'Nondanger' Signal Lowers Immune Reactions; May Be Used to Blunt Transplant Rejection, Autoimmune Diseases

05/15/2007

PHILADELPHIA, May 15/ PRNewswire-USNewswire/ -- Rheumatology researchers have discovered that a well-known cell receptor sends a signal to dampen the immune system.

While not having an immediate application to treating disease, the finding raises the possibility that by targeting that receptor, physicians could stimulate a "nondanger" signal to rein in overzealous human immune responses. Controlling those responses could potentially protect transplant patients from rejection episodes or could relieve symptoms of autoimmune diseases such as rheumatoid arthritis and lupus.

The study, which was performed in mice, appeared in the May 15 issue of the Journal of Immunology.

Researchers from The Children's Hospital of Philadelphia and The University of Pennsylvania reported that complement receptor 3 (CR3), a protein found on cell surfaces, inhibits dendritic cells, the sentinels of the immune system, from setting off an alarm signal that brings on a full immune response.

"Normally, dendritic cells patrol different tissues and organs and look for danger signals sent by tissues undergoing stress or responding to invading microorganisms," said Stefania Gallucci, M.D., leader of the study team at The Children's Hospital of Philadelphia. "We found that when we stimulate CR3 on dendritic cells, CR3 sends a 'nondanger' signal that suppresses the ability of dendritic cells to set off an immune response," added Dr. Gallucci, who is also an assistant professor at the University of
Pennsylvania.

In their study, the researchers used a monoclonal antibody, engineered to bind to CR3, to trigger a cascade of responses that had a net result of decreasing the activation of T cells that would normally be produced. T cells are immune cells that fight infection while contributing to the inflammation seen in an immune response.

"What is exciting about our research is that we have a new agent for modifying dendritic cell function," said pediatric rheumatologist Edward M. Behrens, M.D., the first author of the study. "The monoclonal antibody we used is already in a form that can be used for further studies. It has anti- inflammatory effects, so it may be a potential weapon against
inflammatory diseases."

One such disease is lupus erythematosus, an autoimmune disease in children and adults that may damage many organs. A next step, said Dr.
Gallucci, is to test the antibody in mice that have a disease similar to lupus in humans. The study team also expects to test the antibody in animal models of rheumatoid arthritis. In addition, the researchers may investigate a possible role for the antibody as an immunosuppressant, in preventing a patient's immune system from rejecting cell and organ transplants.

The National Institutes of Health, the Lupus Foundation Southeastern Pennsylvania Chapter and the Arthritis Foundation supported the study. Co-authors with Drs. Gallucci and Behrens, all from Children's Hospital and the University of Pennsylvania School of Medicine, were Terri H. Finkel, M.D., Ph.D.; Uma Sriram, Ph.D.; Debra K. Shivers; and Zhengyu Ma, Ph.D. Marcello Gallucci, Ph.D., of the University of Milano-Bicocca in Italy also was a co-author.

About The Children's Hospital of Philadelphia: The Children's Hospital
of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's
Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In
addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.

SOURCE The Children's Hospital of Philadelphia