A commonly used PET-scanning probe and a new probe developed by UCLA researchers reveal different functions in diverse cells of the immune system and, when used in combination, provide a much clearer picture of an immune response in action, according to a new UCLA study.
In addition to monitoring the extent and cellular composition of an immune response, the probes — FDG, which measures cellular glucose metabolism, and the UCLA-developed FAC, which measures the activity of a distinct biochemical pathway — may be useful in evaluating therapies that target different cellular components of the immune system, said the study's senior author, Dr. Owen Witte, a UCLA professor of microbiology, immunology and molecular genetics and a Howard Hughes Medical Institute investigator.
"We demonstrated with this study that each probe targets different cells in the immune system with a high degree of specificity," said Witte, who is also director of the UCLA Broad Stem Cell Research Center and a researcher at UCLA's Jonsson Cancer Center.
"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," he said. "When tested sequentially, the combined information from the scans using the two probes gives you a better status of immune response."
The study, with lead author Evan Nair-Gill, a student in UCLA's Medical Scientist Training Program, was conducted on mice bearing virally induced sarcomas. The article is currently available in the early online edition of the Journal of Clinical Investigation. Testing the probes in humans is the next step, the researchers say.
The scans provide clues to how the immune system works — for example, in response to cancer or autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis, Witte said. They also could be used to see how therapies, such as vaccines and monoclonal antibodies meant to stimulate an immune response, are functioning within the body of a patient.
"This could give us another way to measure the efficacy of certain drugs," Witte said. "With some drugs, you could measure a change in the immune response within a week."
If the drugs are working, Witte said, doctors could stay the course; if not, the therapy could be discontinued, sparing the patient months of exposure to an ineffective drug.
The researchers say they plan to test the two probes in humans with a range of diseases, including cancer and autoimmune disorders, to confirm the work.
The university licensed the FAC probe to Sofie Biosciences, a startup company owned in part by Witte and other UCLA faculty members. Researchers created the small molecule by slightly altering the molecular structure of one of the most commonly used chemotherapy drugs, gemcitabine. They then added a radiolabel so the cells that take in the probe can be seen during positron emission tomography (PET) scanning.
The probe measures the activity of a fundamental cell biochemical pathway called the DNA salvage pathway, which acts as a recycling mechanism that helps with DNA replication and repair. All cells use this biochemical pathway to different degrees. But in lymphocytes and macrophages that are proliferating during an immune response, the pathway is activated to very high levels. Because of that, the probe accumulates at high levels in those cells, Witte said.
Partial support for this work came from a tools-and-technology grant from the California Institute for Regenerative Medicine.
UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2009, the Jonsson Cancer Center was named among the top 12 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 10 consecutive years.
The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA's stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multidisciplinary, integrated collaboration among scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed toward future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine at UCLA, UCLA's Jonsson Cancer Center, the UCLA Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.
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