Dec. 20, 2004 STANFORD, Calif. - Seeking to find a way to lessen patients' vulnerability to deadly infections following chemotherapy, researchers at the Stanford University School of Medicine have figured out a way to boost the immune function in animals following such treatments. Their approach involves increasing the pool of cells that give rise to neutrophils, a type of white blood cell that is critical for fighting bacterial and fungal infections but is particularly ravaged by chemotherapy.
"Our approach hadn't been studied before, which is interesting because it's a very straightforward concept," said study leader Janice "Wes" Brown, MD, assistant professor of medicine in the divisions of bone marrow transplantation and infectious diseases.
The team reported that an infusion of a type of bone marrow cell from a donor mouse yielded significantly more neutrophils in the laboratory mice a week after a dose of a typical chemotherapeutic agent. The procedure also increased the animals' ability to fight a deadly fungal infection. The team's findings appear in the Dec. 15 issue of the journal Blood.
The condition in which neutrophils are lacking is known as neutropenia. It is the leading cause of death among cancer patients that is not related to their tumor. Because of the seriousness of the condition, doctors will reduce chemotherapy doses if they notice an infection developing in the early phases of the disease, which can decrease the efficacy of the cancer treatment. Additionally, resulting fevers and infections during neutropenia must be fought with antibiotics and antifungals, which can be toxic and spur resistance.
"Clinicians see neutropenia all the time and follow the usual protocols of antibiotics and antifungals," said Brown, who is the sole infectious disease consultant for the bone marrow transplantation division. "We thought, 'Why are we just waiting for the neutropenia to resolve or for the patient to develop an infection? Why don't we try to prevent it?'"
Brown's group sought to circumvent the problem by adding more of one type of cell-the myeloid progenitor. This cell can follow several routes of development. They can turn into red blood cells, platelets or neutrophils. Using the progenitor cells seems to be more effective than using mature neutrophils, the researchers said.
The researchers gave a single dose of the chemotherapeutic agent 5-fluorouracil to mice, and the next day gave some of the mice an infusion of purified myeloid progenitor cells. They then exposed all of the mice to a fungus that had killed a chemotherapy patient.
One week later, researchers found that the mice treated with the cellular boost had significantly more neutrophils in their spleens, blood and bone marrow than the ones that had not received the infusion. More than half of the treated mice survived, while only a third of the ones without it did.
The study follows on the heels of earlier work by Brown and her team on the effectiveness of this strategy following radiation treatment. That earlier research also showed that the use of myeloid progenitors improved the ability of the mice to survive exposure to a fungus as well as a bacterial infection.
Brown's group is now looking at combining cellular infusion with clinical strategies of using antifungals or growth factors to stimulate increases in neutrophil numbers. So far in animal studies, she said, it looks like the therapies merge well and will add together for more effective protection.
Brown noted that the use of the myeloid progenitor cells may be preferential to using mature neutrophils for at least two reasons. First, the myeloid progenitors give rise to a broader spectrum of cells, including platelets and red blood cells, which is helpful in restoring normal blood functions. And second, the myeloid progenitors can survive freezing and thus can be more readily available for treatment. By contrast, the mature cells must be infused immediately into a patient following the collection period, which typically takes four hours per session.
"And the good thing is that we have readily isolated these cells from blood samples from donors and patients," Brown said, "so collection of these cells for clinical use doesn't require the development of new technology."
Brown's team at Stanford included Andrew BitMansour, who is now a graduate student at University of Texas Southwestern Medical Center; Thai Cao, MD, clinical instructor in the division of bone marrow transplantation; life science research assistant Sumana Sashidar; and Stephanie Chao, who is now a medical student at UC-San Francisco. Their study was funded by grants from the National Institutes of Health, Amy Strelzer Manasevit Scholars Program, ASBMT/Roche New Investigator Award, the Center for Clinical Immunology at Stanford and an unrestricted educational grant from Fujisawa Healthcare, Inc.
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