"There is such a big difference in my life now"
Patients with autoimmune diseases are finding success with treatments originally developed to fight cancer
At first, Sandra Seymour paid little attention to the tingling sensation in her toes. But when it became difficult to grip a frying pan while cooking breakfast for her children, she decided her odd symptoms warranted a visit to her doctor. There, Seymour learned the startling news that she had an autoimmune disease called scleroderma.
Like other autoimmune diseases, scleroderma results from an immune system that turns against the body's healthy tissue. In Seymour's case, which eventually progressed to a more severe form known as systemic sclerosis, the disease attacked her skin, joints and later, her lungs.
"Within a year or two after my symptoms began, I could hardly move my arms and the disease moved into my lungs," said Seymour, a data-billing clerk from Inchelium, Washington, a small town on the Colville Indian Reservation. "I couldn't even make it up a flight of stairs."
With no known cures for systemic sclerosis, Seymour's doctor could only prescribe medications to relieve her symptoms, such as anti-inflammatory agents and drugs to suppress the abnormal immune response. When these proved ineffective, Seymour was referred to doctors at Fred Hutchinson Cancer Research Center, where research was under way on experimental therapies for patients with severe autoimmune diseases. By that time, Seymour had quit her job and was unable to care for her four children.
"None of the medications I had tried was working," she said. "The treatment at Fred Hutchinson was my last chance."
Dr. Richard Nash and his colleagues at Fred Hutchinson treated Seymour with a stem-cell transplant, a technique originally developed for patients with leukemia, a cancer of the blood. During the procedure, she received an infusion of healthy stem cells from her brother, Douglas. Within six months of her therapy, the range of motion in her arms dramatically improved and her lungs began to heal. Today, more than three years post-treatment, the scleroderma-hardening of the skin-has almost gone away, except for the skin on her fingers. And she has regained enough energy to return to work.
Seymour is one of many patients with autoimmune disease who benefit from the diverse research conducted at Fred Hutchinson, where studies of cancer often spawn unanticipated benefits for those with other diseases. In turn, research on immune-system disorders - including scleroderma, lupus and AIDS - often yields new insight into cancer, a disease that researchers suspect results from an immune system that has failed to do its job.
For Nash and colleagues, using stem-cell transplantation to treat autoimmune disease was a logical extension of what they had learned while working with leukemia patients. When patients undergo this procedure, they are treated with high-dose chemotherapy, sometimes in conjunction with intensive radiation, to destroy their cancerous immune system. Shortly thereafter, they are "rescued" with a transfusion of blood-forming stem cells, which hopefully regenerate a healthy new blood and immune system. The stem cells come from a tissue-compatible donor or the patient, who has previously stored them.
For weeks after a transplant, until a new immune system is established, even a sneeze from a hospital visitor can be enough to put a transplant patient's outcome in peril. Yet the researchers realized that this vulnerable state may have untold benefits for people who suffer from autoimmune diseases, Nash said.
"It was clear to many doctors early on that the immune system is severely affected by the transplant-conditioning regimen," he said. "With that observation, the logical question is: Can we use the same treatment for other diseases which are immune-mediated, such as autoimmune diseases?"
Based on the successful outcomes of patients like Seymour, Nash and his colleagues believe they can. Fred Hutchinson is one of only two institutions in the country to lead clinical trials that use stem-cell transplantation to treat autoimmune disease. Northwestern University Medical School in Chicago is the other.
Autoimmune diseases, which are much more likely to occur in women than men, include about 50 ailments whose symptoms range from mild rashes to life-threatening conditions that attack major organ systems. Disease symptoms differ depending on which tissue is targeted for destruction. In multiple sclerosis, for example, the immune system reacts against myelin, a protein that coats nerve fibers. Loss of myelin leads to neurological symptoms ranging from weakness to paralysis.
Currently, Nash said, treatment at Fred Hutchinson is targeted toward particularly severe autoimmune diseases, including multiple sclerosis, systemic sclerosis and systemic lupus.
"These are considered pilot studies and are for patients who have failed other therapies and otherwise probably would have a 50 percent risk of mortality or severe disability," Nash said.
Other autoimmune patients, he said, exhibit much milder symptoms.
"These diseases don't look the same in all patients," he said. "For example, there are some multiple sclerosis patients who, just by looking at them, you'd never know they had the disease. They might go 20 or 30 years without serious symptoms. We're trying to choose patients who have severe disease, have clearly progressed and have failed other therapies."
In developing their approach, doctors reasoned that compromising the immune system with high-dose therapy or immunosuppressive drugs would eliminate not only the patient's ability to fight infection, but also the ability to attack itself.
Most patients in these studies have undergone a procedure called autologous transplantation, in which their own blood-forming stem cells are collected prior to a pre-transplant conditioning regimen and transfused back after most remaining immune cells have been weakened by immunosuppressive drugs.
"We are investigating whether patients can be transplanted with their own stem cells and be induced into a sustained remission if the mature types of immune cells, known as T cells, are removed from the graft," Nash said. "It is the T cells in patients with autoimmune diseases that react against their tissue, not the stem cells."
Seymour and one other systemic sclerosis patient have received what is known as an allogeneic transplant, a procedure that relies on stem cells donated by a tissue-matched relative. Before infusion of the cells, the patients' immune systems are destroyed with high-dose therapy.
The first patients underwent the procedure in 1997 with promising results.
"Initially, we thought transplants would prevent the disease from worsening," Nash said. "But to see some of the disease symptoms of the skin actually reverse, as in some of the patients with systemic sclerosis, is especially exciting."
The treatment's ultimate success awaits longer follow-up. But with no known cure for any autoimmune disease, transplants ultimately may be the best hope for patients with extreme symptoms.
For patients like Seymour, the treatment's success is evident each morning when she wakes up and goes to work.
"There is a such a big difference in my life now," she said. "I feel very lucky."
Barbara Berg, Ph.D., is a science writer for Fred Hutchinson.
The gender difference
Dr. Lee Nelson's research seeks to explain why women are four times more likely to develop scleroderma
As a rheumatologist, Dr. Lee Nelson spends much of her time thinking about autoimmune diseases. Yet had her laboratory not been housed in a cancer-research center, she might never have developed a hypothesis to explain why many of these diseases-which cause the immune system to attack the body-occur predominantly in women.
Nelson's research focuses on the autoimmune disease scleroderma, which is four times more likely to occur in women than men. Its hallmark feature is fibrosis, a hardening of the skin. Scleroderma can range from a localized skin condition to a more serious illness known as systemic sclerosis, causing damage to multiple parts of the body. Tissues that can be affected include the skin, heart, digestive tract, lung and kidney.
As a member of Fred Hutchinson's Clinical Research Division, Nelson is surrounded by colleagues involved in research on graft-vs.-host disease (GVHD), a sometimes serious complication of the bone-marrow and stem-cell transplants that are used to treat patients with leukemia and other blood disorders. This post-transplant condition occurs when the donor's immune cells react against the patient's tissue, which appears foreign to the donor cells. Although donors are chosen for their tissue compatibility with the patient, unless the two are identical twins, subtle genetic differences responsible for tissue type exist between them.
Noting similar symptoms caused by scleroderma and GVHD, Nelson wondered whether related mechanisms might be at play for both diseases. Her curiosity was furthered when researchers at Tufts University in 1996 found that in women who have had children, trace fetal cells can persist in their blood for decades after pregnancy. Nelson wondered whether in scleroderma patients, as in GVHD patients, a mixture of immune cell types in the blood might play a role in the disease.
"When I learned that fetal cells persist for years after pregnancy, it all fell into place for me," Nelson said.
Nelson hypothesizes that the rogue fetal cells, which are genetically similar to those of the host, disrupt the normal network of immune-system communication.
"The trace fetal cells are analogous to a computer virus," Nelson said. "They are similar enough to the mother's own cells to remain in her body without being destroyed by her immune system, but different enough so that they can interfere with cell-to-cell communication that is critical for the immune system to function normally."
Persistence of fetal cells in a mother's peripheral blood years after pregnancy may help explain how gender affects susceptibility to scleroderma, although not all women who harbor fetal cells develop scleroderma. Nelson's lab has shown that certain genetic differences can contribute to an individual's susceptibility to develop the disease. Recent studies have also shown that not only do cells pass from fetus to mother, but cells can pass from mother to fetus, meaning that men can harbor trace cells from their mother.
Nelson and her colleagues are now working to isolate persisting fetal cells and maternal cells to analyze their role in the disease process.
Roth's basic research leads to breakthrough lupus test
A laboratory filled with fruit flies and worms seems an unlikely environment in which to study autoimmune diseases. Yet research on these and other simple creatures led Dr. Mark Roth to develop a new diagnostic test for lupus, a disease that is estimated to affect more than 1 million Americans.
The U.S. Food and Drug Administration has cleared for market this new screening test, which is considered the first significant diagnostic breakthrough for systemic lupus erythematosis (SLE) in four decades. The test is expected to pick up the 20 percent of SLE cases that previously fell through the cracks because they could not be detected by the most widely used screening test.
Lupus is a chronic disorder in which a person's immune system attacks the body. SLE is the most severe form, which causes inflammation of connective tissue throughout the body, from the joints to the kidneys. Because symptoms cover a wide range, diagnosis can be difficult.
"This test will improve the ability of doctors to make correct decisions when diagnosing SLE, and we also have evidence that this test is of value in determining where in the body the disease will present itself," said Roth, an investigator in the Basic Sciences Division.
FDA clearance well help facilitate the transfer of the technology to companies that can make the test widely available.
Funding for this research came from the National Institutes of Health and Fred Hutchinson's New Technology Development Fund. The fund helps translate basic-research discoveries to products that could benefit the public.
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