Collaborating with colleagues at the University of California, San Diego, the Johns Hopkins researchers have used their discoveries to develop a new computer model that could help produce medications for immune system-related ailments including septic shock, cancer, lupus and rheumatoid arthritis.
Their findings, which focused on how a large protein molecule called tumor necrosis factor, or TNF, triggers an immune response, were reported in the February issue of the Journal of Biological Chemistry.
"We were surprised by how sensitive cells were to small amounts and brief exposures to TNF," said Andre Levchenko, a Johns Hopkins assistant professor of biomedical engineering and senior author of the paper. "Our analysis may help drug companies solve problems with the regulation of immune response levels, and do it in a smart way."
In their journal article, Levchenko and his colleagues reported several important new discoveries about this cellular signaling system. "You could think of the TNF molecule, which sounds the alarm, as a very weak radio transmitter. It moves very slowly as it carries its warning message to neighboring cells, so it is unable to send that message over long distances," Levchenko said. "However, we discovered that the cellular pathways that pick up this signal act like extremely sensitive radio receivers. They can pick up the alarm message from exposure to even a very small amount of TNF. This turns out to be a very smart strategy on the part of the cells."
He explained that a pricked finger usually generates a very localized fight against infection, involving only nearby cells. If TNF's signal was strong enough to set off an immune response involving the entire body, the result could be a high fever and septic shock. "We've developed a better understanding of why the fight against a local infection stays local," said Raymond Cheong, a graduate student in Levchenko's lab and lead author of the journal article.
The researchers also found that as TNF's warning message travels from the surface of a cell to its nucleus, it receives critical help from a molecule called Inhibitor of KappaB Kinase, or IKK. "IKK filters and interprets the warning message," said Cheong, who is an M.D.-Ph.D. candidate in the Johns Hopkins School of Medicine. "It carefully controls the level of the immune system's response."
That makes IKK a very promising target for new medications designed to boost or suppress the immune system, the researchers said. An overactive immune system, for example, can set off the excessive inflammation associated with rheumatoid arthritis and lupus. In addition, some cancersare more likely to grow where inflammation occurs. These ailments might be helped by a drug that curbs inflammation by reducing the sensitivity of IKK. Still other diseases that are characterized by a weak inflammatory response might be helped by a drug that makes IKK even more sensitive to infection messages.
The researchers believe their computer model of this cellular alarm system, which was refined through lab testing, should be a great help to medication makers. "Models like this are a wonderful tool for experimental drug testing," Levchenko said.
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