SCIENCE sciencemag.org
of the neutrophil elastase inhibitor alve-
lestat to patients with the lung condition
bronchiolitis obliterans. The ailment strikes
a significant percentage of people who re-
ceive hematopoietic stem cell transplants
during cancer treatment, developing when
immune cells from the transplant attack the
recipient’s own tissue. Neutrophils swarm
into the lungs and may encourage scar tis-
sue to build up in the bronchioles, the lungs’
smallest airways, which can cause them to
clog. For transplant recipients, bronchiol-
itis obliterans is like having an unstoppable
asthma attack, Pavletic says.
He adds that alvelestat probably won’t re-
verse bronchiolitis obliterans, but by block-
ing neutrophil elastase, it could stop the
disease from getting worse. “Even a mar-
ginal improvement could lead to a major
improvement in lung function.”
Researchers are further along in evaluat-
ing a way to target neutrophils to treat a
rare autoimmune disease in
which the immune system
produces antibodies against
its own neutrophils—a condi-
tion known as antineutrophil
cytoplasmic autoantibody
(ANCA) vasculitis. The anti-
bodies glom onto the cells,
which then get stuck in small
blood vessels and release their
chemical load, leading to in-
flammation that can cause
kidney damage and other
problems. In the first year after diagnosis,
patients with the disease are nine times
more likely to die than people in the general
population, and current treatments, which
include steroids and immune-suppressing
drugs, are one reason for this high mortal-
ity, notes nephrologist David Jayne of the
University of Cambridge.
In a recent trial involving 331 ANCA
vasculitis patients, Jayne and colleagues
tested the experimental drug avacopan,
which stymies C5a, a protein in the blood
that helps spur neutrophils to release their
inflammation-promoting contents. The re-
sults of the phase III trial, announced late
last year, revealed that the drug was about
20% more likely to produce remissions af-
ter 1 year than steroids were. It improved
patients’ kidney function and was also less
harmful than steroids. Jayne predicts ava-
copan will be approved by the U.S. Food
and Drug Administration and “will be a
complete replacement for steroids” in treat-
ment of ANCA vasculitis.
Although many efforts to target neu-
trophils aim to inhibit them, Sapey and
her colleagues believe rejuvenating neu-
trophils could help boost immune func-
tion in older people. An existing drug, the
cholesterol-lowering medication simvas-
tatin, may do the job, they found. Simvas-
tatin had caught their attention because
some evidence suggested people taking it
for high cholesterol are less vulnerable to in-
fections. When the team members exposed
neutrophils to simvastatin in the lab, they
found it boosts the cells’ migration accuracy
and improves their performance in other
ways. And in a phase II trial of the drug in
62 older people with bacterial pneumonia
and sepsis, Sapey and her colleagues deter-
mined that adding simvastatin to the nor-
mal treatment regimen reduced the severity
of infections and allowed the patients to
spend more time out of the hospital over
the next year.
“That was highly unexpected and very ex-
citing,” says Sapey, whose team reported the
findings last year in the American Journal
of Respiratory and Critical Care Medicine.
They are now planning a larger study of the
drug, and she says it might
also work against other com-
mon bacterial problems in
the elderly, such as urinary
tract and skin infections.THE THERAPEUTIC possibili-
ties are likely to broaden as
researchers learn more about
the biology of neutrophils.
The cells have traditionally
been seen as the immune sys-
tem’s cannon fodder—simple,
expendable killers. But neutrophils, it turns
out, aren’t so simple after all. “They are not
merely the cells that clear microbes from in-
fected sites,” Papayannopoulos says.
“The most exciting thing is that the
cells are much more heterogeneous than
we thought,” says immunologist Leo
Koenderman of University Medical Center
Utrecht in the Netherlands. With tech-
niques such as single-cell RNA sequencing,
researchers have discovered that neutro-
phils come in multiple varieties. And their
properties can vary by time of day. In hu-
mans, the cells are much more aggressive
toward pathogens at night than during
daylight hours, and they crank up different
genes depending on the hour.
This diversity enables the cells to specialize
and take on more tasks than researchers ex-
pected. Some neutrophils have moved up the
chain of command and help control the activ-
ity of other immune cells. For example, they
can either spur T cells to attack pathogens
or rein them in. The cells can also take on
alternative roles when they enter damaged
tissue. If they encounter microbes, they be-
come fighters. But if an injury is not infected,
they become healers. Chemicals they release
can stimulate new blood vessels to form andspark the production of replacement cells.
Intravital microscopy, which reveals the
movements of cells within the body, sug-
gests the lives of these immune cells are
eventful. Researchers long assumed that
once neutrophils left the bloodstream and
moved into infected or injured tissues, they
would eventually self-destruct, allowing the
inflammation at the site to clear. But sev-
eral microscopy studies have revealed more
complex migrations. In a 2011 study, for
example, Anna Huttenlocher of the Univer-
sity of Wisconsin, Madison, and colleagues
tracked neutrophils in zebrafish that had
wounds on their fins. The scientists found
that individual neutrophils moved into and
out of a wound several times before eventu-
ally departing for good.
Now, Ferro and his colleagues are trying
to interrupt one leg of the neutrophils’ jour-
ney. In patients with heart disease, the cells
worm into the fatty plaques lining the coro-
nary arteries. There, they release chemicals,
including neutrophil elastase, that may
make these plaques more likely to fracture
and spawn blood clots, which can trigger
heart attacks.
The drug candidate that Ferro and col-
leagues are testing in people with serious
plaques, AZD5069, blocks CXCR2, the re-
ceptor that helps neutrophils navigate to
infected and inflamed locations. In animal
tests, the compound deters neutrophils
from entering sites of inflammation.
Death rates from cardiovascular diseases
have been dropping for decades in many
countries thanks to lifestyle changes, such as
a decline in smoking, as well as drugs that
lower cholesterol and combat blood clot-
ting. But heart disease still kills more than
600,000 people in the United States every
year. “There’s clearly a big gap that remains
in therapy for these patients,” Ferro says.
Within a couple of years, he hopes to know
whether deflecting neutrophils can help.
Some researchers remain skeptical that
the current crop of experimental neutrophil-
targeting drugs will work outside certain
rare diseases. The cells have multiple re-
dundant pathways that control their ac-
tivity, Koenderman notes. A neutrophil “is
extremely robust,” he says. The idea that a
single drug could correct its misbehavior “is
pretty naïve,” he says.
However, researchers are already de-
veloping new approaches, including DNA-
destroying enzymes that might slice up
NETs and prevent blood clots. And as sci-
entists dig deeper into the cells’ biology,
they may find new ways to keep these im-
mune soldiers in check, Fessler says. “There
is hope that with increasing understanding
of neutrophils, we will have more sophisti-
cated approaches down the line.” j“Neutrophils
are linked to
many diseases
that blight
our population.”
Elizabeth Sapey,
University of Birmingham6 MARCH 2020 • VOL 367 ISSUE 6482 1069
Published by AAAS