Signaling pathway could be a valuable target for future drug therapies against systemic lupus erythematosus

Oct 11 2004

Medical investigators at the Hospital for Special Surgery have identified an important new signaling pathway they believe could be a valuable target for scientists to aim at with future drug therapies that might one day reverse diseases such as systemic lupus erythematosus, according to a recent article published in “Nature Immunology.”

The chemical pathway involves the body’s responses to potent substances called cytokines which have dramatic influence on the progression, or reversal, of diseases such as rheumatoid arthritis and lupus.

Doctors have long known that cytokines can regulate diseases such as lupus, but it is now becoming appreciated that lupus can also make cytokines fail to work properly. What is not fully understood is just how the cytokines become “switched on” to cause damage. Understanding the molecular chemistry that turns on the switch becomes central to stemming disease.

The HHS in vitro and animal study work focused on the key role of interferon chemicals produced in the body as they impact cytokines production and influence inflammation. One particular kind of interferon (IFN), IFN-alpha, was believed to play a key role in lupus and is a therapeutic target for this disease. The investigators found that inflammation, as it occurs in lupus patients, changed cellular responses to IFN-alpha and made cellular response become more inflammatory and toxic.

This work supports a concept that is emerging from the laboratory of, Lionel B. Ivashkiv, M.D., lead investigator in the study at HSS published Oct 3, 2004 in “Nature Immunology.” The paper is titled “Amplification of IFN-alpha induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors.”

Specifically Dr. Ivashkiv believes that cytokine signaling is reprogrammed in patients with rheumatic diseases. This reprogramming amplifies the toxic aspects of cytokines, while compromising the effectiveness of “good cytokines” that patients produce in their bodies in an attempt to heal themselves.

“We found that if we inject these IFNs in a normal mouse, there was no effect but if we injected the IFN-alpha in a mouse with lupus, we saw evidence of an influx of cells and the start of inflammation at the site where it was injected,” said Dr. Ivashkiv.

“People with rheumatic diseases like lupus and arthritis have cytokine response problems that prevent these chemicals from working properly and doing what they are supposed to do to heal the body. If we can identify and influence the chemicals that result in this and prevent it from happening, we can prevent the cycle of inflammatory response that damages these patients instead of helping them,” said Dr. Ivashkiv.

In lupus, the immune system attacks the body’s own cells and tissue, especially the skin, joints, blood, heart, lungs and kidneys. It affects 1-1.5 million Americans and is a leading cause of kidney disease, stroke and cardiovascular disease in young women.