The human immune system is
complex, with multiple cell types stationed all over the body, ready to launch
an attack at the first sign of infection. However, there has been no clinical
tool to measure an immune response as it travels through the body. Such a tool
would be helpful in monitoring immune reactions to diseases such as cancer.
There have been cases in which the immune system successfully fights a tumor,
and others in which it stimulates tumor growth. Finding an effective drug to
treat cancer is also tricky, as many drugs actually suppress immune function,
causing infections that could be life threatening. Understanding how the immune
system reacts to certain cancers and drugs could help clinicians better
diagnose and treat patients.
Now scientists at UCLA’s Jonsson Comprehensive Cancer Center have developed an imaging probe
for positron emission tomography (PET) that tracks an immune response
throughout the body as it fights off cancer and infection. The scientists have
published the results of their study in the online edition of the journal Nature Medicine.
Advertisement
The
researchers’ goal was not to track specific kinds of immune cells, but to image
an immune response as a whole. To do that, they looked for a biological process
characteristic of most types of immune cells and developed a probe to measure
that process.
This story is only available to subscribers.
Don’t settle for half the story.
Get paywall-free access to technology news for the here and now.
“If we
wanted to measure a specific cell type, such as a T cell, we could have made a
marker and attached a radionucleotide,” says Owen
Witte, a researcher at UCLA’s Jonsson Comprehensive Cancer Center and the senior
author of the study. “But we wanted a more global monitor of multiple cell
types, and we came up with looking at a fundamental process called the DNA
salvage pathway.”
This
pathway is essentially a DNA recycling mechanism that immune cells use to
quickly and efficiently generate new cells. Most cells in the body can generate
cells from scratch, slowly building new cells from glucose and sugars. However,
in the presence of infection, immune cells have to act fast to make more cells
for defense. These cells recycle floating bits of nucleotides–the building
blocks of DNA–from food or dying cells, making more DNA that then churns out
new immune cells.
“During
infection, there’s a lot of turnover of DNA,” says Caius
Radu, an assistant professor of molecular and medical pharmacology at UCLA.
“This is essentially a mechanism to allow these cells to scavenge and make DNA
efficiently.”
Radu,
Witte, and their colleagues designed a probe to detect DNA recycling activity.
Specifically, the probe detects a particular enzyme involved in the first step
of DNA recycling within immune cells. Without this enzyme, the process cannot
proceed. The team designed an enzyme-detecting probe by modifying the molecular
structure of a common chemotherapy drug called gemcitabine. After a wide drug screening,
researchers found that this particular drug was effective in entering immune
cells. They then altered the compound slightly so that, in the presence of the
DNA recycling enzyme, the compound is phosphorylated and, in essence, stopped
in its tracks. If the enzyme is not present, the compound simply passes through
the cell.
Witte’s
team also attached a radiolabel to the probe that, during a PET scan, glows
when it enters a cell. The team then tested the probe in mice. Researchers
first injected mice with an oncogenic virus, which caused a tumor to develop.
This particular tumor is immunogenic, meaning that the immune system easily
recognizes it and quickly attacks. After the virus injection, the team then
injected the probe and performed PET scans.
“It’s basically like
a heat map, and if there’s a lot of immune cells, it’s red; if less, green; and
even less, blue,” says Radu. “It looks spectacular. You can see a three-dimensional
image of this mouse, and see these draining lymph nodes, which are close to the
tumor, and just see them lighting up.”
The team was able to
track the immune response as the tumor developed, and it saw that the areas
around the tumor lit up the most after 10 to 14 days, a typical length of time
in which an immune response can clear an infection.
Advertisement
Radu says that in
the future, clinicians may be able to use this new PET probe to image immune
responses, in addition to using other techniques, such as CT scans, that can
image tumors. In combination, these techniques may enable doctors to watch a
tumor shrink as the body’s immune system attacks so that they can determine the
effectiveness of different therapies.
Ronald
Germain, deputy chief of the immunology laboratory at the National
Institute of Allergy and Infectious Diseases, says that while the group’s
images are impressive, it is still not completely clear whether cells other
than immune cells are being imaged–an effect that could create an imprecise
picture.
“It’s not a
completely specific probe, so you’re not going to tell what type of cell is
present at a site, which can be very important in making a diagnosis going
forward,” says Germain. “However, there is a real need to develop ways to
assess immune responses without having to do biopsies, and this is one of
several approaches that could be used.”
The researchers are now looking to
develop a more specific probe, in addition to their general imaging probe. Radu
and his colleagues are systematically examining chemical structures to find
others that resemble gemcitabine. The team plans to test these compounds against each other
to see which may have greater sensitivity and specificity for detecting certain
kinds of immune cells.