Researchers from UCLA’s Jonsson Comprehensive Cancer Center have found that mice lacking an enzyme known as deoxycytidine kinase (dCK) have defects in their adaptive immune system, producing very low levels of both T and B lymphocytes, the major players involved in immune response.
The study finding, published in the current edition of Proceedings of the National Academy of Sciences, could have ramifications for treating autoimmune disorders, in which the body attacks itself, and possibly certain cancers of the immune system.
A drug, for example, could be developed to create lower levels of dCK in the body, thereby tamping down immune response, said senior study author Dr. Caius Radu, a UCLA assistant professor of molecular and medical pharmacology and a Jonsson Cancer Center researcher. Such a drug might also be effective in transplant patients to decrease the risk of organ rejection, he said.
The study is part of a long-term UCLA research project that has already resulted in the creation of a new probe for positron emission tomography (PET) scanning and the development of a non-invasive approach to observe chemotherapy at work in the body.
"It would be desirable to have drugs that can inhibit immune response when that response is detrimental and increase response when needed," said Radu, who is also a scientist with the Broad Stem Cell Research Center at UCLA. "We are now trying to identify drugs that inhibit or activate dCK in the hopes of testing them on certain diseases."
The dCK enzyme helps recycle the products of DNA degradation, allowing cells to efficiently replicate their DNA during cell division. Until now, the enzyme was thought to play a relatively minor role in providing cells the material for DNA replication. However, the current finding challenges that view and indicates that the enzyme plays a profound role in normal lymphocyte development.
Wayne Austin, a UCLA graduate student in molecular and medical pharmacology and first author of the study, said the research team expected to find widespread defects in development when they knocked out the dCK enzyme in the mice.
"Surprisingly, we found that the gene had a highly specific role in the development of organs crucial to a normally functioning immune system," he said. "Mice lacking the dCK enzyme have thymuses that are reduced in size 90-fold. That defect in thymus size resulted in mice having five to 13 times fewer lymphocytes circulating throughout the body."
The first discovery, published June 8, 2008, in the journal Nature Medicine, was the development of a new probe for PET scanning, which UCLA researchers created by modifying a common chemotherapy drug, allowing them to model and measure the immune system in action and monitor the body’s response to new therapies.
To create the probe molecule, called FAC, the researchers slightly altered the molecular structure of gemcitabine, a chemotherapy drug that is activated by dCK activity. They added a radiolabel so the cells that take in the probe could be seen during PET scanning.
The probe was based on a fundamental cell biochemical pathway called the DNA salvage pathway, which includes dCK. All cells use this biochemical pathway to different degrees, but in lymphocytes, which are the active players in the adaptive immune system, the pathway is activated at very high levels. Because of that, the probe accumulates at high levels in those cells, said Dr. Owen Witte, director of the Broad Stem Cell Research Center at UCLA and a Howard Hughes Medical Institute investigator.
The second significant finding, published Feb. 2, 2009, in Proceedings of the National Academy of Sciences, was the development of a non-invasive approach that may allow doctors to evaluate a tumor’s response to a drug before prescribing the treatment; this approach would enable physicians to personalize therapy to a patient’s unique biochemistry.
In that study, the UCLA team injected the FAC probe into mice that had developed leukemias which either had or did not have active dCK enzymes. After an hour, the team imaged the animals’ bodies with a PET scan, which operates like a molecular camera, allowing researchers to watch biological processes inside animals and people.
The PET scan offered a preview of how tumors would react to a specific therapy because the tumor cells that retained the probe also would be sensitive to chemotherapy drugs that are activated by dCK. If the cells didn’t absorb the probe, the tumor might respond more favorably to drugs that don’t need interaction with dCK to be effective.
The next step, outlined in the current study, was to determine what would happen without any dCK in the body at all and what ramifications that might have on certain diseases and their treatment.
The study was funded by grants from the National Cancer Institute/National Institutes of Health, the U.S. Department of Energy, the California Institute for Regenerative Medicine and the Dana Foundation.
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.