The development of drugs that completely suppress the immune system offered a lifeline to patients with pemphigus vulgaris (PV) and other autoimmune disorders, but the drugs themselves can be lethal and often cause serious side effects.
Now, researchers at the University of North Carolina at Chapel Hill have found a safer, more effective way to treat PV patients. In mice, the researchers used a known compound to turn off the signals that trigger skin damage without suppressing the immune system. Similar drugs being developed for human use could offer a potential treatment for PV, the researchers said.
The results appear in the Aug. 22 issue of Proceedings of the National Academy of Sciences. The research was funded the National Institutes of Health."Even if we can't block the immune response, if we can understand the mechanisms behind the damage it causes, we can block that damage," said Dr. David S. Rubenstein, associate professor in the departments of dermatology and pathology in the UNC School of Medicine and a member of the UNC Lineberger Comprehensive Cancer Center. "Targeting these specific events in the cell could enable us to more effectively and safely treat patients."
Rubenstein has previously shown an enzyme called p38 is part of the mechanism by which pemphigus vulgaris autoantibodies cause damage. Autoantibodies are immune-system cells that attack the body's own tissues.
In a mouse model of pemphigus vulgaris, the researchers prevented blistering and other signs of the disease by injecting a drug that inhibits the p38 enzyme. Tests showed t hat the p38 inhibitor drug didn't prevent autoantibodies from binding to the skin cells. Instead, it prevented them from damaging the skin as they normally do. The drug stopped a series of cell-signaling events that lead to the loss of adhesion or "stickiness" between skin cells. Thus, it stops the disease without affecting the immune system.
"There are a number of companies developing inhibitors of the p38 enzyme for treating rheumatoid arthritis and psoriasis," Rubenstein said. "Our study suggests that those same drugs might be valuable in treating pemphigus vulgaris."
Of the 48 mice used in the study, 24 received a high dose of autoantibody which causes gross blistering akin to human PV. The other group of 24 received a lower dose that would cause less severe blistering. Half of each group also received treatment with a p38 inhibitor.
In the two groups that received p38 inhibitor treatment, almost no mice showed clinical signs of pemphigus vulgaris. For instance, in the group that received the high dose of pemphigus vulgaris antibody, 11 out of 12 mice showed blistering, but of the 12 mice that received also received the p38 inhibitor, only one showed blistering.
Source:University of North Carolina School of Medicine
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