Growth Factors Associated with Neutrophil Function

February 8, 2007

CINCINNATI -- Antimicrobial functions of neutrophils are impaired in patients with pulmonary alveolar proteinosis, a rare condition, because of the auto-antibodies to growth factors that are associated with the disease, according to researchers here.

CINCINNATI, Feb. 8 -- Antimicrobial functions of neutrophils are impaired in patients with pulmonary alveolar proteinosis, a rare condition, because of the auto-antibodies to growth factors that are associated with the disease, according to researchers here.

Granulocyte-macrophage colony stimulating factor (GM-CSF) -- which is the target of auto-antibodies in the disease -- plays a central role in neutrophil function, according to Kanji Uchida, M.D., Ph.D., of Cincinnati Children's Hospital.

One implication is that monoclonal antibodies to GM-CSF might be useful to treat patients with chronic inflammatory disorders, Dr. Uchida and colleagues said in the Feb. 8 issue of the New England Journal of Medicine.

Pulmonary alveolar proteinosis has an occurrence rate of about one case per three million population. The disease is characterized by the accumulation in the alveoli of lipids, proteins, and carbohydrates derived from surfactants.

In most cases, the disease is a result of antibodies blocking the GM-CSF receptor of alveolar macrophages, causing a decreased clearance of the surfactant debris.

Nearly one in five (18%) of the deaths attributable to the disease is caused by opportunistic pathogens, Dr. Uchida and colleagues noted. Also, GM-CSF augments the anti-microbial functions of neutrophils through a process called "priming."

The researchers enrolled 12 patients with pulmonary alveolar proteinosis, six controls with cystic fibrosis, six controls with end-stage liver disease, and 61 healthy controls.

Analysis of neutrophils from the volunteers showed there were no differences in ultrastructure or cell-surface differentiation markers between the patients and the controls, the researchers said.

However, neutrophils from the patients had markedly weaker anti-microbial activity. Specifically:

  • The phagocytic index and phagocytic capacity were about 90% and 30% lower, respectively, than control neutrophils. The differences were significant at P<0.001.
  • Neutrophil adhesion capacity was reduced by about 75% (P<0.001).
  • Bacterial killing of Staphylococcus aureus was reduced by about 25% (P<0.007).

As well as the potential for antibody therapy, Dr. Uchida and colleagues concluded, the study also supported the notion of using GM-CSF to spur the immune system in cases of serious infection.

The study "raises important, provocative questions that beg to be pursued," said Claire Doerschuk, M.D., of Rainbow Babies and Children's Hospital in Cleveland.

Among them, she said in an accompanying Perspective article, is the problem of how the defects seen in the lab translate into effects in patients, especially because the patients in the study appeared to have immune systems that were coping with common day-to-day pathogens.

"The absence of repeated infections, particularly in the lungs, is surprising, given the magnitude of the neutrophil defects seen in vitro," she said.