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Tuesday, June 10, 2008

Tracking the Immune System

A new imaging probe illuminates the body's defense system as it fights cancer.
Immune reaction: A new PET imaging probe illuminates immune cells as it attacks infection within a mouse. Green areas indicate the presence of active immune cells.
Credit: UCLA's Jonsson Comprehensive Cancer Center

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.

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.

"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.

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.

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