Hyperactivating immune response to protect against infection

Hyperactivating immune response to protect against infection
 

Researchers report that a fatty chemical naturally found in damaged tissues can induce an unexpected kind of immune response, causing immune cells to go into a "hyperactive" state that is highly effective at rallying infection-fighting T-cells. The findings, published by the journal Science, could enhance vaccines and make them much more effective.

The researchers, got a five times greater adaptive immune response in mice when using the chemical, called oxPAPC (oxidized phospholipids). They believe that oxPAPC or a related synthetic compound could be used to help immunize people against a wide range of infections. "We think this could be a general means to increase response to any type of vaccine," says senior author.

oxPAPC targets only dendritic cells -- sentinels that circulate around the body searching for microbes and activating T-cells to destroy the invaders. Previously, it was thought that dendritic cells (also commonly known as antigen-presenting cells) have just two states: an inactive state, in which they can search for microbes, and an active state, in which they have encountered a microbe and gain the ability to activate T-cells.

In particular, when they gave oxPAPC to mice, they saw strong activation of memory T-cells. Memory T-cells respond more effectively to invaders than other kinds of T-cells, but are not efficiently elicited by ordinary activated dendritic cells.

The team further showed that hyperactivated dendritic cells make a critical protein, IL-1ß, that triggers memory T-cell production. Dead dendritic cells also release IL-1ß, but only for a short period of time. Hyperactivated dendritic cells produce IL-1ß for longer times, which likely explains why they are such effective stimulators of memory T-cells.

Finally, the researchers found that oxPAPC's key target is an enzyme called caspase-11 an enzyme that binds both  oxPAPC and bacterial lipopolysaccharide (LPS). oxPAPC and LPS bind caspase-11 via distinct domains and elicit different inflammasome-dependent activities. . When activated by LPS, caspase-11 triggers cell death and inflammation. But when activated by oxPAPC, the enzyme promotes hyperactivation of dendritic cells.

"These discoveries highlight that dendritic cells and caspase-11 can have more than one activation state, which was never before known," says the senior author.

Researchers have filed for a patent on this work and are seeking investor interest so they can move oxPAPC or a similar compound toward a clinical trial. While the work was in mice, Kagan notes that other studies have shown that the biology of dendritic cells is similar in mice and humans.

http://science.sciencemag.org/content/early/2016/04/20/science.aaf3036

Edited

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