Natural Killer Cells May Improve Marrow Transplants

They help leukemia patients tolerate grafts better

THURSDAY, March 14, 2002 (HealthDayNews) -- Hiring the immune system's hit molecules may help bone marrow transplant patients better tolerate the grafts, and even fight the cancers they're designed to treat.

Leukemia patients who receive a marrow donation with the right kind of "natural killer cells," which do just what their name suggests, are much less likely to reject the grafts, according to a new studies by U.S. and Italian researchers. Experiments in mice show the natural killer cells also appear to help eradicate lingering leukemia. Better yet, targeting an enzyme that seems to arouse them may make bone marrow grafts more palatable to patients.

The findings, reported in tomorrow's issue of Science, could give doctors another layer of screening for bone marrow recipients to improve their chances of success.

"You can try to do these tests before you do the transplant and find not just a well-matched donor, but one whose natural killer cells will react against the patient's leukemic cells," says Alan Kinniburgh, vice president of medical affairs and research for the Leukemia and Lymphoma Society.

William J. Murphy, director of basic research at SAIC, a Maryland research firm that contracts with the National Cancer Institute, says natural killer cells have only lately begun to stir interest in cancer circles. However, the cells are showing promise not only in leukemia and lymphoma, but also in certain metastatic solid tumors.

"Some people are using activated killer cells as an immunotherapy without bone marrow transplant," he adds.

Currently, patients and marrow donors are matched for six immune proteins called HLA (or MHC), expressed on the surface of certain blood cells. Although five of six is considered a close match, many patients have only three or fewer of these proteins in common, and even a single mismatch can lead to devastating rejection of the transplant.

To reduce the chances of rejection, doctors take pains to knock out a patient's T-cells, which help marshal an immune reaction against the foreign tissue. Yet, in doing so they make graft recipients vulnerable to graft-versus-host disease, a potentially deadly reaction that occurs when immune cells in the transplanted marrow turn on the already-weakened patient.

Taken together, Kinniburgh says, the two reports suggest T-cell depletion might not be necessary if scientists pay attention to the natural killer cells of the donor and patient.

In the Italian study, a team led by Dr. Andrea Velardi of Perugia University first analyzed cell samples from 92 people with either acute myeloid (AML) or acute lymphoblastic (ALL) leukemia. All had undergone bone marrow transplants to treat their disease.

The AML patients who received killer cells more antagonistic to their own tissue, based on molecular receptors they expressed, had a five-year rate of relapse 60 times lower than those with more agreeable cells, the researchers say.

Velardi's group also showed that giving mice with severely suppressed immune systems a shot of killer cells wiped out traces of human leukemia with which they'd been injected.

In the second study, Florida scientists showed that manipulating natural killer cells in graft recipients may also prove effective at preventing tissue rejection and treating disease.

"What the Italian study is saying is that if we take NK [natural killer] cells from the donor and let them attack the host, they'll clean things out. We can do that in the host by just getting rid of one gene," says lead author William G. Kerr, of the Moffitt Cancer Center and Research Institute in Tampa.

The gene is called SHIP, and it produces an important enzyme in the immune response. However, when mice lack SHIP their natural killer cells lose their will to attack foreign tissue.

Kerr says the finding could lead to drug treatments to neutralize killer cells by mollifying SHIP. In the meantime, he adds, the Italian research is farther along clinically. When they start a trial in patients, he says, "if I had [acute myeloid leukemia] I'd be signing up."

Murphy, who studies killer cells, says it may also be possible to purify natural killer cells from a graft donor and use them to supplement the therapy and destroy residual leukemia. The Italian researchers had success with this approach in their work in mice, he notes.

However, Kinniburgh says, scientists may "want to creep up on this a little more slowly," especially since the experiments may involve tinkering with the immune systems of severely ill patients.

What To Do

For more on blood cancer, visit the Leukemia and Lymphoma Society.

To learn more about bone marrow transplants, visit the International Bone Marrow Transplant Registry.

To learn more about the immune system, check out How Stuff Works or the National Institute of Allergy and Infectious Diseases.

SOURCES: William J. Murphy, Ph.D., director, basic research, Science Applications International Corp., Frederick, Md.; William G. Kerr, Ph.D., associate professor, oncology and biochemistry, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa; Alan Kinniburgh, Ph.D., vice president, medical affairs and research, Leukemia and Lymphoma Society, White Plains, N.Y.; March 15, 2002, Science
Consumer News