Editorial: Tread carefully in the immune system's shadowlands
DELIBERATE infection with a blood-sucking worm seems an odd way to treat multiple sclerosis (MS). Yet more surprising is what this experiment may tell us about a "shadow" branch of our immune system. Completely unknown until recently, this is pointing to new ways of treating a host of complex diseases.
A couple of recent studies suggest that parasitic infection dampens inflammation and reduces relapse rates in people with MS, in which the body's own cells are attacked by the immune system as if they were "foreign". So Cris Constantinescu at the University of Nottingham, UK, and his colleagues plan to place tiny hookworm larvae on the skin of 32 people with MS, allowing the worms to burrow down and infect the volunteers.
The team won't just be looking for a reduction in volunteers' symptoms though. They will also be watching to see if the parasites boost numbers of a set of newly discovered immune cells, known as regulatory B cells (B regs).
B regs are sending shockwaves through the immunology community. Until recently it was assumed that B cells' main role was to make antibodies at the behest of T-cells. These master regulators enhance or suppress an immune attack depending on the situation, as well as carrying out immune attacks in their own right (See diagram). It was therefore thought that T-cells are at fault when the body attacks itself in autoimmune diseases, such as MS, asthma, diabetes and rheumatoid arthritis - and when it fails to route out disease agents, such as cancer cells.
Now it seems that T-cells are not the immune system's only regulators. Experiments suggest that under some circumstances, B regs regulate T-cells, providing a shadow role for B cells.
"Diseases we've traditionally thought to be mediated by T-cells might actually be regulated by B cells," says Kevan Herold of Columbia University in New York. Boosting B regs might therefore provide new opportunities for treating autoimmune diseases, while inhibiting B regs it could be a new way to treat cancer.
Animal studies are already suggesting that the approach might work in one type of asthma. In a study published in May, Padraic Fallon of Trinity College, Dublin, and his colleagues isolated B regs from the spleens of mice infected with the parasite Schistosoma mansoni. When they transferred the B cells into mice primed to develop asthma, this either reduced their symptoms or stopped them developing asthma in the first place (The Journal of Allergy and Clinical Immunology, DOI: 10.1016/j.jaci.2010.01.018).
"These are major regulators of the immune system in allergic disease," Fallon concludes. B regs seemed to work by releasing a chemical called IL-10 into the lungs, drawing in regulatory T- cells (T regs), which in turn inhibited immune attacks.
IL-10 played a similar role in a subset of B regs, which Thomas Tedder at Duke University School of Medicine in Durham, North Carolina, calls B10 cells. His team found that transferring these cells into mice with a disease similar to multiple sclerosis reduced the severity of disease.
Tedder has also identified similar cells in humans. "We can stimulate them and we can isolate them, but they're fairly rare," he says. He presented both findings in May at the annual American Association of Immunologists meeting in Baltimore, Maryland.
The race is now on to identify drugs that might boost B regs in people with autoimmune diseases or suppress them in people who have cancer.
The race is on to identify drugs that might boost regulatory B cells in people with autoimmune diseasesOne clue that such an approach might work comes from studies of rituximab, which kills B cells. First prescribed for the treatment of B cell lymphoma, a type of cancer, the drug has also reduced symptoms in people with diabetes, MS and rheumatoid arthritis. Rituximab most likely knocked out all the B cells to start with, and then, for some reason only the B regs grew back, which helped suppress autoimmunity, suggests Frances Lund of the University of Rochester Medical Center in New York (Nature Reviews Immunology, DOI: 10.1038/nri2729).
In individuals with cancer, however, it might be desirable to suppress B regs. Preliminary evidence suggests that as well as keeping autoimmunity in check, B regs also help dampen the immune system's natural ability to recognise and destroy tumours.
Tedder's team has already created antibodies that can deplete B10 cells - but not other B cells - in mice, and says he has similar antibodies that may selectively deplete human B10 cells - although he hasn't yet tested them in people.
Arya Biragyn of the US National Institute of Aging, and his colleagues, also announced at the Baltimore meeting that they have identified a separate set of B regs that cancer seems to recruit in order to avoid detection by the immune system. Destroying these cells might make let's hope you have deep pockets cancer immunotherapies work better.
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Wednesday 2 June 2010
Out of the shadows: our unknown immune system
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