"The gut normally is in a chronic state of low-grade inflammation that is beneficial," said Kagnoff. "This study shows that GM-CSF has a profound influence in the regulation of cells that determine whether the gut lives in peace with this inflammation, or becomes severely inflamed during infection. Any time that delicate balance is disrupted, all heck can break loose."

For this study, the researchers exposed mice bred to lack GM-CSF to a bacterial pathogen called C. rodentium, which leads to disease in rodents, by means similar to that caused by some severe diarrhea-causing E. coli in humans. Unlike pathogens that "nuke" their way right through the system, Kagnoff explained, these types of bacteria enter the colon and remain there, binding to the mucosal lining, settling in and colonizing. Once established, they populate, and their growing numbers lead to intestinal disease with severe diarrhea.

Compared with normal mice, the GM-CSF deficient mice were especially susceptible to persistent gut infection, experiencing more severe inflammation and disease that lasted over longer periods of time. Upon examination, the infected GM-CSF-negative mice were found to have very low levels of dendritic cells in the intestine. Administration of GM-CSF in these mice increased dendritic cell levels, corrected the immune response and decreased symptoms of infection.

The UC San Diego team concludes that GM-CSF deficiency leads to a breakdown in the immune response, and a decrease in numbers and viability of dendritic cells in the mucosal lining. In the absence of GM-CSF, the colonizing bacteria flourish, persist, cause significantly more inflammation, and can actually invade the host.

Kagnoff speculates that GM-CSF deficiency could be the reason that patients with Crohn's disease, a chronic inflammatory intestinal disease, have been shown to respond favorably to administration of GM-CSF, experiencing less inflammation and overall improvement following treatment.

Conversely, when GM-CSF is used to boost immune response in immunologically compromised patients (for example, patients who have undergone cancer treatment that has destroyed immune cells), a side effect can be overstimulation of the immune response leading to worsening of inflammatory diseases such as rheumatoid arthritis.

Kagnoff suggests that greater understanding of the role of GM-CSF in the human gut, and discovering whether diminished levels occur in patients with inflammatory bowel diseases like Crohn's, is a next step toward developing appropriate and effective therapies based on this protein.



Source-Eurekalert
THK