Durham, NC -- New insights into how the body eliminates dead
cells could lead to new approaches for treating conditions
including lupus and cancer, or for preventing infections
following trauma. Researchers at Duke University Medical Center
and the Durham
Veterans Administration Hospital say the specialized cells
that clear dead cells from the body have a much more
complicated -- and important -- role than scientists previously
understood.

Most human cells die through a process known as apoptosis,
or "programmed cell death," and are rapidly removed from the
body. In contrast, necrotic death occurs when cells die from
injury or disease. Increased amounts of DNA from dead cells can
be measured in the blood following a wide range of medical
events including trauma, heart attacks, blood clots to the lung
and chemotherapy treatment. Best known as the molecule of
heredity, DNA may perform other activities when it is released
from dead cells and appears in the blood.

Dead cells are cleared from the body by macrophages,
scavenger cells of the immune system. When macrophages do not
remove dead cells, the contents of the dead cells, including
the DNA, can trigger a response from the immune system, which
may eventually weaken the body and leave it susceptible to
infection, a common complication following trauma. For people
with lupus, the contents of the dead cells, especially DNA, may
form immune complexes with antibodies that can cause
inflammation that is not only painful but also damaging to
organs such as the kidneys.

Scientists have long believed DNA from dead cells is present
in the bloodstream only when macrophages become overwhelmed
with more dead cells than they can remove. In other words, the
contents of the dead cells "overflow" from the macrophages.
David Pisetsky, M.D., professor of medicine and chief of the
division of rheumatology and immunology at Duke University
Medical Center, and colleagues recently discovered this may not
be the case. The Duke team reports their findings, from studies
funded by the Alliance
for Lupus Research, in the Sept. 15, 2003, issue of the
journal Blood.

The Duke team was surprised while performing a series of
experiments to determine whether administration of a large
amount of apoptotic and necrotic cells would cause an increased
amount of DNA to appear in the blood of mice. In their first
experiment, the researchers found that injecting mice with a
large quantity of dead cells indeed resulted in increased DNA
in the mice's blood.

In the next experiment, they engineered mice lacking
macrophages and injected the mice with a large quantity of dead
cells. Because macrophages were not present to remove the dead
cells, the team expected to find all of the dead cell DNA in
the bloodstream. Instead, they found none.

"This result was totally unexpected, and caused us to step
back and consider how the macrophages function to remove cell
waste," Pisetsky said. Without macrophages, his team eventually
theorized, dead cells cannot be broken down efficiently enough
for DNA to appear in the bloodstream at a detectable level.
Cells not processed by macrophages and removed from the body
may accumulate and cause inflammation.

"What we hypothesize is that uptake by macrophages is not
just part of the process, but is absolutely crucial to the
appearance of DNA from dead cells in the blood," Pisetsky said.
"The macrophages can't be bypassed by the dead cells, even if
there is more cell DNA than they can process."

According to the researchers, this would mean that DNA from
dead cells appears in the blood only when macrophages "fill" to
capacity and perhaps then die and release all of their
contents, including the DNA from the engulfed cells.

"If we are indeed correct," said Pisetsky, "then macrophages
play a much more crucial role than previously thought. This
finding could potentially have implications for the treatment
of lupus and other inflammatory conditions."

The researchers said macrophages might be reinforced to
clear larger amounts of dead cells, thus reducing the amount of
DNA and other cellular molecules that pass into the blood and
cause inflammation. "This mechanism could apply not only to
lupus, but also to conditions like cancer, where we often
intentionally kill large numbers of cells with chemotherapy and
other treatments," said Pisetsky.

Likewise, bolstering macrophages could help prevent the
immune response following trauma, and thereby help the body
maintain normal levels of immunity to prevent subsequent
infection.

The findings also may lend new insight to the function of
current lupus treatment with corticosteroids, the researchers
said. "Corticosteroids are one of the standard treatments for
inflammation in lupus. We've always thought the steroids worked
by reducing inflammation, but it may be that, in fact, they
strengthen the macrophages and prevent the inflammatory
response from beginning," said Pisetsky.

Joining Pisetsky in this research were Ning Jiang, M.D., of
the division of rheumatology and immunology at Duke University
Medical Center, and Charles Reich of the division of
rheumatology and immunology at the Durham Veterans
Administration Hospital.