Using two positron emission tomography (PET) probes, one common one and one they developed themselves, researchers in the US found they can get a much clearer picture of what happens at the cellular level during an immune response.

You can read about the study, led by Dr Owen Witte, a professor of microbiology, immunology and molecular genetics and a Howard Hughes Medical Institute investigator at the University of California, Los Angeles (UCLA) in the 17 May early online edition of the Journal of Clinical Investigation.

Witte, who is also director of the Broad Stem Cell Research Center at UCLA and a researcher at the university’s Jonsson Cancer Center, said in a statement that:

“We demonstrated with this study that each probe targets different cells in the immune system with a high degree of specificity.”

For this study they used mice, but they said testing in humans is the next step.

Witte and colleagues measured two different pathways: one using a common PET probe to measure activity in a cellular glucose metabolism pathway, and the another using a PET probe they developed themselves to measure a pathway involved in recycling and repair of nucleotides (building blocks of DNA and RNA).

The first pathway uses FDG (short for 2-fluorodeoxyglucose) for glycolysis, and the second uses FAC (short for 2-fluoro-d-(arabinofuranosyl)cytosine) for deoxycytidine salvage.

“When cells are activated to do their job as an immune cell, the FDG probe is good at recognizing the subset of activated macrophages, while the FAC probe is good at recognizing the activated lymphocytes, as well as the macrophages,” explained Witte.

“When tested sequentially, the combined information from the scans using the two probes gives you a better status of immune response,” he added.

To make the FAC probe, Witte and colleages slightly altered the structure of gemcitabine, a commonly used chemotherapy drug, and added radioisotope labels so the cells that take up the probe show up on the PET scan.

For the study, Witte, lead author Evan Nair-Gill, a student in UCLA’s Medical Scientist Training Program, and colleagues used mice with sarcomas that had been induced with a virus.

They isolated innate and adaptive immune cells from the cancerous tissue of the mice and measured their ability to accumulate FDG and FAC.

They found that FDG had a different pattern to FAC. FDG accumulated to the highest levels in innate immune cells, but FAC accumulated primarily in CD8+ cells “in a manner that correlated with cellular proliferation”, they wrote.

The researchers concluded that this shows that:

“Innate and adaptive cell types differ in glycolytic and deoxycytidine salvage demands during an immune response and that these differential metabolic requirements can be detected with specific PET probes.”

Using paired scans like this gives a much clearer picture of how the immune system works in response to challenges like cancer, autoimmune diseases, rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis, said Witte.

He suggested that as well as being able to monitor the extent and composition of an immune response at the cellular level, the two probes could be used to evaluate therapies (eg vaccines and monoclonal antibodies) that target different cellular components of the immune system.

“This could give us another way to measure the efficacy of certain drugs,” said Witte.

“With some drugs, you could measure a change in the immune response within a week,” he added.

Doctors and patients then have a chance to see much earlier in the treatment whether a drug is working or not, saving patients months of exposure to drugs that don’t work.

Witte and colleagues are now planning to test the two probes in humans with disease like cancer, and autoimmune disorders.

“PET probes for distinct metabolic pathways have different cell specificities during immune responses in mice.”
Authors: Evan Nair-Gill, Stephanie M. Wiltzius, Xiao X. Wei, Donghui Cheng, Mireille Riedinger, Caius G. Radu, Owen N. Witte.
J Clin Invest., Published online May 17, 2010
DOI:10.1172/JCI41250.

Source: UCLA.

Written by: Catharine Paddock, PhD