A New View of TNF Inhibitors

Posted 1/22/08

Powerful drugs used to treat rheumatoid arthritis have a profound, previously unrecognized effect on the immune system, breaking up molecular “training camps” for rogue cells that play an increasingly recognized role in autoimmune diseases like rheumatoid arthritis and lupus.

A team of physicians and scientists at the University of Rochester Medical Center reports that anti-TNF agents – which include drugs such as Enbrel, Humira and Remicade – affect our B cells, which play a role in many autoimmune diseases.

In a study published in the January 15 issue of the Journal of Immunology, the team found that anti-TNF compounds help eliminate abnormal B cell activity in patients, raising the possibility that the drugs improve the health of patients in a way no one has realized before.

“The most important considerations for any drug are: Is it safe, and does it work?” said Ignacio Sanz, MD, one of two rheumatologists leading the research. “The answer is certainly ‘yes’ to both questions for these anti-TNF compounds. The drugs have revolutionized the treatment of patients with rheumatoid arthritis. But it also turns out that, even though millions of patients have been treated with these medications, we really haven’t understood to a significant degree how they actually work.”

Sanz teamed with Jennifer Anolik, MD, and worked with ear, nose and throat doctors who took a small snip from a patient’s tonsils. These tissue samples gave the scientists a window directly into the structures of the lymph system, rather than basing their analysis on cells afloat in the bloodstream.

Anolik and Sanz found that anti-TNF drugs disrupt the architecture of structures in our lymph system called germinal centers. These centers appear when we’re sick so that immune cells, like B cells and T cells, can swap information about such invaders as bacteria and viruses. The structures swiftly churn out lots of B cells, which the body uses to tag invaders for destruction.

In healthy people, once an infection is beaten off, the germinal centers fade away. But in people with a chronic autoimmune disease, such as rheumatoid arthritis or lupus, germinal centers stick around too long, preparing an army of immune cells that wreak havoc throughout the body.

“This is a critical piece of the immune response,” said Anolik. “Germinal centers are where crucial education of the B cell takes place – where they learn which cells to attack and which ones not to. Dysregulation in germinal center reactions may play a role in many autoimmune diseases.”

The team found that anti-TNF compounds inhibit the function and organization of cells that help form the germinal centers. They found that arthritis patients who received anti-TNF therapy had about one-quarter the number of germinal centers as other arthritis patients. The germinal centers that did exist were smaller and less organized. The team also found that the anti-TNF medication dropped the percentage of memory B cells in the lymph tissue by about 40 percent.

Previous work by the Rochester team and others indicated that B cells play a key role in rheumatoid arthritis. Theirs is one of the first studies to explore how anti-TNF compounds affect B cells in patients with rheumatoid arthritis.

“There is a lot of excitement about the role of B cells in autoimmune disease,” said Anolik. “The connection between TNF-targeted therapy and B cells in rheumatoid arthritis really hasn’t been appreciated.”

This article was adapted from a press released issued by the University of Rochester medical center.

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