Abstract
The principal targets for anti-chemokine therapy in inflammatory bowel disease (IBD) have been the receptors CCR9 and CXCR3 and their respective ligands CCL25 and CXCL10. More recently CCR6 and its ligand CCL20 have also received attention, the expression of the latter in enterocytes being manipulated through Smad7 signalling. These pathways, selected based on their fundamental role in regulating mucosal immunity, have led to the development of several therapeutic candidates that have been tested in early phase clinical trials with variable clinical efficacy. In this article, we appraise the status of chemokine-directed therapy in IBD, review recent developments, and nominate future areas for therapeutic focus.
Highlights
Effective immune surveillance involves the continuous patrolling of tissues by leukocytes able to respond to foreign antigens and thereby mount protective immune responses
More recently CCR6 and its ligand CCL20 have received attention, the expression of the latter in enterocytes being manipulated through Smad[7] signalling.These pathways, selected based on their fundamental role in regulating mucosal immunity, have led to the development of several therapeutic candidates that have been tested in early phase clinical trials with variable clinical efficacy
Clinical and endoscopic remission was associated with a greater reduction in CCR9 expression on circulating T cells and monocytes.[45]. This led to a subsequent double-blind placebo-controlled trial of leukapheresis to deplete CCR9+ monocytes in ulcerative colitis, which was associated with improvement in the endoscopic Mayo score compared with placebo (Table 2).[56]
Summary
Effective immune surveillance involves the continuous patrolling of tissues by leukocytes able to respond to foreign antigens and thereby mount protective immune responses This process is dependent upon the ability of leukocytes to reach tissues via the blood and traverse vascular beds in response to local signals presented by endothelial cells. Inflammatory chemokines are released by a wide range of cell types in response to pro-inflammatory cytokines, tissue injury, or contact with pathogens Such chemokines are secreted early in response to pathogen recognition receptor activation on epithelial, stromal, and immune cells,[2] to recruit the first wave of innate immune effectors including neutrophils, monocytes, natural killer (NK cells), and NKT cells. These findings suggest that expression of chemokines shape regional differences in immune composition along the normal intestine and determine the nature of inflammation in disease.[11,12,13,14]
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