Preventing the unwanted side effects of autoimmune disease therapy
Treatment for autoimmune and inflammatory disorders such as multiple sclerosis often includes blocking a special cell surface attachment molecule known as alpha4 integrin to prevent migration of white blood cells (WBCs). However, this therapy can cause adverse side effects, such as impaired immunity and hematopoiesis [the process of development of new WBCs in the thymus (T cells) and bone marrow (B cells)]. Now, researcher Mark H. Ginsberg and colleagues at the University of California in San Diego have identified a mechanism to selectively reduce WBC recruitment while sparing hematopoiesis. The study appears online on February 9 in advance of print publication in the March issue of the Journal of Clinical Investigation. The authors created mutant mice known as "alpha4(Y991A) mice," in which the alpha4 integrin can no longer bind to a signaling protein inside the cell called paxillin. Previously generated alpha4 integrin mutant mice died at birth because too many aspects of alpha4 function were changed. The new alpha4(Y991A) mice have an impairment only in the interaction between alpha4 and paxillin, and thus have fewer side effects from the mutation. The authors noticed that, in contrast to wild-type mice, alpha4(Y991A) mice exposed to an inflammation-inducing compound called thioglycollate recruited fewer circulating T and B cells to the region of exposure. However, the development of new B and T cells was unaffected. The authors suggest that these mice are an important model for the identification of signaling mechanisms specific to inflammation, and that a new class of pharmaceutical agents that target the specific interaction of paxillin and alpha4 integrin could be important future treatments of inflammatory disease.