June 18, 2007 An important finding, which could eventually lead to a new therapeutic approach for treating autoimmune and inflammatory diseases such as rheumatoid arthritis, colitis, psoriasis and others, was announced today by researchers at the La Jolla Institute for Allergy & Immunology (LIAI). The studies, conducted in laboratory mice, demonstrated the role of retinoic acid, a substance derived when Vitamin A is broken down in the body, in regulating inflammation.
In these studies, published in the journal Science, the LIAI researchers showed that by manipulating the amount of retinoic acid in mice, they could affect the number of pro-inflammatory T cells, a type of white blood cell responsible for several autoimmune and inflammatory diseases. The finding is an important first step that, if eventually found to be true in humans, points to the potential of a new avenue of therapies using retinoic acid to treat these diseases.
"What's exciting about this finding is they've found that retinoic acid plays a role in modulating the switch between these two distinct (T cell) lineages -- the induced regulatory T cells, which are anti-inflammatory, and the TH-17 lineage, which promotes inflammatory responses, " said Casey Weaver, M.D., a University of Alabama, Birmingham, professor and prominent immunology researcher, who was key in the discovery of TH-17 in 2005.
Further, Dr. Weaver said, the LIAI researchers had developed a "mechanism by which you can prevent the development of the (inflammatory) lineage. This is very exciting because it provides a potential pharmacological application for this finding."
The LIAI team tested three approaches with retinoic acid. In one model, they injected the mice with retinoic acid, essentially giving them more of the substance than they would have through normal body processes. This suppressed the formation of pro-inflammatory T cells in the intestines of the mice, demonstrating that increases in retinoic acid reduced inflammation. In another approach, designed to test how reducing retinoic acid would affect inflammation, the team used an inhibitor to block retinoic acid in the mice.
This led to the decrease of anti-inflammatory T cells, showing that reducing retinoic acid increased inflammation. In a third, particularly exciting approach, the scientists treated T cells with retinoic acid in a test tube. When put back into the mice, these T cells prevented the formation of inflammatory T cells in the mice. This is especially noteworthy because combining the retinoic acid and T cells outside the body may avoid possible side effects that are more likely when scientists attempt to manipulate body processes internally.
"We found that you can control inflammation in a living animal with retinoic acid or you can treat cells with retinoic acid in a test tube and transfer them to the organism to suppress inflammation in vivo," said Dr. Cheroutre. "This may offer an important new avenue for treatment of autoimmune diseases like colitis and rheumatoid arthritis or other inflammatory diseases, as well as potentially providing a mechanism for the control of graft rejections, where you don't want the immune system to attack the grafted tissue."
The finding was published in a paper entitled "Reciprocal Th-17 and regulatory T cell differentiation mediated by retinoic acid." Hilde Cheroutre, Ph.D., led the research team, entirely from LIAI, in which Daniel Mucida, Ph.D., and Yunji Park, Ph.D., were key contributors.
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