COLUMN ONE : Fooling the Body to Heal Itself : The digestive response that lets us eat meat may help fight several debilitating diseases. Early studies show that feeding patients animal proteins eases symptoms of arthritis and multiple sclerosis.
If a calf’s liver is transplanted into a human, it is quickly and violently rejected because the body recognizes proteins in the liver as foreign and attacks them. But if the organ is fried and eaten, those same proteins are easily absorbed.
That’s because the stomach and intestines have their own branch of the immune system, an unusual mechanism that suppresses, rather than triggers, immune responses to foreign material. Without it, we would not be able to eat meat and many other foods.
Scientists are beginning to take advantage of this dietary phenomenon, called oral tolerization, in an effort to treat a wide variety of autoimmune diseases, in which the body attacks itself. The procedure has been effective in treating animal models of the diseases.
Now, researchers are moving on to humans.
If successful, oral tolerization could revolutionize treatment of, and perhaps prevent, such debilitating diseases as rheumatoid arthritis, multiple sclerosis and diabetes. “I really think this is an exciting new approach, letting the body do the work for us,” said Dr. Robert Nussenblatt of the National Eye Institute in Bethesda, Md.
By feeding patients simple proteins that mimic human proteins involved in the diseases, researchers are finding that they can suppress the autoimmune attack, retard the course of the disease and alleviate suffering. Moreover, the treatments seem to be free of side effects.
Conventional treatments for autoimmune diseases, in contrast, rely on powerful immunosuppressant agents that have many serious side effects and can be used for only short periods.
Last month, Harvard researchers reported that they could significantly reduce arthritis flare-ups by feeding patients a chicken protein called collagen II. Earlier this year, another Harvard team found similar results with multiple sclerosis.
An ongoing trial is testing this approach for uveitis, an autoimmune attack on the eye. Researchers are also preparing trials against diabetes, myasthenia gravis, Grave’s disease, psoriasis and organ transplants.
“The fact that we are beginning to get positive results in more than one human disease is very encouraging,” said Dr. Howard L. Weiner of the Harvard Medical School and Brigham & Women’s Hospital in Boston, who was involved in both the arthritis and multiple sclerosis trials.
One of Weiner’s test subjects is Robert Basso, 36, a country club manager in Amesbury, Mass., who developed dizziness and numbness on one side of his body, the first signs of multiple sclerosis, in 1986.
Basso had his first severe attack three years later. “I had no balance at all, the numbness on my right side was more severe, and I couldn’t drive for a month and a half” because his vision was blurred so badly. The whole episode lasted seven months.
When his multiple sclerosis went into remission, he enrolled in the first trial of oral tolerization against the disease. Since then, he has not had an attack and his body has shown no further deterioration. Most people with multiple sclerosis have at least one attack a year.
“I’m feeling very good,” he said recently. “I don’t think my body will ever get back to 100%, but (myelin) has maintained it at a level where I know what I am capable of.”
The ideas behind oral tolerization have been around for hundreds of years, immunologist Caroline Whitacre of Ohio State University said. Some evidence exists that American Indians chewed poison ivy leaves to suppress symptoms of exposure to it.
The first scientific experiments began in 1911, when researchers fed guinea pigs foreign proteins that would normally produce a strong allergic reaction when injected and observed that subsequent injections had no effects. Similar research occurred in the 1940s, but it was not until the last decade that Weiner and a handful of others began studying the phenomenon intensively, using animal models.
One model was devised for multiple sclerosis, which occurs when the immune system attacks the myelin sheaths that enclose and insulate nerves much like the plastic coating of electrical wires. When the myelin is partially destroyed, the nerves are “short-circuited,” causing loss of function. The crippling disease afflicts as many as 250,000 Americans, two-thirds of them women. Patients often undergo relapse periods of intense pain and disability between remissions.
Researchers can produce an MS-like disease called experimental allergic encephalomyelitis, or EAE, in mice by injecting them with myelin basic protein, a crucial component of the nerve sheaths, from a different species of mouse. When the host mouse’s immune system attacks this foreign protein, the attack spills over onto its myelin sheath, causing symptoms of the disease.
Many scientists believe that autoimmune diseases in people are triggered in a similar fashion by a viral infection. For example, if a viral protein resembles a human protein in the pancreas, then the attack on the virus might trigger an attack on the insulin-secreting cells of the pancreas, causing diabetes.
Weiner and Whitacre have independently shown that feeding myelin basic protein to the mice can halt the progress of EAE. Feeding it before the protein injections prevents EAE. The animals are made tolerant of the protein; hence the name, oral tolerization.
Scientists are not completely sure how oral tolerization works, but Weiner has produced some important clues. In particular, he has shown that white cells isolated from the blood of tolerant animals and injected into other animals render them tolerant as well.
In February, Weiner and his colleagues reported results from a one-year study of 30 multiple sclerosis patients.
The test group was too small to make the findings statistically significant, but the results encouraged Weiner to begin a larger trial, with 300 patients at several medical centers, by year’s end. Whitacre is planning a trial at Ohio State University.
Results were even more promising with rheumatoid arthritis, a crippling disorder that occurs when the immune system attacks collagen in the joints, causing painful inflammation and deterioration of the bone. It afflicts an estimated 2.1 million Americans.
Weiner and Dr. David E. Trentham, a rheumatologist at Harvard and Beth Israel Hospital, studied 59 arthritics for three months. The patients were taken off all other medication and 28 received daily doses of chicken collagen in orange juice, while the others received a placebo.
While the patients who received the placebo worsened slightly, those who received the collagen had a 25% to 30% reduction in observed swelling and pain. Virtually all symptoms disappeared in four of them.
“It’s almost too good to be true,” Dr. Arthur Grayzel of the Arthritis Foundation said. “If it does pan out, it’s going to be a very significant advance in terms of safety and, probably, cost.”
“This could be the first really safe therapy that is effective,” Trentham added.
Jean Arns, 57, was among the patients in the arthritis trial who showed marked improvement. Arns, a nurse at Boston Specialty and Rehabilitation Hospital, developed rheumatoid arthritis 13 years ago and had futilely tried various drugs to ease her symptoms.
Before she entered the trial 15 months ago, the pain was so bad that she had difficulty opening pill bottles for her patients or moving from room to room.
The treatment made a tremendous difference, she said: “I could walk up the stairs without holding onto the handrail. I could go bicycle riding.” In the year since she stopped taking collagen, she said, very little pain has returned.
But other researchers cautioned that there are potential problems with the study. It did not last long enough, said Dr. Joel Kremer, a rheumatologist at Albany Medical College in New York, and did not include a “washout” period, in which the subjects received no drugs, before the collagen was administered. Thus, the results could possibly be caused by lingering effects of the immunosuppressant drugs the patients had been taking. The team will soon begin a larger, longer trial that includes a washout period.
The third disease for which clinical trials are under way is uveitis, a general term for an eye inflammation that can cover a broad range of symptoms and severity, including blindness. Various forms affect 2.3 million Americans. The National Eye Institute’s Nussenblatt has shown that feeding mice a protein called S-antigen can prevent the development of the most serious form of the disorder.
Two years ago, Nussenblatt began feeding S-antigen from cow eyes to two patients who were expected to become blind. Their uveitis went into remission, and they are still receiving S-antigen once a week. Nussenblatt and his colleagues are at the halfway point of a 45-patient trial whose results also look promising.
Diabetes will probably be next up. Dr. Noel MacLaren and his colleagues at the University of Florida College of Medicine in Gainesville have shown that feeding either insulin or a diabetes-related enzyme called GAD can delay or prevent the onset. “It’s a very powerful effect,” he said. The National Institutes of Health is expected to approve a trial of insulin feeding at several universities within a month.
Trials for other diseases are further off.
As researchers learn to adjust dosages and begin using human proteins in their experiments, they believe they can get better results.
Researchers have used biotechnology to produce human myelin basic protein, human collagen and human S-antigen that they hope will produce greater tolerance than animal proteins. But the use of these products in human trials has not yet been approved by the Food and Drug Administration.
Meanwhile, researchers and health authorities caution against people trying to use oral tolerization techniques themselves. Whitacre noted that the effectiveness of the treatment in animals depends greatly on the precise dose given and “it’s very difficult to try a single dose (in humans) and hit the right one.”
Although health food stores sell collagen, it is not the same material used in arthritis trials and is unlikely to produce any benefit, Grayzel said.
