-L2 were similar between non-inﬂamed controls and patients (both inﬂamed and non-inﬂamed).
“A very signiﬁcant loss of dendritic cells … indicates a reduction in the capacity of the immune system to provide protection against pathogens as well as a potential absence of [immunogenic tolerance] control,” the researchers wrote.
Additional analysis of dendritic cells isolated from blood samples of patients revealed they had high levels of PD-L2 that were often localized close to PD-L1 in the surface of the cells.
These blood dendritic cells were cultured in the lab and exposed to an anti-PD-L2 antibody, which would block the receptors’ activity. The PD-L2 blockade was able to effectively prevent the production of pro-inflammatory molecules including TNF-alfa and IFN-gamma by dendritic cells.
“This study highlighted the anti-inﬂammatory potential of using PD-L2 blockade as a therapy for Crohn’s disease,” the researchers concluded.
They are now seeking funding to support continued studies on a larger group of patients and to better understand the role of PD-L2 in Crohn’s disease.
“This is just the start. We believe that understanding this protein will have big implications for a range of autoimmune conditions,” said Michelle Wykes, PhD, senior author of study.
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