Suppressing Entire Immune System Unlikely To Be Best Way To Treat Autoimmune Diseases, New Findings Show

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Suppressing Entire Immune System Unlikely To Be Best Way To Treat Autoimmune

Diseases, New Findings Show

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 s 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 s 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 ackievirus. 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.

Co-authors are Yan Wang, Ziya Kaya (supported by a fellowship from the Deutsche

Herzstiftung e.V.), Stafford and Malte Dohmen, of the department of

pathology at the s 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