Pitt scientists discover a 'precursor' cell under the skin that points the way to manipulating the immune system

Monday, November 12, 2001

By Byron Spice, Science Editor, Post-Gazette

A cell that doctors might someday use to manipulate the body's disease-fighting immune system is, like beauty, only skin deep.

The cell, which researchers at the University of Pittsburgh have found lurking in the skin's lower layer, is thought to play a key role in the process by which the immune system is alerted to the presence of foreign invaders and signalled whether those invaders should be attacked.

Other cells play a similar role in other parts of the body. But this cell, because of its location in the skin, is easily accessible to doctors and thus might be used for a variety of treatments, said Dr. Louis Falo Jr., chairman of dermatology at the University of Pittsburgh School of Medicine.

By performing a simple skin biopsy, for instance, doctors could obtain a quantity of the cells from a patient that could be grown and altered in the laboratory. The cells could then be administered back to the patient to prevent transplant organ rejection, treat asthma and other autoimmune diseases, or mount an attack on cancers.

In burn patients, the cells might be used to seed artificial skin grafts so that the grafts not only cover open wounds, but also fight infections in a way similar to natural skin.

A report on Pitt's identification of the cells, called Langerhans cell precursors, will be published next month in the journal Nature Immunology and is being posted today on the journal's Web site, www.nature.com/ni/.

"I think it's a significant finding, if true," said Dr. Gregory Glenn of the membrane biochemistry department at Walter Reed Army Institute of Research in Silver Spring, Md. Langerhans cells have been a very hot research topic for the past six or seven years, noted Glenn, who is developing a vaccine patch that targets them. "I think there will be a lot of interest in the paper."

"We suspect there's a lot of immune regulation going on in the skin," said Falo, the study's senior investigator. The discovery of the new cell in the dermis fills what has been a long-sought missing link in the immune-response process, he added.

Throughout the body, a class of cells called dendritic cells play the role of training the immune system. They are called antigen-presenting cells because they identify antigens -- an enzyme, protein or toxin that the immune system can target -- and tell the myriad other cells in the immune system whether that antigen is foreign and whether it should be destroyed.

The subset of dendritic cells found in the skin's outer layer, the epidermis, are called Langerhans cells. They are named for Paul Langerhans, the German physician who, as a medical student in 1868, described the structures in the skin that later were found to contain these dendritic cells. (In 1869, he described the insulin-producing structures of the pancreas that are known as the islets of Langerhans).

For 100 years, nobody knew what Langerhans cells did, Glenn said. But now it is known that they normally sit in the epidermis like sentries. When they encounter a foreign invader, the cells are activated and crawl to a nearby lymph node, where other immune cells pick up the information and mount an attack.

An excess of Langerhans cells causes such skin disorders as psoriasis and eczema.

Until activated, Langerhans cells are not fully developed. But for physicians who are trying to manipulate the immune system, Falo said, an even less-developed version of the cell might be more suitable.

So researchers have been looking for the precursor cell from which the Langerhans cell develops. These cells presumably could be altered in ways that might retrain the immune system, such as turning off the autoimmune reaction that causes rheumatoid arthritis.

They knew where to look: beneath the epidermis, in the dermis. Falo said the cells, coming from the blood stream below, would have to pass through the dermis to reach the epidermis. But that didn't narrow the search too much, because the dermis is a virtual soup of immature cells.

"No one knows why [the many types of cells] are there or what they're doing there," Falo said.

So for the study leaders, Drs. Adriana Larregina and Adrian Morelli, researchers in Pitt's dermatology and surgery departments, respectively, the feat was to identify which of these would develop into Langerhans cells. They cultured the immature cells in the lab and used natural growth factors to coax them into developing, identifying which ones became what appeared to be Langerhans cells. They were then able to demonstrate that these cells could be activated by an antigen and stimulate an immune response.

Now that the precursor cells have been identified and described, researchers might be able to remove these cells from patients, grow them in culture and then engineer them to accomplish set goals. Angus Thomson of Pitt's Starzl Transplantation Institute, for instance, is working to use dendritic cells to teach the immune system to recognize the tissue of a transplanted organ as self, not as foreign, and thus train the body not to reject the transplant graft.

This approach might also be used to treat autoimmune diseases, in which the body's immune system attacks parts of the body as if it is foreign.

Just as the presence of the precursor cells in the skin makes them easy to remove, it also makes it convenient to program the cells without removing them. For instance, Falo has experimented with a pressurized-gas "gene gun" to fire beneficial genes into dendritic cells in the skin; the genes are intended to direct the cells to launch an attack on cancer.

It now may be possible to find other ways to deliver this form of gene therapy specifically to the Langerhans percursors in the skin, he added.