Aug. 25, 1999 (Blacksburg, Va., August 24, 1999) -- At Virginia Tech, Prakash and Mitzi Nagarkatti have discovered a step in dioxin toxicity that may enable them to develop diagnostic, treatment, and even prevention methods in the future. They received an $816,000 four-year grant from the National Institutes of Health this spring that will enable them to pursue research aimed at discovering ways to prevent the attachment of a killer molecule to other cells, or even prevent its activation by dioxins.
Dioxin is a highly toxic environmental pollutant formed as a byproduct during the manufacture and bleaching of paper. It is one of the most biologically potent chemicals, a member of the family of compounds known as halogenated aromatic hydrocarbons (which includes PCBs) that are found in herbicides, pesticides, automobile exhausts, and municipal and industrial waste, according to Prakash Nagarkatti, professor of biology.
Nagarkatti and Mitzi Nagarkatti, a professor in the Virginia-Maryland Regional College of Veterinary Medicine, have already shown in their lab that dioxin kills the immune cells using a unique process called apoptosis. "In this process," Prakash Nagarkatti said, "the cells commit suicide by destroying their own DNA." The Nagarkatti lab has identified a protein molecule involved in such killing, and dioxin treatment seems to activate the molecule, resulting in the killing of the immune cells.
The molecule, CD-95 ligand, is a member of a family of proteins that occurs naturally in the body, and its function is to kill cells that are not needed. The Nagarkattis were the first to demonstrate that the dioxin turned on the CD-95 ligand molecule in a way that it could not be turned off, and that the molecule then killed immune cells.
"It remains to be seen whether other related environmental pollutants use a similar mechanism to cause toxicity," Nagarkatti said. In the research funded by the latest NIH grant, the Nagarkattis will use antibodies to the toxic molecule. The antibodies are molecules that can spcifically recognize the toxic molecule and prevent it from attaching to and killing other cells.
The existing antibodies are protein molecules, produced by the immune cells, that are able to neutralize the toxicity. "Normally we don't produce antibodies against our own molecules," Nagarkatti said. So they will try to take the human killer molecule and inject it into mice and produce antibodies because the mice immune system can recognize the killer molecule as a toxin. Then the antibody can be used in humans because the human body's immune system will recognize it as not belonging and will destroy it or keep it from attaching to other cells. Graduate students Iris Camacho, Lisa Hudson, and Ahmet Zeytun are helping in the current research.
Now that the Nagarkattis know the mechanism by which dioxin becomes toxic, they can aid in finding ways to diagnose, treat, and prevent dioxin's damage in the body. They can help with diagnosis by developing tests to determine whether a person has been exposed to a high level of dioxin (by determining if the killer molecule shows up in high levels). They can help develop treatments for people who have been exposed by developing antibodies, and they can determine the safe levels of the dioxin to help prevent toxicity in the first place.
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