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A new role is discovered for mast cells

By Jennifer Durgin

Mast cells usually get a bad rap, as the culprits behind allergies and asthma symptoms. But their reputation got a boost recently, when DMS researchers discovered that they play a crucial role in transplantation tolerance.

Blue: Mast cells, it turns out, are a bit like Jekyll and Hyde. In some situations, like during an allergic reaction, they promote inflammation and immune responses; in other situations, however, they do just the opposite. This finding is "so out of the blue!" says Dartmouth immunologist Randolph Noelle, Ph.D., who heads the lab that made the discovery.

For many years, Noelle's lab has been studying how the body rejects or accepts a transplanted organ or skin graft, and they've found a way to induce transplant tolerance in mice. "We can do a skin graft on a mouse and have it stay forever," says Noelle, without the mouse's immune system attacking the foreign skin and without the long-term use of immunosuppressive drugs. Prolonged tolerance, they noticed, was associated with two types of immune cells—regulatory T-cells and mast cells. But what were mast cells—known for promoting strong immune responses— doing in a place that was protected from immune system attacks, they wondered?

The researchers hypothesized that the mast cells were actually suppressing inflammation and protecting the graft. To test this theory, they tried inducing prolonged graft tolerance in mice that were deficient in mast cells. The grafts didn't take. The team then tested whether injecting such mice with lab-grown mast cells—prior to the graft transplant and the immunosuppressive treatment—made a difference. It did. These mice were able to

Randy Noelle—center, surrounded by members of his lab—had a paper on mast cells in Nature.

maintain their grafts twice as long. Although other factors may be involved, "these results strongly suggest an indispensable role for mast cells" in skin transplant tolerance, Noelle and his team wrote recently in Nature.

The results may also explain "why mast cells are located in very specific sites within tissues (for example, nerves, vessels, hair follicles, or epithelia)," wrote a University of Oxford immunologist in an accompanying editorial. "Also, is it possible that the mast cells found within tumours contribute some immune privilege?"

Heal: High concentrations of mast cells in certain tumors often indicate a bad prognosis, Noelle explains. And other

research has suggested that mast cells promote blood vessel growth and tissue remodeling— both of which help tumors grow. "What [the mast cells] are trying to do is wound heal," says Noelle. In the case of a transplant, dampening inflammation, facilitating blood vessel growth, and assisting in tissue remodeling are helpful. In cancer, those actions are anything but.

Noelle's team is now searching for molecular targets that could be used to shut down mast cell accumulation in tumors. They're also working with DHMC transplant surgeons to see if what they've found in mice correlates with what happens in humans. "We're not mast cell people," Noelle says, so "a number of us are completely retooling."

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