Promising New Way to Block Inflammation in Autoimmune Disease

Their research in laboratory mice suggests that blocking this receptor could slow or block the debilitating inflammation characteristic of autoimmune diseases, potentially without leaving the body susceptible to serious infections, as do many current therapies.

DR3 is a protein on the surface of cells. It is a member of the tumor necrosis factor (TNF) family of receptors, which bind to molecules related to TNF, a cell-signaling protein that promotes inflammation. Many of the current powerful treatments for inflammatory diseases, such as psoriasis and rheumatoid arthritis, interfere with the action of TNF, thereby blocking inflammation. Because current anti-TNF therapies do not work in all autoimmune diseases, however, the researchers turned to the study of DR3, which is a close relative of TNFR1, the main receptor for TNF. They published their findings online in the July 2008 issue of the journal Immunity,

Working with mouse models of asthma and multiple sclerosis (both immune system diseases) the researchers, from the U.S. National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; Bethesda, MD, USA), a part of the National Institutes of Health (NIH), discovered that mice engineered to lack DR3 were resistant to those diseases. "The implication is that blocking DR3 in mice, and possibly in humans, is a potential therapy for these diseases and perhaps others in which the immune system goes awry,” said Richard Siegel, M.D., Ph.D., a scientist in the NIAMS' Immunoregulation Group, who led the research effort.

While closely related to TNFR1, DR3 is expressed in T cells, a different type of immune cell (a white blood cell that identifies and fights infection) than those that express TNFR1, according to Dr. Siegel. The NIAMS group collaborated with a laboratory in Cardiff, Wales, UK, which had generated genetically engineered mice deficient in DR3, as well as with a research group at the NIH's National Institute of Allergy and Infectious Diseases (NIAID), which has developed mouse models of disease with strong T cell components, such as asthma and multiple sclerosis. "These findings open up new avenues for therapy of these two diseases as well as to other autoimmune diseases in which T cells play a role in causing or perpetuating the disease,” said Dr. Siegel.

The researchers hope that DR3-blocking agents will be effective anti-inflammatory treatments someday. Dr. Siegel noted that if they were to be used in rheumatic diseases, they would be a complement to strategies that block TNF because they hit a different arm of the immune system. "It could be potentially synergistic or complementary,” he said.

Of vital importance, the NIAMS scientists found that removing DR3 did not appear to inhibit the immune response or the ability to fight infection within the mice--a problem with many other treatments for autoimmune disease. "We could see the effect of DR3 deficiency in the diseased organ, but when we looked systemically at the immune response at other places in the mouse, it was barely affected,” said Dr. Siegel. The group's findings suggest that DR3-blocking agents might be more effective at specifically treating autoimmune disease without breaking down the body's defenses against infections, a long-sought goal of researchers in the field.

The mission of the NIAMS is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases.


Related Links:
U.S. National Institute of Arthritis and Musculoskeletal and Skin Diseases