Suppressing entire immune system unlikely to be best way to treat autoimmune diseases, new findings show

December 18, 2001

Suppressing the immune system is one way to treat autoimmune diseases, frustrating conditions in which the body's tissues are attacked by "friendly fire." But a new study shows that such blanket defenses are probably not the best way, say scientists from The Johns Hopkins University School of Medicine.

One of the immune system's soldiers, interferon-gamma, actually helps prevent tissue damage in mice given a condition similar to a heart-damaging autoimmune disease in humans, the scientists report in the Dec. 18 issue of the journal Circulation.

"In treating autoimmune disease," says Noel Rose, M.D., Ph.D., a professor of pathology at Hopkins, "it's possible that treatments that alter the immune system's overall function could make one autoimmune disease better but make a second one worse."

The scientists discovered interferon-gamma's protective role as they were trying to figure out how an immune soldier called interleukin-12 causes heart damage in this disease, known as myocarditis. Because interleukin-12 "recruits" interferon-gamma, increasing its presence in cells, the scientists suspected interferon-gamma might be involved in damaging tissue.

Unexpectedly, mice without normal interferon-gamma function had more heart damage, and mice treated with extra interferon-gamma had less damage than normal mice. Extra interferon-gamma prevented heart damage completely in seven of the 11 mice studied, says Rose, whose studies were funded by the National Institutes of Health.

"Scientists generally thought that interferon-gamma was responsible for many actions of interleukin-12, so it was surprising that the two proteins really have opposite effects in these mice," explains Marina Afanasyeva, M.D., M.P.H., a Ph.D. candidate in molecular microbiology and immunology at Johns Hopkins University's Bloomberg School of Public Health. "Interleukin-12 probably depends on interferon-gamma for its effects in some circumstances but not others."

Many autoimmune diseases are poorly understood, says Rose, but some are linked to viral infections. Treating these diseases can be frustrating, as opportunistic autoimmune diseases -- those that rise from the ashes of another -- are frequently seen, he adds.

Critical to the scientists' discovery was their mouse model of autoimmune myocarditis, which in humans stems from infection with the Coxackievirus. While most people shake off the infection's flu-like symptoms, for reasons still unknown at least 50,000 people per year subsequently develop an errant, long-lasting autoimmune reaction that damages the heart muscle.

The Hopkins team had already identified the target of this immune attack as a protein called cardiac myosin. By injecting mice with excess cardiac myosin, they created the autoimmune response and heart damage without using the virus.

Because interleukin-12 was already a primary suspect in this autoimmune process and it stimulates production of interferon-gamma, the scientists thought interferon-gamma might be responsible for its damaging effects.

However, mice whose gene for interferon-gamma was knocked out and mice whose interferon-gamma protein was blocked with an antibody both had larger hearts and more physical evidence of heart tissue inflammation than mice with normally functioning interferon-gamma, says Afanasyeva. They're still evaluating the effects on heart function, she adds, and they don't yet know whether interferon-gamma actively protects the heart or its absence allows another as-yet-unknown damaging activity to emerge.

Despite its apparent protective role in myocarditis, interferon-gamma is unlikely to be useful as a treatment, notes Rose. "Interferon-gamma is a very potent agent but it can also be toxic," adds Afanasyeva. "If we study more how interferon-gamma acts, perhaps we can design safer agents that mimic it."

The scientists emphasize that different auto-immune diseases likely have different "good" and "bad" soldiers. Even though it is protective in myocarditis, for example, interferon-gamma is known to make multiple sclerosis worse.
-end-
Co-authors are Yan Wang, Ziya Kaya (supported by a fellowship from the Deutsche Herzstiftung e.V.), Elizabeth Stafford and Malte Dohmen, of the department of pathology at the Johns Hopkins School of Medicine; and Amir Sadighi Akha, now in the pathology department at the University of Michigan Medical School.

On the Web:
http://circ.ahajournals.org

Media Contact: Joanna Downer (410)614-5105 Email: jdowner1@jhmi.edu

Johns Hopkins Medical Institutions' news releases are available on an EMBARGOED basis on EurekAlert at http://www.eurekalert.org, and from the Office of Communications and Public Affairs' direct e-mail news release service. To enroll, call 410-955-4288 or send e-mail to bsimpkins@jhmi.edu.

On a POST-EMBARGOED basis find them at http://www.hopkinsmedicine.org.

Johns Hopkins Medicine

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