Penn prof develops ‘passport’ for the immune system

Dennis Discher

Dennis Discher, the Robert D. Bent Professor of Chemical and Biomolecular Engineering in the School of Engineering and Applied Science.

The body’s innate immune system is its first line of defense against invaders. A disease-causing bacterium or a piece of wood from a splinter are treated the same: Cellular agents of the immune system identify these objects as foreign and try to destroy them. 

Macrophages—literally “big eaters”—are a main part of this response. These cells find and engulf invaders, or call for back up and form a protective wall around the foreign object. Unfortunately, macrophages also eat helpful foreigners, such as nanoparticles that deliver drugs or help image tumors.

Along with members of his lab, Dennis Discher, the Robert D. Bent Professor of Chemical and Biomolecular Engineering in the School of Engineering and Applied Science, has developed a “passport” that could be attached to therapeutic particles and devices, tricking macrophages into leaving them alone.  

The immune system’s macrophages act like border guards, binding to objects as they pass through the bloodstream and inspecting them to see if they belong there or not. One way a body’s cells identify themselves is via a protein on their membranes. When a macrophage binds to such a cell, this protein tells it, “don’t eat me.”

“We simulated and synthesized the simplest functional version of that membrane protein, and then stuck this ‘minimal peptide’ on the exterior of some plastic nanoparticles,” Discher says. “We then tested whether they would fool the immune system into thinking they were part of the body.”

Researchers performed the test of this minimal peptide’s efficacy in mice that were genetically modified so their macophages were similar to the human version. The team injected two kinds of nanoparticles, dyed different colors to show which had the peptide passport and which didn’t, and then measured how fast the mice’s immune systems cleared them.

“Just 20 minutes later, there was up to four times as many particles with the peptide,” Discher says.

 

Giving therapeutic nanoparticles a few more minutes before they are eaten by macrophages could be a major boon for treatments. Such nanoparticles might need to make several trips through the macrophage-heavy spleen and liver to find their targets, but shouldn’t stay in the body indefinitely. Other combinations of exterior proteins might be appropriate for more permanent devices, such as pacemaker leads, enabling them to hide from the immune system for longer periods of time.   

While more research is necessary before such applications become a reality, the relative simplicity of this passport molecule makes it an attractive component for future therapeutics.  

“It can be made cleanly in a machine,” Discher says, “and easily modified during synthesis in order to attach to all sorts of implanted and injected things, with the goal of fooling the body into accepting these things as ‘self.’”

Originally published on February 28, 2013