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Leukocyte-endothelial adhesion in the pathogenesis of inflammation

Leukocyte-endothelial adhesion in the pathogenesis of inflammation
Author:
Amos Etzioni, MD
Section Editor:
Luigi D Notarangelo, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Nov 2022. | This topic last updated: Mar 26, 2021.

INTRODUCTION — Inflammation is a crucial process in the normal defense mechanisms against various pathogens, and leukocytes are the principal cellular mediators of inflammation. Inflammation is characterized histologically by the accumulation of leukocytes in the affected tissue due to migration of circulating leukocytes out of the vasculature, a process which is actively mediated and precisely controlled by leukocytes, the cytokines they produce, and the vascular endothelium [1]. However, excessive or uncontrolled inflammatory responses can lead to the pathologic inflammation seen in many rheumatologic and inflammatory disorders.

Leukocyte trafficking from the bloodstream into tissue is important for surveillance of foreign antigens and for rapid leukocyte accumulation at a site of inflammatory response or tissue injury. Although the importance of leukocyte movement toward sites of inflammation was well-recognized more than a century ago, the precise molecular mechanisms for leukocyte interactions with the endothelium and the emigration of these cells through the endothelium were elucidated only decades later [2].

The process of leukocyte-endothelial adhesion during inflammation and the various adhesion molecules involved will be discussed in this topic review. Defects and deficiencies in adhesion molecules are presented separately. (See "Leukocyte-adhesion deficiency".)

OVERVIEW — Leukocyte-endothelial adhesion requires dynamic interactions between leukocytes and endothelial cells, involving multiple steps. These steps must be precisely orchestrated to ensure a rapid response with only minimal damage to healthy tissue [3].

Interactions between leukocytes and the endothelium are mediated by several families of adhesion molecules, each of which participates in a different phase of the process. The surface expression and activation of these molecules during an inflammatory response is tightly controlled under normal conditions [3].

ADHESION MOLECULES — Three families of adhesion molecules are of particular importance to the process of leukocyte-endothelial adhesion (table 1):

Selectins – Selectins primarily mediate cellular margination and slow rolling. They are located on both leukocytes and endothelial cells.

Integrins – Integrins are located on leukocytes and are involved in rolling, but they are most important for arrest on the vascular endothelium.

Members of the immunoglobulin superfamily of proteins – These molecules are important for firm adhesion and transmigration and are largely expressed on endothelial cells.

Selectins — Selectins are type I transmembrane glycoproteins expressed on both leukocytes and endothelial cells. The genes for the various members of this family are closely linked on chromosome 1, reflecting their common evolutionary origin. Three selectins exist, including E-, P-, and L-selectin, named for the cell type in which they were originally identified (ie, endothelium, platelet, and leukocyte). All three selectins share similar structural features and an N-terminal lectin-like domain that is crucial for ligand binding. The lectin-like domain is followed by an epidermal growth factor-like domain, a variable number of consensus repeats, a single transmembrane domain, and a short cytoplasmic tail (figure 1) [4].

P-selectin – P-selectin (also called cluster of differentiation molecule 62P or CD62P) is involved in early leukocyte recruitment during the inflammatory response. It is constitutively expressed and stored in secretory granules within endothelial cells. Once the endothelium is stimulated by inflammatory mediators, these granules fuse with the plasma membrane, increasing surface expression.

E-selectin – E-selectin (CD62E) is synthesized de novo and expressed on endothelial cells and leukocytes after stimulation by various inflammatory mediators, such as interleukin-1 (IL-1), endotoxin, and tumor necrosis factor-alpha (TNF-alpha). Its importance had been illustrated in one patient with a defect in E-selectin production and expression. (See "Leukocyte-adhesion deficiency", section on 'Abnormal E-selectin expression'.)

L-selectin – L-selectin (CD62L) is only expressed on leukocytes, unlike the other two selectins. It was originally discovered as a homing molecule that allowed lymphocytes to enter lymphoid tissue. This selectin is unique in that it mediates lymphocyte recruitment on high endothelial venules in lymphatic tissue.  

Selectin ligands — The selectins bind to specialized fucosylated sialoglycoconjugates, such as sialyl Lewis X, which decorate selected surface glycoproteins. A well-characterized example is P-selectin glycoprotein ligand-1 (PSGL-1), which is expressed as a dimer on most leukocytes and can interact with all three selectins under inflammatory situations [5,6].

The importance of fucosylation is demonstrated by the human genetic disease leukocyte-adhesion deficiency II (LAD II), which is due to a mutation in the guanosine diphosphate (GDP)-fucose specific transporter. Defective fucosylation results in an absence of selectin ligands and inability of leukocytes to initiate the adhesion process. Clinically, this disease is characterized by recurrent infections and intellectual disability. (See "Leukocyte-adhesion deficiency", section on 'LAD II'.)

Integrins — Integrins are largely responsible for adhesion of leukocytes to endothelial cells. Integrins are composed of heterodimers of covalently-associated alpha and beta protein chains. Individual integrins are categorized and named according to the specific alpha and beta chains present (figure 2).

Certain members of the beta-1 and beta-2 subclasses of integrins are primarily responsible for the migration of leukocytes into areas of inflammation.

Beta-1 integrins — Eosinophils, lymphocytes, and monocytes express the beta-1 integrin, very late antigen-4 (VLA-4). This molecule binds to endothelial vascular cell adhesion molecule-1 (VCAM-1, an immunoglobulin superfamily protein) and is critical for the accumulation of these cell types at sites of chronic infection [7].

Beta-2 integrins — The beta-2 leukocyte integrins all share a common beta-2 subunit (CD18) and differ in their alpha chains (CD11a, CD11b, and CD11c). The three beta-2 integrins are:

Lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18b)

Macrophage antigen-1 (Mac-1, CR3, CD11b/CD18b)

Glycoprotein 150/95 (gp 150/95, CD11c/CD18b)

All three of these integrins are expressed constitutively and must be "activated" in order to become adhesive for their ligands [8]. (See 'Leukocyte activation and arrest' below.)

The importance of the beta-2 integrins is illustrated in a rare condition called LAD I, which is mentioned briefly here and discussed in detail elsewhere. LAD I results from mutations in the gene encoding the beta-2 (CD18) subunit, resulting in deficiencies in the three integrins containing CD18 and impaired migration of leukocytes into sites of inflammation.

The main clinical features of LAD I are delayed separation of the umbilical cord, recurrent severe infection without pus formation, defective wound healing, and marked leukocytosis (neutrophilia). (See "Leukocyte-adhesion deficiency", section on 'LAD I'.)

Immunoglobulin superfamily molecules — Immunoglobulin superfamily molecules expressed on endothelial cells interact with integrins on leukocytes and are involved in firm adhesion and transendothelial migration. The molecules of this family that are important in leukocyte-endothelial adhesion are intercellular adhesion molecule-1 (ICAM-1), intercellular adhesion molecule-2 (ICAM-2), and VCAM-1. Variable numbers of these molecules are expressed on the surface of the endothelial cells both constitutively and after cellular activation [9].

No human disease with congenital defects in the immunoglobulin superfamily molecules has been described. VCAM-1 deletion is lethal in the mouse model [10], and this may also be the case in humans.

The defining structural characteristic of the immunoglobulin superfamily of molecules is a variable number of intramolecular loops linked by disulfide bonds (figure 3).

ICAM-1 is constitutively expressed at low levels on endothelial cells. Expression is upregulated upon stimulation with multiple factors, including IL-1, TNF-alpha, and endotoxin.

ICAM-2 is constitutively expressed at high levels on endothelial cells and does not increase upon cell stimulation.

VCAM-1 is only synthesized by and expressed on endothelial cells following stimulation with IL-1, TNF-alpha, or endotoxin. It is not expressed on resting endothelial cells.

Platelet-endothelial cell adhesion molecule-1 (PECAM-1 or CD31) is a member of the immunoglobulin superfamily that is expressed at low levels on most leukocytes and platelets but at high levels in endothelial cells where it is localized to intercellular junctions. PECAM-1 is involved in phagocyte transendothelial migration, primarily in migration through the subendothelial basement membrane [11].

THE ADHESION CASCADE — Under normal conditions, leukocytes move rapidly in the vasculature, carried along in the laminar flow of blood. The movement of leukocytes from the bloodstream to the tissue occurs in several distinct steps. A simplified version of this process is described in this review (figure 4). First, under conditions of flow, loose adhesion to the vessel wall causes leukocyte rolling on the endothelium, which primarily occurs in postcapillary venules. This transient and reversible step is a prerequisite for activation of leukocytes. Arrest and firm adhesion occur next, followed by transmigration across the vascular endothelium. Each of these steps involves different adhesion molecules and can be differentially regulated.

Rolling — In response to local inflammatory stimuli, endothelial cells become activated and dramatically increase surface expression of selectins. Selectins interact with carbohydrate ligands on the surface of leukocytes. P-selectin glycoprotein ligand-1 (PSGL-1), enriched at the very tip of leukocyte microvilli, plays a major role in this initial interaction [12]. (See 'Selectin ligands' above.)

The interaction of selectins on endothelial cells with their ligands on leukocytes results in slow rolling of leukocytes along vessel walls adjacent to the site of injury. The process of rolling is dependent upon flow. Rolling cells will detach if flow is interrupted because the strength of binding of platelet (P)- and leukocyte (L)-selectin to their ligands is enhanced by shear stress [4,13]. Neutrophil rolling is primarily mediated by L-selectin on neutrophils and their ligands on endothelial cells [14]. Binding to the selectins tethers the leukocytes, exposing them to chemokines and other stimuli in the microenvironment. No firm adhesion occurs at this very early stage of the cascade.

Leukocyte activation and arrest — Slow rolling allows leukocytes to sample the chemokines being synthesized in the local microenvironment. Rolling is reversible until integrins on the leukocytes become sufficiently activated. Chemokines and their receptors provide the activation signals for integrins [15]. Activated integrins on the leukocyte surface then mediate arrest [16].

All chemokine receptors signal through heterotrimeric G protein-coupled receptors (GPCRs). Binding of a chemokine to its GPCR triggers a complex intracellular signaling network within milliseconds (figure 5). Rap-1 (repressor activator protein-1), one of these signaling molecules, has emerged as a key regulator of integrin activation. It transmits regulatory signals to the cell surface that induce conformational changes in integrin molecules [17]. Thus, control of integrin function occurs via signals that originate within the cell cytoplasm in response to changes in the cell's status, a process called "inside-out signaling."

In response to activation signals, surface integrins undergo a dramatic transition from a bent low-affinity conformation into a fully extended high-affinity structure, with separation of the alpha and beta subunit cytoplasmic tails and opening of the ligand binding site (figure 5). This process is called affinity regulation. Kindlin-3 (a signaling protein) and talin-1 (an actin-binding protein) also play a major role in integrin activation and affinity upregulation [18]. Kindlin-3 binds to the intracellular portions of beta-1, -2, and -3 integrins and is believed to enhance their binding to talin-1 at the cell membrane, which leads to increased integrin affinity. Thus, talin-1 and kindlin-3 are critical coactivators and have distinct roles in the induction of integrin conformational rearrangements [19].

In addition to affinity regulation, the overall strength of adhesiveness (avidity) of the leukocyte-endothelial cell interaction is further increased by the clustering of the integrin molecules on the leukocyte surface [20]. These changes are important for leukocyte arrest.

Activation of leukocyte integrins results in their increased binding to immunoglobulin superfamily molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells. This ensures that adhesion is firm enough to withstand the continuous shear forces present within the blood vessels.

Defects in integrin activation — Defective integrin activation underlies the rare disorder, leukocyte-adhesion deficiency III (LAD III). This disease arises from a general defect in the activation of all integrins due to mutations in kindlin-3 [21]. All patients identified had mutations in kindlin-3, although it is possible that in the future, mutations in other genes involved in integrin activation will be discovered. LAD III is characterized by severe infections, as well as a bleeding tendency due to a defect in beta-3 activation, which is important in platelet aggregation.

Knockout mice models of various cytoplasmic adaptors for integrin activation, such as diacylglycerol guanine nucleotide exchange factor 1 (CalDAG-GEF1) and kindlin-3, have been very helpful to understanding the role of these molecules. A knockout of talin, which is important in many other cellular functions, was found to be lethal [22]. (See "Leukocyte-adhesion deficiency", section on 'LAD III'.)

Crawling and transmigration — Transmigration through venular walls is the final step in the process of leukocyte emigration into tissue. Emigration takes place mainly at junctions between endothelial cells (paracellular transmigration) [23], and a leukocyte temporarily arrested at a location distant from a junction site must "crawl" to one nearby while resisting detachment [24]. Specific molecules, such as platelet-endothelial cell adhesion molecule-1 (PECAM-1), are located at these junction sites and actively mediate leukocyte transendothelial migration [25].

A small fraction of leukocytes follow a different route through the endothelial cell layer, passing directly through endothelial cells via membrane-associated passageways, a process called transcellular emigration [26]. The same families of adhesion molecules may be involved in this form of emigration [27], although the mechanisms have not been extensively studied.

Leukocytes leaving the vasculature must traverse the endothelial cell layer, the underlying basement membrane, and a loose network of pericytes. Pericytes are long cells composed largely of smooth muscle elements that are wrapped discontinuously around endothelial cells in postcapillary venules. A leukocyte requires approximately 2 to 5 minutes to traverse the endothelial cell layer and 5 to 15 minutes to pass through the basement membrane. Passage through pericytes varies in duration, depending upon the density of these cells in different tissue types [2].

CLINICAL APPLICATIONS — In many human disorders, excessive inflammation plays a pathogenic role. Several well-established anti-inflammatory therapies act, in part, by interfering with the adhesion cascade, including aspirin, glucocorticoids, colchicine, and others [28-30]. The therapeutic mechanisms of these agents are discussed elsewhere. (See "NSAIDs: Pharmacology and mechanism of action", section on 'Non-prostaglandin-mediated effects' and "Glucocorticoid effects on the immune system", section on 'Effects on immune cells'.)

Targeting of adhesion molecules has been proposed as a new direction for the development of anti-inflammatory biologic therapies. Several new drugs affecting the adhesion cascade have either become available or are in development. These agents can be divided into four groups [31]:

Anti-selectins and agents binding selectin ligands (inhibit rolling)

Anti-chemokines and agents inhibiting chemokine receptors (affect the activation phase)

Anti-integrins and agents inhibiting their receptors (block firm adhesion)

Inhibitors of intracellular signaling molecules downstream of G protein-coupled receptors (GPCRs)

The challenge with these therapies is to identify the key leukocyte subset that initiates a given disease and the trafficking molecules that will most specifically inhibit that subset of cells, while leaving most leukocytes unaffected to avoid untoward infectious complications.

Inflammatory diseases in which trials of these therapies have been performed include asthma [32,33], psoriasis [34-36], inflammatory bowel disease [37-40], multiple sclerosis [41,42], and rheumatoid arthritis [43-45].

Efalizumab — Efalizumab is a humanized monoclonal antibody (mAb) against CD11a, the alpha subunit of the beta-2 integrin, lymphocyte function-associated antigen-1 (LFA-1). (See 'Beta-2 integrins' above.)

It was evaluated for use in the treatment of in asthma and psoriasis. However, a small number of cases of progressive multifocal leukoencephalopathy (PML) were reported in patients taking efalizumab continuously for more than three years. PML is a severe demyelinating disease of the central nervous system that is caused by reactivation of the polyomavirus JC (JC virus). This infectious complication led to withdrawal of efalizumab from the American market in 2009 [46]. Other therapies and disorders associated with PML are discussed elsewhere. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

This devastating complication emphasizes the need for greater understanding of the components of host defense mediated by specific leukocyte subsets and trafficking molecules, as well as a need for more precise and specific inhibitors of leukocyte trafficking.

Natalizumab — Natalizumab is a humanized mAb against alpha-4 integrin. Trials of natalizumab have been performed in Crohn disease, multiple sclerosis, and some other diseases.  

Natalizumab can induce remission in Crohn disease, although its use is limited because of its association with serious adverse events, including progressive multifocal leukoencephalopathy (PML). (See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease".)

Natalizumab is effective for the treatment of relapsing-remitting multiple sclerosis. The formation of inflammatory lesions in patients with multiple sclerosis may involve lymphocytes and monocytes that gain access to the brain parenchyma from the circulation by first adhering to vascular endothelial cells. (See "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects", section on 'Natalizumab'.)

Natalizumab has also been tested in patients with rheumatoid arthritis with positive effect [43-46].

Vedolizumab — Vedolizumab is a humanized immunoglobulin G1 (IgG1) mAb against alpha-4-beta-7 integrin that interferes only with the alpha-4-beta-7/mucosal addressin cell adhesion molecule-1 (MAdCAM-1) interaction. It is therefore believed that the effect of vedolizumab will be limited to the gastrointestinal tract, with no effect on the trafficking of lymphocytes to other organs, including the central nervous system [47]. Several clinical trials showed that vedolizumab was effective in the induction and maintenance of remission in active inflammatory bowel disease and had a very good safety profile [48].

Etrolizumab — Etrolizumab is a humanized mAb that binds the beta-7 subunit of alpha-4-beta-7 integrin heterodimers, thereby inhibiting interaction with their ligands MAdCAM-1 and E-cadherin, respectively. It has been studied in patients with moderate-to-severe ulcerative colitis. (See "Management of moderate to severe ulcerative colitis in adults", section on 'Investigational therapies'.)  

Investigational agents — PF-00547659 is an investigational monoclonal antibody directed against the gut-specific endothelial adhesion molecule MAdCAM-1. Results of phase II studies in patients with ulcerative colitis and Crohn disease were conflicting. In one study, no beneficial response to the drug was observed, while in the second trial, a moderate positive effect was found [49]. Further phase III trials are scheduled.

Other anti-integrin monoclonal antibodies, such as AJM300 (on oral antagonist of alpha-4 integrin) [50] and AMG 181 (anti-alpha-4-beta-7 integrin), are in the first phases of clinical trials [51].

SUMMARY — Migration of circulating leukocytes out of the vasculature to sites of inflammation is an orchestrated process mediated by adhesion molecules on both leukocytes and vascular endothelial cells. These molecules are normally expressed and activated in a precisely controlled manner. (See 'Introduction' above and 'Overview' above.)

Important adhesion molecules include selectins, integrins, and members of the immunoglobulin superfamily of proteins. (See 'Adhesion molecules' above.)

The movement of leukocytes from the bloodstream into sites of inflammation may be divided into specific steps: rolling on the endothelium, leukocyte activation and arrest, and transmigration (figure 4). Each of these steps involves different adhesion molecules. (See 'The adhesion cascade' above.)

Several well-established anti-inflammatory agents act, in part, by inhibiting the expression of adhesion molecules, such as glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs). Novel agents are in development, although the beneficial therapeutic effects must be balanced against negative consequences, such as increased susceptibility to infection. (See 'The adhesion cascade' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.

  1. Zarbock A, Ley K. Mechanisms and consequences of neutrophil interaction with the endothelium. Am J Pathol 2008; 172:1.
  2. Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 2007; 7:678.
  3. Nourshargh S, Alon R. Leukocyte migration into inflamed tissues. Immunity 2014; 41:694.
  4. McEver RP. Selectins: initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovasc Res 2015; 107:331.
  5. Stadtmann A, Germena G, Block H, et al. The PSGL-1-L-selectin signaling complex regulates neutrophil adhesion under flow. J Exp Med 2013; 210:2171.
  6. Alon R, Rosen S. Rolling on N-linked glycans: a new way to present L-selectin binding sites. Nat Immunol 2007; 8:339.
  7. Zarbock A, Ley K, McEver RP, Hidalgo A. Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow. Blood 2011; 118:6743.
  8. Schmidt S, Moser M, Sperandio M. The molecular basis of leukocyte recruitment and its deficiencies. Mol Immunol 2013; 55:49.
  9. Kelly M, Hwang JM, Kubes P. Modulating leukocyte recruitment in inflammation. J Allergy Clin Immunol 2007; 120:3.
  10. Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol 2007; 25:619.
  11. Duncan GS, Andrew DP, Takimoto H, et al. Genetic evidence for functional redundancy of Platelet/Endothelial cell adhesion molecule-1 (PECAM-1): CD31-deficient mice reveal PECAM-1-dependent and PECAM-1-independent functions. J Immunol 1999; 162:3022.
  12. Wagner DD, Frenette PS. The vessel wall and its interactions. Blood 2008; 111:5271.
  13. Finger EB, Puri KD, Alon R, et al. Adhesion through L-selectin requires a threshold hydrodynamic shear. Nature 1996; 379:266.
  14. Ivetic A, Hoskins Green HL, Hart SJ. L-selectin: A Major Regulator of Leukocyte Adhesion, Migration and Signaling. Front Immunol 2019; 10:1068.
  15. Thelen M, Stein JV. How chemokines invite leukocytes to dance. Nat Immunol 2008; 9:953.
  16. Alon R, Ley K. Cells on the run: shear-regulated integrin activation in leukocyte rolling and arrest on endothelial cells. Curr Opin Cell Biol 2008; 20:525.
  17. Kinashi T. Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol 2005; 5:546.
  18. Wegener KL, Partridge AW, Han J, et al. Structural basis of integrin activation by talin. Cell 2007; 128:171.
  19. Lefort CT, Ley K. Neutrophil arrest by LFA-1 activation. Front Immunol 2012; 3:157.
  20. Banno A, Ginsberg MH. Integrin activation. Biochem Soc Trans 2008; 36:229.
  21. Hidalgo A, Frenette PS. When integrins fail to integrate. Nat Med 2009; 15:249.
  22. Montanez E, Piwko-Czuchra A, Bauer M, et al. Analysis of integrin functions in peri-implantation embryos, hematopoietic system, and skin. Methods Enzymol 2007; 426:239.
  23. Muller WA. Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol 2003; 24:327.
  24. Alon R, Luscinskas FW. Crawling and INTEGRating apical cues. Nat Immunol 2004; 5:351.
  25. Nourshargh S, Krombach F, Dejana E. The role of JAM-A and PECAM-1 in modulating leukocyte infiltration in inflamed and ischemic tissues. J Leukoc Biol 2006; 80:714.
  26. Carman CV, Springer TA. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J Cell Biol 2004; 167:377.
  27. Engelhardt B, Wolburg H. Mini-review: Transendothelial migration of leukocytes: through the front door or around the side of the house? Eur J Immunol 2004; 34:2955.
  28. Ince LM, Weber J, Scheiermann C. Control of Leukocyte Trafficking by Stress-Associated Hormones. Front Immunol 2018; 9:3143.
  29. Cronstein BN, Molad Y, Reibman J, et al. Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J Clin Invest 1995; 96:994.
  30. Nuki G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep 2008; 10:218.
  31. Mackay CR. Moving targets: cell migration inhibitors as new anti-inflammatory therapies. Nat Immunol 2008; 9:988.
  32. Gauvreau GM, Becker AB, Boulet LP, et al. The effects of an anti-CD11a mAb, efalizumab, on allergen-induced airway responses and airway inflammation in subjects with atopic asthma. J Allergy Clin Immunol 2003; 112:331.
  33. Millard M, Odde S, Neamati N. Integrin targeted therapeutics. Theranostics 2011; 1:154.
  34. Lebwohl M, Tyring SK, Hamilton TK, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 2003; 349:2004.
  35. Gordon KB, Papp KA, Hamilton TK, et al. Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 2003; 290:3073.
  36. Leonardi CL, Papp KA, Gordon KB, et al. Extended efalizumab therapy improves chronic plaque psoriasis: results from a randomized phase III trial. J Am Acad Dermatol 2005; 52:425.
  37. Sakuraba A, Keyashian K, Correia C, et al. Natalizumab in Crohn's disease: results from a US tertiary inflammatory bowel disease center. Inflamm Bowel Dis 2013; 19:621.
  38. Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn's disease: results of the ENCORE Trial. Gastroenterology 2007; 132:1672.
  39. Luster AD, Alon R, von Andrian UH. Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 2005; 6:1182.
  40. Stefanelli T, Malesci A, De La Rue SA, Danese S. Anti-adhesion molecule therapies in inflammatory bowel disease: touch and go. Autoimmun Rev 2008; 7:364.
  41. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354:899.
  42. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354:911.
  43. Yonekawa K, Harlan JM. Targeting leukocyte integrins in human diseases. J Leukoc Biol 2005; 77:129.
  44. Voulgari PV. Emerging drugs for rheumatoid arthritis. Expert Opin Emerg Drugs 2008; 13:175.
  45. Genovese MC. Biologic therapies in clinical development for the treatment of rheumatoid arthritis. J Clin Rheumatol 2005; 11:S45.
  46. The full FDA statement of withdrawl is available online. http://www.fda.gov/medwatch/safety/2009/safety09.htm#Raptiva (Accessed on January 20, 2011).
  47. Lobatón T, Vermeire S, Van Assche G, Rutgeerts P. Review article: anti-adhesion therapies for inflammatory bowel disease. Aliment Pharmacol Ther 2014; 39:579.
  48. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369:699.
  49. Biswas S, Bryant RV, Travis S. Interfering with leukocyte trafficking in Crohn's disease. Best Pract Res Clin Gastroenterol 2019; 38-39:101617.
  50. Yoshimura N, Watanabe M, Motoya S, et al. Safety and Efficacy of AJM300, an Oral Antagonist of α4 Integrin, in Induction Therapy for Patients With Active Ulcerative Colitis. Gastroenterology 2015; 149:1775.
  51. Mitroulis I, Alexaki VI, Kourtzelis I, et al. Leukocyte integrins: role in leukocyte recruitment and as therapeutic targets in inflammatory disease. Pharmacol Ther 2015; 147:123.
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