Treatment of Inflammatory Bowel Disease with Biologics

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Tissue injury in Crohn’s disease (CD) and ulcerative colitis (UC) occurs in areas
heavily infiltrated with subsets of activated lymphocytes that produce an array of
inflammatory mediators [ 1 ]. These cells are recruited from the bloodstream as a
result of increased expression of adhesion molecules on the intestinal vascular
endothelium and integrins on lymphocytes and excessive production of chemokines
within the inflammatory microenvironment [ 7 ]. Evolution in our understanding of
the involvement of T-lymphocyte biology orchestrating gut inflammation has led to
the development of several agents directed against trafficking of effector T lympho-
cytes towards the gut mucosa. In this chapter, we discuss the available data on
agents that block integrins or adhesion molecules and combat gut inflammation.

The Biological Basis of Leucocyte Trafficking in IBD

Active IBD is characterised by the recruitment of leucocytes into the gastrointestinal
mucosa in a highly coordinated, multistep process [ 8 ]. As they travel at high speed
through the vascular tract, a highly coordinated sequential adhesion pathway is activated,
consisting of tethering, rolling, activation, adhesion and migration through the vascular
wall [ 8 , 9 ] (Fig. 16.1). The capture of T cells to the endothelium is mediated through the
interaction between selectins (L-selectins expressed by local sites and P- and E-selectins
on the endothelium) which act as ligands allowing local sites to slow their speed in the
vascular flow and then roll through the vascular wall moving from one selectin to another.
Infiltrating leucocytes perpetuate the inflammatory process through the secretion of pro-
inflammatory cytokines, further endothelial cell activation and up-regulation of adhesion
molecules with enhancement of inflammatory cell recruitment [ 9 ]. Adhesion molecules
belong to the integrin family (leucocyte cell-surface adhesion molecules), which allow
them to stop rolling and start migration through the vascular wall [ 8 , 9 ].

Tethering

L-selection

receptor

chemokines

Chemokine-

Rolling Integrin activation Firm adhesion Diapedesis

Selection-ligand

MadCAM-1

MadCAM-1

α 4 β 7 -integrin

CCX282-B

PF-00547659

Natalizumab,

Vedolizumab,

Etrolizumab

Fig. 16.1 Mechanism of action of adhesion molecules in the intestinal endothelium and their
blockage by anti-adhesion drugs

J.K. Limdi and F.A. Farraye