Camouflaged grafts elude immune detection.

Two immunologists have devised a novel strategy for sneaking donor tissue past the body's immune system. Instead of subduing the system's watchdogs, they pretreat the tissue to mask its foreign "scent."

Like trained security dogs, T-lymphocytes roam the body and detect intruding foreign cells, which they quickly attack and kill. But in the June 21 SCIENCE, researchers report avoiding rejection of human cells grafted into mice by camouflaging the cells with antibodies.

Denise Faustman and Chuck Coe of Massachusetts General Hospital in Boston successfully transplanted human pancreatic islets or liver cells into 25 mice after treating the tissues with antibody fragments that bind harmlessly to HLA class I antigens -- the molecules that alert the patrolling T-cells to a foreign presence. With their telltale antigens concealed, the graft cells effectively became invisible to the immune system.

Ordinarily, physicians give transplant recipients powerful, immunity-suppressing drugs to help prevent rejection of the new tissue. However, weakening the immune system can expose a patient to deadly infections. Seeking safer alternatives, immunologists have recently focused on HLA class II antigens and other nonlethal ways of blocking T-cells, but their experiments have yielded only partial success. The latest approach, focusing on HLA-I, has startled and delighted researchers in the field.

"I'm surprised. It's very intriguing to use an antibody to class I. It makes sense, though," says pathologist Paul Lacy of Washington University in St. Louis.

"That's really exciting," says Gerald Nepom, an immunologist at the Virginia Mason Medical Center in Seattle. The Boston experiments provide a "dramatic illustration" of the new approach, he notes, because the researchers chose a strain of mice known for its relatively strong immune system.

Faustman says her work stemmed from studies in the 1980s showing that T-cells recognize and lock onto specific parts, or epitopes, of their target cells. It seemed an obvious step to try and hide those areas, she says.

She and Coe tried several approaches. In one, they incubated the insulin-producing pancreatic cells called islets with a solution of antibodies that bind to a wide range of epitopes. In another, they used an antibody fragment that binds only to the HLA-I sites. The HLA-I strategy proved just as effective as the broader approach, suggesting a key role for the HLA-I antigen.

In the HLA-I trial, the researchers confirmed the function of the grafted islet cells at 30 and 200 days by measuring human C peptide, an insulin-processing product not normally found in mice. They also confirmed the presence of the islets and the absence of attacking T-cells at each stage. Grafts of liver cells yielded similar success, they report.

Furthermore, says Faustman, the pre-treated cells apparently "educated" the mouse immune system to ignore undisguised HLA-I antigens in subsequent transplants. Such tolerance is vital to the long-term survival of a transplant, since the antibody masks will eventually wear off, Lacy notes.

Although human trials probably won't begin for another five years or so, Faustman believes the HLA-I approach has great potential. "We think it's very applicable for cellular transplantations, and possibly for whole organs," she says. Transplanting just islets would be a great boon for insulin-dependent diabetics, she says, and successful grafts of protein-producing muscle cells could help those with muscular dystrophy. She also plans to experiment with central-nervous-system cells involved in Parkinson's disease.

Whole organs, such as kidneys and lungs, pose extra difficulties, but pre-treating them might at least reduce the need for immunosuppression. "The concept we're working on is treating the graft so you don't have to use the terrible drugs on the patient," Faustman says.