Lupus Discovery May Lead To Improved Drugs

In an important development in the treatment of lupus as well as certain cancers, scientists at the Feinberg School of Medicine at Northwestern University have discovered how autoimmune lupus T cells stave off programmed cell death and drive production of autoantibodies directed against the body’s own DNA.

Syamal Datta, M.D., and colleagues found that lupus T cells increase production of an enzyme called cyclooxygenase 2 (COX-2), which helps trigger inflammation, in tandem with another molecule called c-FLIP, which then prevents the autoimmune T cells from self-destructing.

Using commonly prescribed drugs called COX-2 inhibitors, which suppress COX-2 activity and, as a result, inflammatory chemicals called prostaglandins, the Northwestern researchers caused autoimmune T cells to die and blocked lupus autoimmunity.

Results of their study, published in the April issue of Nature Medicine, may pave the way for the design of better COX-2 inhibitors with less kidney toxicity or other candidate drugs that interfere with the lupus T cell’s death resistance pathway, said Datta, who is Solovy Professor of Medicine and professor of microbiology/immunology at the Feinberg School.

Currently, COX-2 inhibitors are widely prescribed to treat rheumatoid arthritis and other inflammatory conditions, and have been tested for use in a number of cancers, including colorectal cancer.

Most unexpectedly, the researchers found that only some COX-2 inhibitors have a beneficial effect in lupus, which may depend on their structural peculiarity and not because they inhibit prostaglandin production and reduce inflammation, something all COX-2 inhibitors do.

COX-2 inhibitors also have been used, with limited success, to treat patients with lupus and in laboratory models of lupus, but in doses much lower than the concentration required to achieve cell death and elimination of autoimmune T cells, Datta said.

Datta’s co-researchers were Luting Xu, Li Zhang, Yajun Yi and Hee-Kap Kang. Yajun Yi is now at Vanderbilt University, Nashville.

This study was supported by grants from the National Institutes of Health.