Nilamadhab Mishra, M.D., an instructor in internal medicine (rheumatology and clinical immunology), and his colleagues report in the Feb. 14 issue of the Journal of Clinical Investigation that they had found a drug that reduces symptoms of systemic lupus in mice.
The drug, called Trichostatin A or TSA, and other similar compounds "may have therapeutic benefit in treatment of systemic lupus erythematosus," the researchers said.
They said TSA leads to a significant reduction of excess protein in the urine, inflammation of the kidneys and spleen weight in the test mice when compared to control mice. Half of all untreated mice with systemic lupus die from kidney failure. Mice with lupus also develop massive spleens. "TSA-treated mice had significantly smaller spleens," Mishra and his colleagues said.
About half of human patients with systemic lupus have kidney problems, but achy joints, frequent fever, arthritis and prolonged or extreme fatigue are far more common symptoms. Some of these other symptoms also occur in the mice. Systemic lupus accounts for 70 percent of all lupus patients; the rest have one of three other varieties.
Lupus is known as an autoimmune disorder because the body's own immune system turns on the rest of the body and attacks tissue and organs including the joints, kidneys, heart, lungs, brain and blood. The immune system, which ordinarily protects the body from viruses, bacteria and other "foreign" invaders, loses the ability to tell the difference between foreign substances and its own cells and tissue.
The researchers also used TSA and another drug called SAHA (suberonylanilide hydroxamic acid) to study how systemic lupus occurs. Mishra said that patients with lupus may have variation in gene expression. They said they demonstrated that TSA and SAHA "can target expression of disease-modifying genes without affecting the expression of other genes."
Furthermore, the researchers said, since the two compounds reduced kidney disease in mice with systemic lupus, that might indicate a potential use as drugs for people with lupus.
The investigators cautioned that lupus in mice is not the same as lupus in people. For one thing, male and female mice are almost equally affected with the disease, compared to a 9 to 1 ratio of women over men. The pattern of symptoms in systemic lupus in people "is greater and the outcomes more variable" compared to the almost uniform progression of the disease in mice.
"These disease differences emphasize that the positive effects of TSA treatment in mice do no necessarily mean it will be effective in human lupus," Mishra said.
SAHA is available for testing because of studies indicating that it suppresses the growth of prostate cancer; THA has potent antitumor activity in breast cancer.
"Investigation of the potential role of these agents in autoimmune diseases are just beginning," said Mishra.
He said that Christopher M. Reilly of the Medical University of South Carolina, a member of the laboratory of Gary S. Gilkerson M.D., contributed equally to the experiments.
Contact: Robert Conn (rconn@wfubmc.edu), Karen Richardson (krchrdsn@wfubmc.edu) or Barbara Hahn (bhahn@wfubmc.edu) at (336) 716-4587
Journal
Journal of Clinical Investigation