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Dartmouth Medical School Dartmouth-Hitchcock Medical Center

Discoveries

A boost for the immune system

By Lauren Ware

A new study led by DMS immunologist Edward Usherwood, Ph.D., hints at a potential target for treating chronic viral infections in patients whose immune systems are compromised by an organ transplant, AIDS, or some other cause.

Other researchers have since reported the same phenomenon.

Researchers in Usherwood's lab examined mice missing CD4 T cells, a type of immune cell that is depleted in people with AIDS. The mice were infected with a virus specific to mice (MHV-68) that is similar to two viruses that can infect humans: the Epstein-Barr virus and human herpesvirus 8, both of which can be deadly in people with compromised immune systems.

Intact: They then examined the activity of another type of immune cell, CD8 T cells, which were intact and functioning in the mice. From previous studies, they knew that those cells respond to infection with MHV-68, which puzzled them. Why was the infection running rampant if the immune system was responding?

"Initially, the mice are okay," says Usherwood. "After six weeks, they lose control of the virus, a process we refer to as virus reactivation. We've been trying to understand why we see initial control of infection, followed by reactivation."

One possible explanation was that there was nothing wrong with the CD8 T cells, but there was some other factor hampering the ability of those cells to clear the infection. When the researchers took a closer look, they realized that levels of a cytokine, interleukin-10 (IL-10), were higher in the mice that experienced viral reactivation. The next step was to block IL-10 to see if the virus was better controlled without this inflammatory protein involved. The findings bore out this premise.

"What was particularly exciting for us was that if we blocked IL-10 at a late stage in the virus reactivation, we still saw better control of the virus," says Usherwood. "This leads us to think that targeting IL-10 might help patients who are suffering from these viruses."

Surprise: Finally, the group wanted to find out which cells were responsible for producing IL-10. To the researchers' surprise, they discovered that it was the CD8 T cells themselves. Since the publication of these findings in the Journal of Immunology, other researchers have reported the same phenomenon in other types of viral infections. "Even though the role of CD8 T cells in those infections is different, the fact that they make IL-10 is a common theme that has been under appreciated," says Usherwood.

Next, he and his collaborators plan to try to figure out what specifically may be present in a mouse without CD4 T cells that causes its CD8 T cells to produce IL-10, as that does not happen in mice with an intact immune system. "Ultimately," he says, "it would be nice to translate some of these studies into patients as well, to see if we can improve prognosis in patients by blocking IL-10."


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