Can we hypercharge vaccines? Tapping a chemical we already make could enhance T-cell production

Researchers at Boston Children's Hospital 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 online by Science on April 21, could enhance vaccines and make them much more effective.

The researchers, led by Jonathan Kagan, PhD, got a five times greater adaptive immune response in mice when using the chemical, called oxPAPC. 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 Kagan, also an associate professor at Harvard Medical School.

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.

"We identified a naturally-occurring molecule that creates a heightened, 'hyperactive' state of dendritic cell activation," says Kagan. "These hyperactive cells live for a long time and are the best activators of T-cells that we know of, so this could be a very useful tool in vaccine development."

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.

Kagan's 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. When activated by other molecules, 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 Kagan.

Kagan and Boston Children's Hospital's Technology and Innovation Development Office (TIDO), 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. (For inquiries, contact Abbie.Meyers@childrens.harvard.edu.) 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.