JAML & IBD
New Antibodies for Treating IBD
Approximately 1.4 million Americans today suffer from chronic inflammation of the digestive tract, clinically referred to as Inflammatory Bowel Disease. Complex diseases like Crohn's disease and ulcerative colitis are the primary ailments that fall under the umbrella diagnosis of Inflammatory Bowel Disease (termed IBD), typically causing symptoms of diarrhea, severe abdominal pain, and weight loss. Furthermore, inflammatory bowel diseases are often associated with additional conditions such as anemia, arthritis, and non-thyroidal illness syndrome. Unfortunately, there is no existing cure for inflammatory bowel diseases and the existing therapies to address the deleterious symptoms are reported to only benefit about 50% of the patients who use them.
A characteristic feature of IBD that is linked to patient symptoms is interaction between neutrophils, a type of white blood cell, and the lining of the intestine. Neutrophils serve as the body’s first immune response, attacking any invading alien bacteria or virus. However, in the case of inflammatory bowel diseases, neutrophils can behave as “a double edged sword.” While they serve the body in fighting off infection, they also damage the cells that line the intestine lining and create leaks that allow for passage of noxious intestinal contents into the body. In IBD, large scale neutrophil migration across the intestinal lining is often a recurrent phenomenon, leading to repeated and long term injury to the digestive tract, and delayed healing.
Charles A. Parkos, MD, PhD, formerly at Emory but currently at the University of Michigan School of Medicine, became interested in the mechanisms regulating migration of neutrophils across the intestinal lining and how it impacts individuals suffering from IBD. He has worked in the laboratory for years to identify and understand the molecules on neutrophils and intestinal lining cells that regulate passage of neutrophils and damage the intestinal lining. Parkos theorized that researchers could develop a therapy that would inhibit the migration of neutrophils across the intestinal lining, thereby preventing further damage to the digestive tract and facilitating the healing process.
Research done by Parkos and his team found that a neutrophil protein termed Junctional Adhesion Molecule Like protein (JAML) was involved in regulating the migration of neutrophils across the intestinal lining. He and his team also found that JAML molecules are shed from the surface of migrating neutrophils by enzymes, and the shed JAML subsequently bind to the intestinal lining cell receptor termed coxsackie-adenovirus receptor (CAR). They determined that JAML-CAR binding on the intestinal lining cells resulted in disruption of intestinal barrier and impeded wound repair, thereby enabling continued migration of neutrophils and delayed healing of injured tissue. However, the Parkos team found that anti-JAML antibodies could be used to inhibit JAML-CAR binding thereby reducing the damaging impact of neutrophil migration on the intestinal lining and promoting improved wound healing.
Parkos’ research on anti-JAML antibodies has the possibility to be translated to a clinically applicable treatment as “It has the potential to be a safer and possibly more effective alternative to the existing technologies and treatments. The current prescriptions and regimens for inflammatory bowel disease have many adverse side effects,” says Hyeon (Sean) Kim, licensing associate with Emory Office of Technology Transfer who is managing the licensing process of Parkos’ research and antibody development. Using anti-JAML antibodies would represent a new approach to treating IBD and might help induce remission in patients who have not responded to other conventional therapies. A few barriers to realizing the clinical application of this treatment remain in that Parkos’ research has not yet been extended from rodent models to humans. For human studies, anti-JAML antibodies would need to be humanized and used in a clinical trial. However, the success so far in experiments with rodents has generated optimism for this as a potential treatment in humans.
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