Leukocyte adhesion molecules in animal models of inflammatory bowel disease

Abstract

The dysregulated recruitment of leukocytes into the intestine is required for the initiation and maintenance of inflammatory bowel disease (IBD). Several families of molecules regulate the influx of these cells into sites of inflammation. Interference with some of these molecules has already shown efficacy in the clinics and antibodies that target the molecules involved have been approved by the FDA for use in Crohn's disease (CD), multiple sclerosis (i.e., natalizumab), and psoriasis (i.e., efalizumab). Here, we discuss basic aspects of the different families of relevant molecules and compile a large body of preclinical studies that supported the targeting of specific steps of the leukocyte adhesion cascade for therapeutic purposes in colitis and in novel models of CD-like ileitis.

Figure 1

The original steps of the leukocyte adhesion cascade are shown in red: rolling, mediated by selectins, activation, mediated by chemokines, and arrest, mediated by integrins. This has been expanded to include additional steps: capture (or tethering), slow rolling, adhesion strengthening and spreading, intravascular crawling, and paracellular and transcellular transmigration. Crucial molecules involved are indicated in boxes. ESAM, endothelial cell-selective adhesion molecule; ICAM-1, intercellular adhesion molecule 1; JAM, junctional adhesion molecule; LFA-1, lymphocyte function-associated antigen 1 (also known as α_Lβ₂-integrin); Mac-1, macrophage antigen 1; MAdCAM-1, mucosal vascular addressin cell-adhesion molecule 1; PSGL-1, P-selectin glycoprotein ligand 1; PECAM-1, platelet/endothelial-cell adhesion molecule 1; PI3Ki ases, phosphoinositide 3-kinases; VCAM-1, vascular cell-adhesion molecule 1; VLA-4, very late antigen 4 (also known as α₄β₁-integrin) .

Figure 2

Selectins and their ligands. During the inflammatory response, leukocyte adhesion to endothelial cells is controlled by the binding of selectins to complementary carbohydrate ligands. All known selectin ligands relevant for lymphocyte trafficking are transmembrane glycoproteins, which present oligosaccharide structures to the selectins. Transient bond formations between the selectins and their ligands mediate the early steps of the adhesion cascade. All three selectins can recognize glycoproteins presenting the tetrasaccharide sialyl-LewisX (sialyl-CD15). This tetrasaccharide is found on all circulating myeloid cells and some activated T cells. It is composed of sialic acid, galactose, fucose, and N-acetyl-galactosamine. It is unclear how selectins achieve specific interactions with ligands, given this common carbohydrate recognition.

Figure 3

The integrins are αβ heterodimers; each subunit crosses the membrane once. Mammalian integrins form subfamilies that share common subunits that bind distinct ligands. Illustrated in color are the integrins that have been targeted for the treatment of human diseases. RGD: arginine-glycine-aspartic acid sequence found in some integrin ligands. C3bi: Complement 3b inactivated

Figure 4

Immunoglobulin superfamily. Members of this family contain two to seven immunoglobulin domains and serve as ligands for leukocyte integrins. ICAM-1 and ICAM-2 exist as homodimers on the cell surface

Figure 5

Combined selectin blockade did not significantly attenuate established ileitis in SAMP1/YitFc mice. SAMP1/YitFc mice at 10 weeks of age received antibodies against P-, E- and L-selectins (mAb RB40.34, 9A9, MEL-14), their respective isotype antibodies combined or dexamethasone (Dex 100 μg I.P) and the histological severity of the ileitis was assessed as described previously (villus-villus architectural distortion, active- neutrophilic infiltrates, chronic-predominantly lymphocyte infiltrates and total- sum of villus active and chronic indices, mean ± S.E.M., n= 7 mice/treatment group).

Figure 6. Role of PSGL-1 in leukocyte recruitment to small intestine

A. Effector T cells and other leukocytes (PMN, monocytes) express PSGL-1 which enables their interaction with P-selectin on activated endothelium or platelets. B. In addition L-selectin-expressing cells may alternatively bind to PSGL-1 on endothelium or other leukocytes. C. Platelets may also bind to endothelial PSGL-1 perpetuating dysregulated recruitment to the small intestine. Modified from Ley&Kansas 2004