Tracking the immune system in action

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.