LA JOLLA, Calif. , October 7, 2005
A collaboration led by the Burnham Institute for Medical Research has found that an antibody which binds to an unusual sugar molecule residing in the gut halts the inflammation seen in Crohn's disease and other intestinal inflammations. The antibody could prove to be a promising drug target for these common chronic intestinal disorders.
Professor Hudson Freeze, Ph.D., director of Burnham's glycobiology and carbohydrate chemistry program, together with staff scientist Geetha Srikrishna, Ph.D., and other colleagues found that a naturally "tweaked" sugar chain normally present on white blood cells and intestinal cells plays a role in inflammation. In addition, the team found that an antibody produced in reaction to the sugar's presence curbed intestinal inflammation induced in mice. These findings will be published in the October 15th edition of Journal of Immunology.
"We looked at a number of sugar-binding molecules that may have had a role in inflammation," said Freeze. "One of the sugar chains elicited an antibody response, so we wondered whether the antibody would be able to block inflammation in mice. If so, this could have implications for inflammatory bowel disease, Crohn's, and also might help combat other autoimmune inflammatory diseases, like arthritis."
The team identified a modified version of very common sugars known as N-linked glycans, which are found on the surface of white blood cells, as well as normal colon cells. These sugars are also found in colon tissue of patients suffering from Crohn's disease.
The antibody was tested in a mouse model for Crohn's disease created by transferring white blood cells with the capacity to induce severe intestinal inflammation into mice with compromised immune systems. "When administered 10 days after disease onset, the antibody was able to reverse early symptoms of inflammation and halt further progress of disease," said Srikrishna. The antibody also reduced the accumulation of white blood cells armed to fight disease and inhibited the expression of cellular messengers (cytokines) typically seen in inflammation.
"There are a large number of signaling molecules that are activated in inflammation," said Freeze. "Antibodies against these sugar chain molecules, however, appear to curb inflammation before cytokines associated with inflammation, like NF-kB and TNF, are activated. The sugar chain must be used at an earlier stage, but in a more specific manner."
The sugar chain's specificity could be crucial to developing treatments for Crohn’s and other inflammatory disorders. The body's inflammation response usually is a healthy reaction to harmful foreign agents; inflammation disposes of pathogens before they cause disease. Crohn's disease and other inflammatory bowel diseases, generally known as auto-immune disorders, are a result of the body's immune system overreacting to non-existent pathogens, causing the body to attack its own tissues. The optimal treatment would inhibit excessive inflammation linked with disease, leaving normal immune function unaffected.
The antibody, Freeze suggests, could prove to be an effective remedy for autoimmune disorders if it can act specifically on hyperactive inflammation, while preserving the immune system. Remicade™, an antibody-based drug currently used for Crohn's, works by inhibiting the cytokines that are summoned into action at a later phase of these diseases.
"Our next step is to identify the molecular players in the body's early inflammatory response in the intestine," said Freeze. The team is focusing on one particular molecule called RAGE (short for Receptor for Advanced Glycation End Products), which has been implicated in the pathology of inflammation, as well as cancer, diabetes and Alzheimer's disease. They are also determining the exact molecular structure of the tweaked sugar chain, and will determine what other molecules and receptors may interact with it.
Eventually, the researchers hope that they will have enough promising information to merit a clinical trial to test the antibody’s effectiveness. "Our antibody was developed for use in mice. We need to "humanize" it, make the antibody suitable for human consumption. This could take some development, but the results could be very beneficial," Freeze said.
Freeze's and Srikrishna's colleagues included Professor Mitchell Kronenberg, Olga Turovskaya and Raziya Shaikh of the La Jolla Institute for Allergy and Immunology, Robbin Newlin of Burnham, Dirk Foell of the University of Muenster, Germany, and Simon Murch of the University of Warwick, England. The team's research is supported by grants from the Broad Medical Research Program of The Eli and Edythe L. Broad Foundation and the National Institutes of Health.