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Animation Description:
Animation reviews novel agents for the treatment of Crohn's Disease that target key biologic steps in the inflammatory process.
Crohn's disease is an autoimmune disorder characterized by chronic transmural inflammation
of the gastrointestinal tract.
Inflammation can be seen anywhere along the GI tract but is most often found in the terminal ileum and cecum of the ascending colon.
In Crohn's disease, there is a disruption to the normal physiologic balance between immune activated gastrointestinal inflammation and the down regulation of the inflammatory response, thus resulting in chronic inflammation.
Leukocyte recruitment is a crucial step in the inflammatory process and involves a cascade of events that consist of the sequential action of molecular signals and adhesion molecules. Blocking any of these steps reduces inflammation by preventing leukocyte accumulation at the site of inflammation.
Novel biologic therapies for Crohn's disease are available that target key biologic steps in the inflammatory process such as tumor necrosis factor-alpha (TNF-alpha) and alpha-4 (alpha4) integrin subunits.
TNF-alpha is a transmembrane protein produced by macrophages and T-cells. It is released from the membrane of activated cells in response to endotoxins, IL-1, and TNF-alpha.
The matrix metalloproteinase, TNF-alpha converting enzyme (TACE), is responsible for cleaving TNF-alpha from the membrane. TNF-alpha binds to TNF receptors on target cells, such as the endothelium.
Through endothelial activation, TNF-alpha mediates the upregulation of adhesion molecules, such as E-selectin and VCAM-1, which leads to leukocyte migration and subsequent leukocyte accumulation at the site of inflammation.
Anti-TNF-alpha agents are monoclonal antibodies that help to reduce inflammation by binding to TNF-alpha and preventing receptor contact, therefore blocking the pathway to leukocyte migration.
The alpha4beta1 and alpha4beta7 surface integrins are selective adhesion molecules that bind to the endothelial cell receptors: VCAM-1 and MAdCAM-1 respectively, facilitating leukocyte adhesion and subsequent migration to areas of inflammation.
Anti-alpha4 integrin agents are monoclonal antibodies that bind to the alpha4 subchain and block leukocyte adhesion, thus reducing leukocyte trafficking.
These novel agents are advancing the standard of care in Crohn's disease. In select patients these drugs are now being used with the goal of altering the course of disease and bringing about mucosal healing.
