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Applying vaccines to the upper layers of the skin could stimulate a different and more powerful immune system response than the traditional approach of injecting a vaccine into muscle, according to a growing body of research by Boston scientists.

In the battle between germs and the immune system, scientists have long thought much hinged on cells circulating in the blood that could remember old foes and be deployed to defend against reinfection. But a growing body of research is revealing that areas such as the skin or the lungs also appear to be important base camps for cells with good memories for invading pathogens. Immune system cells stationed in such tissues may play an underappreciated role in fighting disease - a paradigm-shifting possibility that could alter the way vaccines are administered and designed.

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New research by scientists at Brigham and Women’s Hospital is helping elucidate the role those recently discovered cells play in recognizing and fighting disease.

Dr. Thomas Kupper, chairman of dermatology at the hospital, who led the new study, last year received a $5.6 million, five-year grant through a federal program designed to support the research, which is considered risky but carries the potential to upend current thinking. His work has also laid the foundation for a Boston start-up, TREM Rx, focused on developing vaccines that could be delivered through the skin.

“Right now, we deliver vaccines into muscle . . . Muscle has never evolved to fight off infection,’’ Kupper said. “We think that we really need to rethink the way we’re delivering vaccines.’’

Immune system cells called “resident memory T cells’’ have been found in tissue in many areas of the body, including the skin, lining of the gut, and lungs. What has been unclear is the exact role those cells play in the body’s defense against disease. Kupper’s study, published in the journal Nature last month, begins to answer that question, providing evidence those cells play an important role.

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Researchers used a virus to cause a skin infection in mice. Then they paired those mice with partners that had not been exposed to the virus and therefore had immune systems with no memory of the infection.

Scientists stitched together the circulation systems of those two types of mice so both groups had the same immune cells in their blood, but only one group had the resident memory T cells in their skin. Then the researchers separated the mice.

When the mice were reexposed to the virus, the ones that had the immune cells in their skin were able to rapidly clear the virus, while the ones that lacked the cells struggled to fend off the infection.

Kupper said the result helps explain the work that led to the eradication of smallpox. In the late 1700s, Edward Jenner developed the smallpox vaccine, using a needle to scratch the surface of people’s skin and then applying a live cowpox virus, instead of giving an injection.

The way the vaccine was administered may help explain why it was successful at eradicating smallpox, Kupper said.

TREM Rx will focus initially on forging partnerships with companies that have been developing vaccines to be delivered through this alternate route, said Eric Stromquist, the company’s president. He said he could not disclose which diseases the company intends to focus on, but said the families of viruses that cause herpes and hepatitis C have promise for such an approach.

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The research is still in early stages, but the idea of developing different types of vaccines and different delivery methods is being tried in other contexts, too.

Stephen Jameson, a professor at the Center for Immunology at the University of Minnesota Medical School, said the new work is a “tour de force’’ in beginning to tease out the different roles the cells play in orchestrating an immune response.

“Those cells have been seen for a long time, and the idea of there being a population of memory cells that are at those barrier surfaces has been appealing for a while,’’ Jameson said. “The trick has been knowing how important they are, and whether they are there to be an early sentinel to say there’s a pathogen, an infectious agent, coming in through the skin.’’

This year, Jameson and colleagues, including scientists from the Whitehead Institute for Biomedical Research in Cambridge, examined how a cholera toxin and a foreign protein could be applied to the surface of the skin to prime the immune system.

The ultimate hope for that line of work is that vaccines could be applied simply, through a Band-Aid that could be mailed to patients, Jameson said.


Carolyn Y. Johnson can be reached at cjohnson@globe.com. Follow her on Twitter @carolynyjohnson.