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Integrins involved in T-cell migration are leucocyte function-associated antigen 1
(LFA-1 or α 2 β2) and the two α4 integrins (α 4 β1 and α 4 β7). The subunit α is implied
in the specificity and subunit β in signalling pathways [ 10 ]. These integrins bind to
specific ligands at the endothelium called addressins or adhesion molecules. LFA-1
is expressed on neutrophils and interacts with ICAM-1, which is expressed on leuco-
cytes, dendritic cells, fibroblasts, epithelial cells and endothelial cells [ 8 , 11 ]. Integrin
α 4 β1 is expressed on most leucocytes but not neutrophils and interacts with VCAM-

1. The α 4 β7 integrin is expressed on lymphocytes in gut-associated lymphoid tissue
   and interacts with MAdCAM-1. This ligand is expressed on endothelial venues in the
   small intestine and the colon, especially in the Peyer’s patches. The interaction
   between α 4 β7 and MAdCAM-1 activates migration of lymphocytes to Peyer’s
   patches; this interaction is gut-specific [ 8 , 11 ]. Finally, αEβ7 is a member of the β 7
   integrin family, expressed only in mucosal intra-epithelial T lymphocytes, that binds
   selectively to E-cadherin on epithelial cells, expression of which is elevated in UC
   and CD in the active phase of disease [ 12 ]. Inhibition of leucocyte trafficking to the
   gut mucosa during the inflammatory process is now a major therapeutic target, fol-
   lowing on from anti-cytokine agents [ 13 ]. The predominant targets of this group of
   biological agents are the integrins α 4 β1, α 4 β7 and α 2 β2, which interact with VCAM-
   1, MAdCAM-1 and ICAM-1, respectively [ 13 ]. They include the monoclonal anti-
   bodies natalizumab (anti-α4 integrin), vedolizumab (anti-α 4 β7 integrin), AMG 181
   (anti-α 4 β7 integrin), etrolizumab (anti-β7 integrin targeting both α 4 β7 and αEβ 7
   integrin). Other molecules include AJM300 (inhibitor of the α4 integrin subunit) and
   alicaforsen, an antisense nucleotide against ICAM-1 messenger RNA [ 13 ] (Fig. 16.2).

Brain

Bone marrow, skin... Gut

Leukocyte

Integrins

Natalizumab

Natalizumab

Vedolizumab

AMG 181

Addressins

VCAM-1 MAdCAM-1

PF-00547659

E-cadherin

Endothelial cell Epitelial cell Endothelial cell

Etrolizumab

Etrolizumab

α 4 β 1

αEβ 7

α 4 β 7

Fig. 16.2 Systemic effects of blocking MAdCAM-1 addressin and α 4 β1, α 4 β7 or αEβ7 integrins

16 Anti-integrin Agents in IBD: Efficacy and Risk of Complications