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Immune cells repair damaged gut in children with IBD

Fri, 12/13/2019 - 11:23
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Immune cells of a certain kind which regulate inflammatory processes and even help restore normal gut function after inflammation could be of great use to treat children with inflammatory bowel disease (IBD), according to researchers from the University of British Columbia, Vancouver, Canada. The researchers said that the Tr1 cell, which is a specific type of immune cell, secretes a molecule that promotes the repair of the mucosal barrier produced by the cells of the gut epithelium and enhances mucus production.

The study, ‘Suppressive and Gut-Reparative Functions of Human Type 1 T Regulatory Cells Cook’, published in Gastroenterology, is the first time that Tr1 cells can turn inflammation back and restore normal structure and function to a gut damaged by IBD.

“As a new therapy, Tr1 cells could both suppress the inflammation that is ravaging the lining of the gut and help heal the tissue lining that keeps out harmful bacteria,” the authors write.

When the immune system of the body ‘recognises’ a gut antigen as a foreign one, it instantly sets its forces into action, causing inflammation. This is the normal response of the body to injury and to sickness. However, the issue in IBD, including Crohn’s disease and colitis, is that it can result in serious damage to healthy gut tissue.

IBD is typically treated using antibodies to block the inflammatory cascade. About one in three patients fail to respond, however, and many others respond at first but later experience relapses and flare ups of the disease.

T regulatory (Treg) cells are important in maintaining immune responses at a helpful but not harmful level, preventing hyperactivation and keeping the body systems running normally. There are two subsets of these, the type 1 Treg cells or Tr1, and the FOXP3 positive Treg cells. Tr1 cells secrete the cytokine IL-10 which is anti-inflammatory in action. This suggests its use in repairing bowel damage due to IBD.

The researchers built up three-dimensional colon organoids to examine the kind of interaction that occurs between Tr1 cells and other gut epithelial cells. Calling these structures self-organised mini-guts, the researchers examined them for cell-specific signals. They came across an unexpected finding. In mice, Tr1 cells were shown to modulate the activity of inflammasomes by secreting IL 10.

Tr1 cells stimulate the mini-gut to promote the differentiation of more goblet cells, so that they can secrete more mucus so as to protect the cells from damage by improving the intestinal barrier function. They also realized that only Tr1 cells and not other Treg cells can promote a better gut microenvironment.

This study demonstrated for the first time that when Tr1 cells are taken from parents and cultured, those from IBD patients are also just as much anti-inflammatory in their activity as those from healthy people. They prevent the proliferation of effector T cells that mediate the specific adaptive immune response, which damages gut mucosa. They also suppress the innate immune cytokines IL 1B and TNF. Instead, their mucus-enhancing function is because they secrete IL 22.

“Kids with IBD develop abnormal immune responses to normal gut bacteria,” said co-author, Dr Theodore Steiner. “Training our immune system to fight off infections and bad gut bacteria while maintaining normal relationships with the good bacteria is critical for the health of children with these diseases.”

The scientists don’t know why people with IBD still develop the disease if their Tr1 cells are working normally. One possibility is that there are too few cells to prevent the inflammatory reaction. The researchers hope to take out this cell type, which can be then encouraged to multiply. This could be the basis for personalized treatment of this condition and consequent control of CD or ulcerative colitis.

The researchers will then try to establish the ideal environment for laboratory culture of these cells. They could then inoculate such cells into children with IBD, so that the new Tr1 cells will have the best shot at repairing the inflamed and damaged gut. Later on, they hope, it will be possible to extract Tr1 cells from each patient and grow them in the laboratory, before giving them back to the same host – a novel cell-based treatment for IBD in children.

To access this paper, please click here