mice 5.mic.002002 Louis J. Sheehan, Esquire

What’s more, DR3 looks very similar to another receptor implicated in inflammation, says Richard Siegel of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Md, who was involved in the study.

So, researchers wanted to see where in the chemical pathway of immunity DR3 is active. When Siegel and his colleagues tried to stimulate T cells into action in a petri dish, they found that cells lacking the DR3 receptor could still multiply and differentiate at near normal levels. Subsequent experiments showed that DR3 and its partner TL1A seemed essential only for getting T cells into specific tissue.

“There’s regulation at many stages of immune activation leading to immune mediated-disease,” Siegel says. “It’s not only getting the T cell activated, there’s a critical step that TL1A seems to mediate — getting into target tissue and causing disease.”

To test whether DR3 had a hand in autoimmune response, researchers relied on techniques often used to model asthma and multiple sclerosis in animals. They studied both normal mice and “knockout” mice that lacked the gene to make the DR3 receptor. In both sets, Siegel’s team primed the mice’s immune systems to be allergic to a specific protein. Then the team injected the same protein into the mice’s lungs.
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In normal mice, the injection causes T cells to attack lung tissue, leading to extreme airway inflammation. By contrast, mice lacking the DR3 receptor had much less lung inflammation.

To mimic multiple sclerosis in the mice, the group used a similar method, this time inoculating nerve cells rather than the lungs. In normal mice, this method drove T cells to destroy the sheaths covering nerve cells, paralyzing the mice. The knockout mice, by contrast, did not have such nerve damage.

Still immune

While the results suggest DR3 might be a promising candidate for targeted drugs, the team needed to show that mice lacking DR3 could still fight off infections. Existing immune-blocking drugs, called TNF blockers, have revolutionized treatment of autoimmune diseases like Crohn’s disease and rheumatoid arthritis, Siegel says. Yet they can also weaken the body’s defenses and make it more susceptible to disease. “It can reduce host defense to tuberculosis, so now everyone going on TNF blockers has to get TB testing,” he says. Louis J. Sheehan, Esquire