(La Jolla, Calif.) -- A collaboration led by the Burnham Institute forMedical Research has found that an antibody which binds to an unusualsugar molecule residing in the gut halts the inflammation seen inCrohn's disease and other intestinal inflammations. The antibody couldprove to be a promising drug target for these common chronic intestinaldisorders.
Professor Hudson Freeze, Ph.D., director of Burnham's glycobiologyand carbohydrate chemistry program, together with staff scientistGeetha Srikrishna, Ph.D., and other colleagues found that a naturally"tweaked" sugar chain normally present on white blood cells andintestinal cells plays a role in inflammation. In addition, the teamfound that an antibody produced in reaction to the sugar's presencecurbed intestinal inflammation induced in mice. These findings will bepublished in the October 15th edition of Journal of Immunology.
"We looked at a number of sugar-binding molecules that mayhave had a role in inflammation," said Freeze. "One of the sugar chainselicited an antibody response, so we wondered whether the antibodywould be able to block inflammation in mice. If so, this could haveimplications for inflammatory bowel disease, Crohn's, and also mighthelp combat other autoimmune inflammatory diseases, like arthritis."
The team identified a modified version of very common sugarsknown as N-linked glycans, which are found on the surface of whiteblood cells, as well as normal colon cells. These sugars are also foundin colon tissue of patients suffering from Crohn's disease.
The antibody was tested in a mouse model for Crohn's diseasecreated by transferring white blood cells with the capacity to inducesevere intestinal inflammation into mice with compromised immunesystems. "When administered 10 days after disease onset, the antibodywas able to reverse early symptoms of inflammation and halt furtherprogress of disease," said Srikrishna. The antibody also reduced theaccumulation of white blood cells armed to fight disease and inhibitedthe expression of cellular messengers (cytokines) typically seen ininflammation.
"There are a large number of signaling molecules that areactivated in inflammation," said Freeze. "Antibodies against thesesugar chain molecules, however, appear to curb inflammation beforecytokines associated with inflammation, like NF-kB and TNF, areactivated. The sugar chain must be used at an earlier stage, but in amore specific manner."
The sugar chain's specificity could be crucial to developingtreatments for Crohn's and other inflammatory disorders. The body'sinflammation response usually is a healthy reaction to harmful foreignagents; inflammation disposes of pathogens before they cause disease.Crohn's disease and other inflammatory bowel diseases, generally knownas auto-immune disorders, are a result of the body's immune systemoverreacting to non-existent pathogens, causing the body to attack itsown tissues. The optimal treatment would inhibit excessive inflammationlinked with disease, leaving normal immune function unaffected.
The antibody, Freeze suggests, could prove to be an effectiveremedy for autoimmune disorders if it can act specifically onhyperactive inflammation, while preserving the immune system. Remicade
"Our next step is to identify the molecular players in thebody's early inflammatory response in the intestine," said Freeze. Theteam is focusing on one particular molecule called RAGE (short forReceptor for Advanced Glycation End Products), which has beenimplicated in the pathology of inflammation, as well as cancer,diabetes and Alzheimer's disease. They are also determining the exactmolecular structure of the tweaked sugar chain, and will determine whatother molecules and receptors may interact with it.
Eventually, the researchers hope that they will have enoughpromising information to merit a clinical trial to test the antibody'seffectiveness. "Our antibody was developed for use in mice. We need to"humanize" it, make the antibody suitable for human consumption. Thiscould take some development, but the results could be very beneficial,"Freeze said.
Freeze's and Srikrishna's colleagues included ProfessorMitchell Kronenberg, Olga Turovskaya and Raziya Shaikh of the La JollaInstitute for Allergy and Immunology, Robbin Newlin of Burnham, DirkFoell of the University of Muenster, Germany, and Simon Murch of theUniversity of Warwick, England. The team's research is supported bygrants from the Broad Medical Research Program of The Eli and Edythe L.Broad Foundation and the National Institutes of Health.
The Burnham Institute for Medical Research, founded in 1976, is anindependent not-for-profit biomedical research institution dedicated toadvancing the frontiers of scientific knowledge and providing thefoundation for tomorrow's medical therapies. The Institute is home tothree major centers: the Cancer Center, the Del E. Webb Neuroscienceand Aging, and the Infectious and Inflammatory Disease Center. Since1981, the Institute's Cancer Center has been a member of the NationalCancer Institute's prestigious Cancer Centers program. Discoveries byBurnham scientists have contributed to the development of new drugs forAlzheimer's disease, heart disease and several forms of cancer. Todaythe Burnham Institute employs over 700, including more than 550scientists. The majority of the Institute's funding derives fromfederal sources, but private philanthropic support is essential tocontinuing bold and innovative research. For additional informationabout the Institute and ways to support the research efforts of theInstitute, visit www.burnham.org.
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