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September 29, 2011

Master key found which could lead to treatment for all autoimmune disorders

Imagine a single drug that would treat most, if not all, autoimmune disorders, such as asthma, inflammatory bowel disease, and Lupus. That might not be so hard to do thanks to a team of researchers who have discovered a molecule normally used by the body to prevent unnecessary immune reactions. This molecule, pronounced "alpha v beta 6," normally keeps our immune systems from overreacting when food passes through our bodies, and it may be the key that unlocks entirely new set of treatments for autoimmune disorders.

Journal of Leukocyte Biology - Intestinal epithelial cell-derived integrin αβ6 plays an important role in the induction of regulatory T cells and inhibits an antigen-specific Th2 response



"Currently we do not have special methods to radically treat most immune diseases; all we can do is to temporarily inhibit the clinical symptoms for those diseases," said Ping-Chang Yang, a researcher involved in the work from the Department of Pathology and Molecular Medicine at McMaster University in Ontario, Canada. "Our findings have the potential to repair the compromised immune tolerant system so as to lead the body immune system to 'correct' the ongoing pathological conditions by itself."

Scientists made this discovery in mice when they noticed that their intestines secreted alphavbeta6, when absorbing food. Alphavbeta6, together with the absorbed food, induced the body to produce immune tolerant cells, which ensured that the food did not cause an excessive immune reaction. Researchers then generated alphavbeta6 using cultured intestinal cells and found that both could be used to generate the immune tolerant cells needed to reduce or eliminate out-of-control immune reactions.

"Development of new treatments and cures for diseases is usually a long process involving a series of incremental steps taken from the laboratory all the way through to the patient's bedside," said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. "Occasionally, however, scientists make large leaps forward instead. While considerable work remains to determine whether or not this discovery will directly translate into new therapies, the alphavbeta6 discovery reported by these scientists is exciting, if not stunning."

Toleroge nic DCs and Tregs are believed to play a critical role in oral tolerance. However, the mechanisms of the generation of tolerogenic DCs and activation of Tregs in the gut remain poorly understood. This study aims to dissect the molecular mechanisms by which IECs and protein antigen induce functional tolerogenic DCs and Tregs. Expression of αvβ6 by gut epithelial cell-derived exosomes, its coupling with food antigen, and their relationship with the development of functional tolerogenic DCs and Tregs were examined by using in vitro and in vivo approaches. The results show that IECs up-regulated the integrin αvβ6 upon uptake of antigens. The epithelial cell-derived exosomes entrapped and transported αvβ6 and antigens to the extracellular environment. The uptake of antigens alone induced DCs to produce LTGFβ, whereas exosomes carrying αvβ6/antigen resulted in the production of abundant, active TGF-β in DCs that conferred to DCs the tolerogenic properties. Furthermore, αvβ6/OVA-carrying, exosome-primed DCs were found to promote the production of active TGF-β in Tregs. Thus, in vivo administration of αvβ6/OVA-laden exosomes induced the generation of Tregs and suppressed skewed Th2 responses toward food antigen in the intestine. Our study provides important molecular insights into the molecular mechanisms of Treg development by demonstrating an important role of IEC-derived exosomes carrying αvβ6 and food antigen in the induction of tolerogenic DCs and antigen-specific Tregs.

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