Hutch News

Best hope may lie in vulnerability

Jan. 17, 2002
Dr. Richard Nash in his lab.

Dr. Richard Nash, shown in his Thomas Building lab, finds it exciting to see autoimmune-disesase symptoms reverse as a result of transplantation.

Photo by Michelle Hruby

For weeks after a bone-marrow or stem-cell transplant, until a new immune system is established, even a telltale sneeze from a hospital visitor can be enough to put a transplant patient's outcome in peril.

Yet this vulnerable state may have untold benefits for people who suffer from a group of debilitating disorders known as autoimmune diseases, said Dr. Richard Nash, an investigator in the Hutch's Clinical Research Division.

"It was clear to many doctors early on that the immune system is severely affected by the transplant-conditioning regimen," he said. "Based on that observation, the logical question is: Can we use the same treatment for other diseases which are immune-mediated, such as autoimmune diseases?"

One of only two

Nash and his colleagues think they can. The Hutch is one of only two institutions in the country (Northwestern University Medical School is the other) to lead clinical trials that use stem-cell transplantation for treating autoimmune disease.

Already, the Hutch team has seen success in some of the earliest patients to undergo this experimental procedure.

Currently, Nash said, the Hutch protocols target particularly severe autoimmune diseases, including multiple sclerosis, systemic sclerosis and systemic lupus.

Autoimmune diseases include about 50 ailments whose symptoms range from mild rashes to life-threatening conditions that attack major organ systems. Though each disease is different, all share an immune-system malfunction: destruction of the body's own normal tissue by cells that typically fight infections caused by bacteria, viruses and other microorganisms.

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 from weakness to paralysis.

Many autoimmune diseases occur predominantly in women, particularly those who have borne children. Dr. Lee Nelson, a co-investigator for these studies in the Clinical Research Division, studies the role that trace fetal cells play in these illnesses.

But scientists have not yet determined the precise trigger - likely a complex interplay of factors - for the onset of disease, Nash said.

High rate of MS

"I come from Winnipeg in Canada, which has a high rate of multiple sclerosis," he said. "The incidence of MS is higher in the more northern latitudes, suggesting there is an environmental component to the genesis of the disease.

"The environmental component seems to have its effect early in life, because when people move to regions in the south later in life, they retain the risk profile associated with where they lived when they were young. The higher risk may be due to some kind of a viral infection in early life that triggers an autoimmune reaction, but the disease may remain indolent for many years."

With other Hutch physicians, Nash convened a meeting in 1995 on treating patients with severe autoimmune diseases with stem-cell transplants, a procedure typically reserved for blood and immune system cancers and aplastic anemia.

Expecting that the benefits of the procedure would outweigh the risks, the group decided to develop an initial set of treatment protocols.

The 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 autologous transplantation, in which their own hematopoietic stem cells (the progenitor cells that form the blood and immune systems) are collected prior to the conditioning regimen and transfused back after most remaining immune cells have been weakened by immunosuppressive drugs

Two systemic sclerosis patients have received allogeneic transplants, a procedure in which stem cells are donated by a tissue-matched relative. These patients' immune systems were first completely destroyed with high-dose therapy (a conventional conditioning regimen).

"Patients can be transplanted with their own stem cells (which are selected from their own blood, using specific markers on those cells' surfaces) because only the mature T-cells are autoreactive, not the stem cells," Nash said. "However, it is unclear at this time if patients will have long-term remissions. Longer follow-up on the study is still required."

The first patients underwent the procedure in 1997 with promising results.

"As with any cancer therapy, autologous and allogeneic transplants are not uniformly successful," Nash said. "We've seen the most promise with systemic sclerosis with, in some cases, the disease reversing. We see a significant reduction in the thickening of the skin, which is one of the major symptoms of the disease."

The Hutch leads four clinical trials for autoimmune disease: a trial for multiple sclerosis, which has completed its accrual goal of 26 patients, two systemic sclerosis studies (an allogeneic and an autologous study) that are in the accrual phase, and a lupus study that has just opened. Studies are being developed of allogeneic stem-cell transplantation after a conditioning regimen that does not completely destroy the immune system.

Pilot studies

"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 MS 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."

Nash believes the transplant procedure may owe its success to multiple immune-system effects.

"Our hypothesis is that in autologous transplants, not only are we diminishing the autoreactive cells, we may also be causing changes in the signals that regulate T-cell response," he said.

"We think this may be true because the course of an autoimmune disease often waxes and wanes without resulting in significant differences in the number of autoreactive cells detected by laboratory studies. The variability of the disease may be due to changes in the signals that these T-cells receive from other regulatory cells."

With no known cure for any autoimmune disease, transplants ultimately may be the best hope for patients with extreme symptoms.

"Initially, we thought transplants would prevent regression," Nash said, "but to see the some of the disease symptoms actually reverse, as in patients with systemic sclerosis, is especially exciting."

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