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Originally published online as doi:10.1189/jlb.0804460 on November 17, 2004

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(Journal of Leukocyte Biology. 2005;77:129-140.)
© 2005 by Society for Leukocyte Biology

Targeting leukocyte integrins in human diseases

Karyn Yonekawa* and John M. Harlan{dagger},1

* Division of Nephrology, Department of Pediatrics, and
{dagger} Division of Hematology, Department of Medicine, University of Washington, Seattle

1 Correspondence: Division of Hematology, Harborview Medical Center, Mailstop 359756, 325 Ninth Avenue, Seattle, WA 98115. E-mail: jharlan{at}u.washington.edu


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ABSTRACT
 
As our understanding of integrins as multifunctional adhesion and signaling molecules has grown, so has their recognition as potential therapeutic targets in human diseases. Leukocyte integrins are of particular interest in this regard, as they are key molecules in immune-mediated and inflammatory processes and are thus critically involved in diverse clinical disorders, ranging from asthma to atherosclerosis. Antagonists that interfere with integrin-dependent leukocyte trafficking and/or post-trafficking events have shown efficacy in multiple preclinical models, but these have not always predicted success in subsequent clinical trials (e.g., ischemia-reperfusion disorders and transplantation). However, recent successes of integrin antagonists in psoriasis, inflammatory bowel disease, and multiple sclerosis demonstrate the tremendous potential of antiadhesion therapy directed at leukocyte integrins. This article will review the role of the leukocyte integrins in the inflammatory process, approaches to targeting leukocyte integrins and their ligands, and the results of completed clinical trials.

Key Words: adhesion • clinical • trials • inflammation


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INTRODUCTION
 
Inflammatory and immune diseases affect millions of people in the United States alone [1 , 2 ], providing an impetus to develop new anti-inflammatory and immunomodulatory therapies. Although critical for host defense and repair, leukocytes are also the primary effectors of inflammation and immune responses. During the process of emigration from bloodstream to extravascular tissue, leukocytes may injure the vessel wall, provoking thrombosis or promoting edema. Emigrated leukocytes may initiate and sustain tissue damage by release of diverse mediators, such as oxidants, proteases, bioactive lipids, and cytokines.

Over the past two decades, there has been dramatic progress in elucidating the molecular basis of leukocyte trafficking from bloodstream to extravascular tissue (reviewed in refs. [3 4 5 6 7 ]), thus identifying potential new targets for therapeutic intervention. The integrin receptors involved in leukocyte trafficking have been recognized as particularly attractive targets for several reasons. First, integrins are critically involved in several steps of the adhesion cascade, and preclinical studies have shown that leukocyte integrin blockade is efficacious in diverse disease models [8 ]. Second, elegant studies have provided important details of integrin structure and function, thereby facilitating drug development (reviewed in refs. [9 10 11 12 ]). Third, platelet integrin antagonists have already been shown to be effective drugs in acute coronary syndromes (reviewed in refs. [13 , 14 ]), thus validating integrins as "drugable" targets. Consequently, many pharmaceutical and biotechnology companies have worked to develop leukocyte integrin antagonists (reviewed in refs. [12 , 15 16 17 18 19 ]). In this article, we will review therapeutic approaches directed at leukocyte integrins and their ligands, emphasizing those therapies that have completed clinical trials.


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INTEGRINS
 
The term "integrin" was first proposed in 1986 to describe a protein complex that was felt to be integral to the transmembrane connection between the extracellular matrix (ECM) and the cytoskeleton [20 ]. Soon after, homology with other transmembrane proteins was discovered, and integrin came to describe a family of structurally related cell-surface receptors. These molecules are heterodimeric receptors comprised of noncovalently associated {alpha} and ß subunits. Integrins are expressed by all multicellular animals, although the repertoire varies amongst phyla [21 ]. The human integrin family now includes at least 18 known {alpha}-subunits and eight known ß-subunits. Some {alpha}-subunits contain an inserted I domain, which is a major ligand-binding site [22 ]. A given {alpha}-subunit may interact with more than one ß-subunit, resulting in 24 different heterodimers identified to date. Integrin expression varies from one cell type to another. However, certain integrins are limited to one cell lineage or to a specific cell type. ß2 integrins, for example, are expressed only on hematopoietic cells, and {alpha}Eß7 is expressed primarily by T lymphocytes in mucosal tissue [23 ].

Although originally identified as adhesion molecules, integrins are now known to mediate a wide variety of signaling functions, and consequently, integrins influence many biologic systems. They are involved in hematopoiesis, hemostasis, immune regulation, and the inflammatory response. Additionally, they are crucial for embryonic development, influencing cellular survival, proliferation, and differentiation [24 ]. Genetic deletion models highlight the impact that the integrin has on organism viability as well as the unique role of each integrin subunit [21 ].

Several human genetic diseases provide tangible evidence of the clinical importance of this family of cell adhesion receptors (reviewed in refs. [25 , 26 ]). Originally described in 1918, Glanzmann’s thrombasthenia is an autosomal recessive disease characterized by serious mucocutaneous bleeding. Almost 60 years later, it was found to result from mutations in the platelet integrin {alpha}IIbß3 [integrin nomenclature: {alpha}IIbß3, glycoprotein (GP)IIb/IIIa, CD41/CD61; {alpha}Mß2, macrophage adhesion molecule-1, CD11b/CD18; {alpha}Lß2, lymphocyte function-associated antigen-1, CD11a/CD18; {alpha}Xß2, p150, 95, CD11c/CD18; {alpha}Dß2, CD11d/CD18; {alpha}4ß7, lymphocyte Peyer’s patch adhesion molecule-1; {alpha}4ß1, very late antigen-4 (VLA-4), CD49d/CD29; {alpha}1ß1, VLA-1, CD49a/CD29; {alpha}Vß3, CD51/CD61; {alpha}5ß1, CD49e/CD29; refs. 27 , 28 ]. Leukocyte adhesion deficiency syndrome (LAD I) was also described before the molecular defect was discovered (reviewed in refs. [29 , 30 ]). LAD I patients exhibit recurrent bacterial infections and persistent, marked leukocytosis between infectious episodes. They were found to be quantitatively deficient in the ß2 integrins {alpha}Mß2, {alpha}Lß2, {alpha}Xß2 [31 ], and {alpha}Dß2 as a result of heterogeneous mutations in the common ß2 subunit. More recently, LAD I "variants" have been reported [32 33 34 35 ] and proposed to constitute a distinct syndrome [36 ]. These patients have dysfunctional but structurally intact ß1, ß2, and ß3 integrins, suggesting a defect in a common signaling molecule for integrin activation [36 ]. Other integrin-dependent diseases include epidermis bullosa variants caused by mutations in the {alpha}4ß6 complex [37 38 39 ] and congenital myopathy resulting from mutations in the {alpha}7 gene [40 , 41 ].


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LEUKOCYTE INTEGRINS
 
Trafficking
As evidenced by the diverse human diseases resulting from these genetic defects, integrins are crucial for physiologic homeostasis. Integrins are critically involved in the trafficking of leukocytes from the bloodstream to extravascular tissue at sites of active inflammation as well as during routine immune surveillance. Studies by intravital microscopy have established a sequence of adhesive events involved in leukocyte emigration. Under conditions of flow, leukocytes are first observed to roll along the endothelium of postcapillary venules at sites of inflammation. Subsequently, some of the rolling leukocytes stick firmly, migrate along the endothelial surface, diapedese between endothelial junctions, and then migrate through a subendothelial matrix. These early steps in emigration—rolling, firm adhesion, and transendothelial migration—result from the interaction of distinct leukocyte and endothelial receptors in an adhesion cascade (reviewed in refs. [3 4 5 6 7 ]; Fig. 1 ). Rolling is observed only under flow conditions and is the consequence of shear forces acting on the leukocyte and adhesive interactions between the leukocyte and endothelium. This primary phase of adhesion is mediated predominantly by leukocyte L-selectin and endothelial P- and E-selectins and their glycoprotein counter-receptors, particularly P-selectin glycoprotein-1 (reviewed in ref. [42 ]). P-selectin is rapidly translocated from Weibel-Palade bodies to the luminal surface upon endothelial cell activation, whereas E-selectin is expressed after several hours following de novo synthesis.



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  		Figure 1. Leukocyte trafficking and post-trafficking events. The trafficking of leukocytes from the bloodstream to extravascular tissue is a multistep process. Under conditions of flow, leukocytes are first captured and tethered to endothelium by predominantly selectin-mediated adhesive interactions that allow the leukocyte to roll along the vessel wall. The rolling cells are stimulated by chemokines or chemoattractants, triggering inside-out signaling that increases the affinity and/or clustering of integrins. The activated integrins bind avidly to endothelial ligands, firmly attaching the leukocyte to the endothelium. The subsequent migration of leukocyte across the endothelial surface, diapedesis between endothelial cells, and migration in extravascular tissue is also integrin-dependent. Furthermore, outside-in signaling via integrin receptors modulates a number of important post-trafficking events.

The initial contact of the leukocyte with the endothelial surface "tethers" the leukocyte, allowing endothelial membrane-bound chemokines, membrane-expressed platelet-activating factor, or locally secreted chemoattractants to activate leukocyte integrins. This "inside-out" activation results in changes in integrin affinity [10 ] or affinity-independent integrin clustering [43 ]. The activated leukocyte integrins initiate the secondary phase of adhesion with firm binding to endothelial ligands, which are members of the immunoglobulin gene superfamily (IgSF; IgSF nomenclature: intercellular adhesion molecule-1 (ICAM-1), CD54; ICAM-2, CD102; vascular cell adhesion molecule-1 (VCAM-1), CD106; platelet-endothelial cell adhesion molecule-1 (PECAM-1), CD31; mucosal addressin cell adhesion molecule-1 (MAdCAM-1); junctional adhesion molecule (JAM); receptor for advance glycation end products (RAGE); Fig. 2 ). These IgSF ligands are constitutively expressed (ICAM-1; ICAM-2) or further up-regulated (ICAM-1) or are induced (VCAM-1). Recently, the pattern recognition receptor RAGE, which is up-regulated by diabetic conditions [44 ], has been identified as an endothelial IgSF ligand for leukocyte ß2 integrins [45 ].



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  		Figure 2. Leukocyte integrins and their ligands. Leukocyte integrins bind to IgSF ligands on the vascular endothelium in nonlymphoid tissue and to high endothelial venules (HEV) in lymphoid tissue as well as to components of the ECM, such as the connecting segment-1 (CS-1) of fibronectin (FN), osteopontin (OPN), thrombospondin (TSP), collagen (COL), vitronectin (VN), and laminin (LN). Antagonists of the leukocyte integrins depicted have shown efficacy in preclinical models ({alpha}Mß2, {alpha}1ß1, {alpha}vß3) and in clinical trials ({alpha}Lß2, {alpha}4ß1, {alpha}4ß7).

Once firmly adherent, the leukocyte migrates over the endothelial cell surface, using {alpha}Lß2 and {alpha}Mß2 integrins and their endothelial IgSF ligands [46 ], and then emigrates through an intercellular junction. The process of transendothelial migration involves several junctional proteins, including the IgSF proteins PECAM-1 [47 ] and JAMs [48 , 49 ] as well as CD99 [50 ]. In some vascular beds, leukocytes may enter the extravascular tissue by traversing through, rather than between, endothelial cells [51 ].

Immune surveillance of tissue is mediated by similar adhesion mechanisms. Lymphocytes recirculate between blood and lymphatics, gaining entrance to the latter at specialized HEV of postcapillary venules in lymphoid tissue [7 ]. The HEV express vascular addressins recognized by specific lymphocyte-homing receptors that support the primary phase of adhesion. L-selectin recognizes sialyl LewisX-like sugars on the peripheral node-addressin, and the integrin {alpha}4ß7 binds to MAdCAM-1 [52 ]. In the secondary phase of firm adhesion, the binding of locally expressed chemokines to cognate lymphocyte receptors activates {alpha}Lß2, attaching the lymphocyte firmly to the endothelial cell. When similarly activated, {alpha}4ß1 and {alpha}4ß7 also promote firm adhesion. Once attached, the lymphocyte can then diapedese between endothelial cells and enter lymphoid tissue.

There are a number of exceptions to the general model of selectin-mediated rolling followed by integrin-mediated firm adhesion and transmigration depicted in Figure 1 . Tethering and rolling can also occur via {alpha}4ß7 [52 ], {alpha}4ß1 [53 ], and under some circumstances, {alpha}Lß2 [54 ] integrins. CD44 [55 ] and vascular adhesion protein-1 [56 ] may also support selectin-independent rolling. Moreover, selectins do not appear to play a major role in leukocyte emigration in the pulmonary microcirculation, where emigration occurs predominantly in capillaries [57 ], or in the liver microvasculature, where leukocytes emigrate primarily in sinusoids [58 ]. Additionally, leukocyte interactions with platelets may contribute to recruitment to inflammatory sites. Following a vascular injury that produces endothelial denudation or retraction, platelets rapidly adhere to the exposed subendothelium. The platelets adherent to the damaged vessel wall may recruit leukocytes directly by initiating selectin- and integrin-dependent leukocyte adhesion to surface-bound platelets [59 60 61 ]. Finally, there are a number of other potentially important adhesion pathways that have yet to be fully characterized in vivo [62 ], including leukocyte integrin-dependent interactions such as binding of {alpha}Mß2 to ICAM-1 via bridging by fibrinogen [63 ], {alpha}Mß2 to GPIb [64 ], {alpha}Lß2 to JAM-A [48 ], {alpha}Mß2 to JAM-C [49 , 65 ], {alpha}4ß1 to JAM-B [66 ], and {alpha}9ß1 to VCAM-1 [67 ].

Post-trafficking events
Leukocyte integrins also play a critical role in multiple "post-trafficking" events that follow transendothelial migration. Neutrophil {alpha}Mß2 binds to plasma-derived proteins, such as iC3b, factor X, and fibrinogen, which may be present tissue at sites of vascular leakage. These interactions may contribute significantly to the pathogenesis of the local inflammatory response (e.g., ref. [68 ]). A variety of stimuli drives the continued movement of the leukocyte through the subendothelial matrix and the extravascular tissue to the site of inflammation or immune reaction. The interaction of leukocyte integrins with ECM components is critical for migration in tissue (reviewed in refs. [69 70 71 72 ]). In addition to regulating migration, "outside-in" signaling via leukocyte integrins modulates the activation, proliferation, and survival of leukocytes in extravascular tissue (reviewed in refs. [21 , 73 74 75 76 ]; Figs. 1 and 2 ). The importance of these integrin-dependent post-trafficking events in inflammatory and immune responses of leukocytes is illustrated by several in vivo studies of blockade of integrins on tissue leukocytes. In sheep [77 ] and in mice [78 ], blockade of {alpha}4 on intrapulmonary leukocytes (in contrast to circulating leukocytes) decreased allergen-induced lung inflammation. Integrin {alpha}1ß1 is expressed on activated lymphocytes and monocytes in tissue but not on circulating leukocytes in the bloodstream. Nevertheless, blockade of {alpha}1ß1 significantly ameliorates inflammatory responses in animal models of arthritis [79 ], colitis [80 ], influenza infection [81 ], and asthma [82 ], demonstrating that post-trafficking signaling via {alpha}1ß1 regulates leukocyte function. Finally, {alpha}vß3 is expressed on monocytes in culture [83 ] and on monocyte-derived macrophages, including osteoclasts. A peptidomimetic antagonist of {alpha}vß3 inhibited bone resorption in vitro and osteoporosis in a rat model [84 ].

Leukocyte development and hematopoiesis
The ß1 integrins, particularly {alpha}4ß1, play a critical role in B lymphocyte development in bone marrow and germinal centers and T lymphocyte development in the thymus [74 , 85 86 87 ]. The ß1 integrins, {alpha}4ß1 and {alpha}5ß1, are essential for fetal hematopoiesis [88 , 89 ], and in the adult, {alpha}4ß1 is important in the distribution of progenitors and regeneration of hematopoiesis after stress [90 ]. The interaction of {alpha}4ß1 on hematopoietic stem cells (HSC) with VCAM-1 on marrow stromal cells is pivotal in the mobilization and homing of hematopoietic progenitors [91 , 92 ]. The ß2 integrins interact synergistically with {alpha}4ß1 in HSC mobilization [93 ]. Antagonists of {alpha}4ß1 have been proposed as adjunctive agents for mobilization of HSC for transplantation. It is important that chronic blockade of {alpha}4 in clinical trials in patients with multiple sclerosis (MS; see below) has not, to date, revealed a defect in hematopoiesis.

Outside-in signaling via {alpha}4ß1 interactions with stromal VCAM-1 or fibronectin is also important in the survival of leukemic cells in the marrow microenvironment [94 ]. Expression of {alpha}4ß1 has been correlated with poor prognosis in myeloid leukemia, and blockade of {alpha}4 sensitizes leukemic cells to chemotherapy-induced killing [94 ], raising the possibility that {alpha}4ß1 antagonists could synergize with chemotherapy in treatment of leukemia.


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APPROACHES TO TARGETING LEUKOCYTE INTEGRINS AND THEIR IgSF LIGANDS
 
There are a number of approaches to "antiadhesion" therapy directed to leukocyte integrins and their IgSF ligands (Fig. 3 ).



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  		Figure 3. Approaches to targeting leukocyte integrins and their IgSF ligands. In addition to direct blockade of receptor-ligand interactions by monoclonal antibody (mAb) or ligand mimetics, there are small molecule antagonists that inhibit the conformational changes necessary for increases in receptor affinity. Antisense technology has been used to target IgSF ligands. Signaling pathways regulating integrin function and those involved in IgSF ligand expression are potential targets for small molecule inhibitors.

Receptor-ligand blockade
This approach is the most obvious, and mAb that block integrin binding to ligand have been used extensively in preclinical and clinical trials. A murine mAb to ICAM-1 was tested in several clinical trials [95 , 96 ]; however, most other mAb (e.g., anti-{alpha}4, anti-{alpha}L, and anti-{alpha}4ß7) in clinical trials have been humanized by various techniques to minimize mouse sequences and thereby reduce host antibody response. Many peptidomimetic and small molecule ligand mimetic antagonists of leukocyte integrins have also been developed (reviewed in refs. [12 , 15 16 17 18 ]). Several {alpha}4ß1 ligand mimetic antagonists have been shown to be effective in animal models (e.g., refs. [97 , 98 ]).

Allosteric inhibitors
Conformational changes in the I domain of the {alpha}-subunit of ß2 integrins are necessary for an increase in the binding affinity of the metal ion-dependent adhesion site (MIDAS), which is the ligand-binding site in the I domain [22 ]. Two classes of allosteric I domain inhibitors have been identified [12 ]. Several small molecules inhibit ligand binding to the distal MIDAS by binding to and stabilizing the closed conformation of the I domain, preventing its conversion to the high-affinity, open conformation [99 100 101 ]. Another class of small molecule antagonists maintains the I domain in the low-affinity, closed conformation by affecting interactions between the I domain and the I-like domain in the ß-subunit [102 , 103 ].

Inside-out and outside-in signaling pathways
The signaling pathways modulating integrin-affinity modulation and clustering have been studied intensively. Several key proteins involved in inside-out signaling have been identified (reviewed in refs. [70 , 104 , 105 ]), including the GTPase Rap1 and its ligand RAPL [106 ], the GTPase RhoA [107 ], the tyrosine kinase Pyk2 [108 ], and the cytoskeletal protein talin [109 ]. Inside-out signaling is an important target for small molecule inhibitors of integrin function. For example, statin drugs have the potential to block integrin function by preventing the prenylation and thereby, inhibiting the function of Rap1 [110 ]. Similarly, the multiple outside-in signaling pathways initiated by integrin ligation (reviewed in refs. [21 , 73 74 75 76 ]), which regulate important post-trafficking events, are also potential candidates for disruption by small molecule antagonists. For example, in neutrophils, Vav guanine nucleotide exchange factors [111 ] and the Src homology 2 domain-containing adaptor leukocyte phosphoprotein of 76 kD [112 ] have been shown to regulate several key functions induced by ligation of ß2 integrin.

Intracellular pathways regulating expression of IgSF ligands
Antisense oligonucleotides or RNA interference [113 ] can be used to decrease synthesis of adhesion molecules. Antisense oligonucleotides that target ICAM-1 have undergone extensive clinical trials with only limited success (Table 1 ). RNA interference has been used in vitro to decrease the expression of integrin receptors (e.g., ref. [138 ]), but trials targeting integrins or IgSF ligands in vivo have not yet been reported. The signaling pathways that up-regulate expression of endothelial IgSF ligands by cytokines are also potential targets for small molecule inhibitors (e.g., refs. [139 , 140 ]).


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  		Table 1. Clinical Trials Targeting Leukocyte Integrins and Their IgSF Ligandsa


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TARGETING LEUKOCYTE INTEGRINS AND THEIR IgSF LIGANDS IN HUMAN DISEASE
 
In reviewing clinical trials of antiadhesion therapy directed at leukocyte integrins or their IgSF ligands, we will consider only completed Phase II and III studies (Table 1) .

Ischemia-reperfusion disorders
Ischemia-reperfusion injury has been postulated to contribute to many pathologic conditions, including MI, stroke, and shock. Preclinical studies in animal models of ischemia-reperfusion disorders showed striking protection against reperfusion injury with blockade of leukocyte or endothelial adhesion molecules (reviewed in ref. [141 ]). It is disappointing, however, the clinical trials that followed in these indications were not successful.

MI
Two multicenter, randomized, placebo-controlled trials tested the efficacy of ß2 blockade in the setting of acute MI. Rovelizumab, a recombinant, humanized anti-ß2 mAb, failed to reduce infarct size following angioplasty [124 ]. In the second study, erlizumab, another recombinant, humanized anti-ß2 mAb, did not modify cardiac endpoints when administered in conjunction with thrombolytic therapy [123 ].

Stroke
Rovelizumab was also tested in acute stroke, but Phase III studies were discontinued at approximately 15 months after initiation as a result of a lack of efficacy [132 ]. Likewise, Phase II trials in acute stroke of recombinant neutrophil inhibitory factor protein, which inhibits {alpha}Mß2, were discontinued secondary to early determination that treatment had no effect on outcome [131 ]. A Phase III trial of enlimomab, a murine anti-ICAM-1 mAb, showed no efficacy and in fact, worsened stroke outcome [95 ]. It has been postulated that the adverse outcome observed with enlimomab treatment in this trial was a result of complement-dependent activation of neutrophils by the antibody [142 ].

Traumatic shock
Two Phase II trials tested blockade of ß2 in the setting of hemorrhagic shock following trauma. Neither rovelizumab nor erlizumab demonstrated efficacy compared with control upon analysis of a number of clinical endpoints [136 , 137 ].

There are several potential explanations for the failure of adhesion blockade in these clinical disorders with putative ischemia-reperfusion injury. The design of the trials may not have been adequate to test the underlying hypothesis. For example, in the case of the two hemorrhagic shock trials [136 , 137 ], mortality in all groups was low compared with the reported rates in similar populations, making the studies too small to have adequate power to demonstrate efficacy in reducing mortality. Second, it is possible that selectins rather than ß2 integrins are a better target. However, in the preclinical models, ß2 integrin or selectin blockade appeared equally efficacious in preventing reperfusion injury [141 ], including comparisons in the same model (e.g., refs. [143 , 144 ]). Moreover, to date, there have been no reports of successful clinical trials of selectin antagonists in MI, stroke, or shock [18 ]. Third, it is possible that leukocytes are not a significant component of clinical reperfusion injury, particularly with longer ischemic periods [145 146 147 ]. Other mediators, such as complement or oxidants, may play larger roles in this setting. Finally, the general issue remains that animal models may not always accurately reflect human disease processes.

Atherosclerosis
The endothelial IgSF ligand VCAM-1 is thought to play a pivotal role in atherogenesis (e.g., ref. [148 ]). AGI-1067 is an oral antioxidant that inhibits the transcription of VCAM-1 as well as several other cytokine-induced, redox-sensitive genes [139 ]. AGI-1067 improved luminal dimensions at the intervention site and reduced restenosis in the Canadian antioxidant restenosis trial [149 ]. Whether the benefit of AGI-1067 was a result of an inhibition of VCAM-1 expression or to other mechanisms is uncertain.

Asthma
The asthmatic response to allergen is characterized by airway hyper-responsiveness and inflammation with the accumulation of lymphocytes and eosinophils. In animal models, the trafficking of these effector cells involves {alpha}Lß2 and {alpha}4ß1 (e.g., refs. [77 , 78 , 150 , 151 ]). {alpha}4ß1 [78 ] and {alpha}1ß1 [82 ] are also involved in post-trafficking events regulating the allergic response. Efalizumab, a humanized anti-{alpha}L mAb, was tested in patients with mild asthma. Although the number of activated eosinophils was significantly decreased after 4 weeks of treatment, the early and late percent fall in forced expiratory volume at 1 s after allergen challenge did not reach statistical significance [114 ]. Recently, an oral, dual {alpha}4ß1/{alpha}4ß7 antagonist was reported to show some efficacy in a Phase II trial in asthma [115 ].

Burns
Tissue injury following a burn can worsen as a result of progressive destruction from the acute inflammatory response [152 ]. The murine mAb to human ICAM-1, enlimomab, was tested in the treatment of partial thickness burns. There was improved healing at high-risk sites with enlimomab compared with placebo and trends toward significance for the primary endpoint of reduction in the total area of primary grafts [96 ]. However, the scar ratings at long-term follow-up were not statistically different from control [96 ].

Inflammatory bowel disease
Although distinct diseases, Crohn’s disease and ulcerative colitis are chronic inflammatory conditions, which are theorized to stem from repeated stimulation of the immune system by normal bowel flora [153 ]. Endothelial IgSF ligands VCAM-1 [154 , 155 ], ICAM-1 [154 ], and MAdCAM-1 [156] are expressed in normal and inflamed bowel. Consequently, there have been several trials of antiadhesion therapy directed at the IgSF ligands or leukocyte integrins.

Alicaforsen, an antisense oligonucleotide to ICAM-1, failed to show efficacy in Phase II trials for Crohn’s disease [118 , 119 ].

A humanized mAb against {alpha}4ß7 (MLN02) has a completed Phase II trial for ulcerative colitis. There were significant improvements in the clinical remission rates of patients treated with MLN02 compared with placebo [120 ]. A Phase II clinical trial in Crohn’s disease did not achieve superior clinical response compared with placebo, the primary endpoint of the trial. However, the clinically important, secondary endpoint of disease remission was achieved in the higher dose group [117 ].

Natalizumab is a recombinant, humanized mAb to the {alpha}4 subunit, which inhibits binding of {alpha}4ß7 to MAdCAM-1 and {alpha}4ß1 to VCAM-1. In Phase II trials in Crohn’s disease, patients who received two infusions of natalizumab had higher clinical response rates and improved remission rates when compared with placebo at predetermined time-points [116 ]. Additionally, the midpoint analysis of Phase III trials showed that those patients who had previously achieved a clinical response and who had received monthly infusions of natalizumab were better able to maintain clinical response and remission at 6 months [157 ]. With these positive results, there are plans to file for approval for the use of natalizumab in Crohn’s disease in Europe [158 ].

MS
MS is a presumed autoimmune disorder characterized pathologically by demyelinated plaques in the white matter of the central nervous system (CNS). The majority of patients has relapsing-remitting MS with the relapses secondary inflammation in the CNS white matter mediated by autoreactive T lymphocytes [159 ]. Blockade of {alpha}L, {alpha}M [160 ], or {alpha}4 [161 ] showed efficacy in rodents with experimental allergic encephalomyelitis (EAE), a model for MS. However, in a Phase II trial of patients with acute exacerbations of MS, the humanized anti-ß2 mAb, rovelizumab, did not demonstrate significant clinical benefit as determined by changes in the Scripps scale, a neurological instrument [122 ].

Over a decade after the seminal study by Yednock et al. [161 ], demonstrating the efficacy of {alpha}4 blockade in the EAE model, a Phase II trial of natalizumab showed short-term efficacy in relapsing-remitting MS [121 ]. At 6 months, patients who received monthly natalizumab had fewer new enhancing lesions, as assessed by monthly magnetic resonance imaging scans. Based on a 1-year analysis of ongoing Phase III trials, natalizumab has been submitted for approval for treatment of MS to the U.S. Food and Drug Administration (FDA; Rockville, MD) [162 ] and European Medicines Agency [163 ].

Psoriasis
Psoriasis is an inheritable, chronic, inflammatory condition, which primarily affects the skin with scaly papular or plaque-like lesions and extracutaneous manifestions including psoriatic arthritis and inflammatory bowel disease. The pathophysiology of psoriasis remains unknown, but one possibility is that it begins with stimulation of the keratinocytes by, for example, mild trauma. Dendritic cells and T cells are then activated, initiating the inflammatory cascade with the ensuing release of cytokines and growth factors causing keratinocyte proliferation. Eventually, epidermal thickening, an angiogenic tissue reaction, and plaque formation result [164 ].

The interaction of {alpha}Lß2 with ICAM-1 is important for lymphocyte trafficking to inflamed skin as well as for immunologic synapse formation between resident T lymphocytes and antigen-presenting cells [165 ]. In Phase III trials, patients that received weekly subcutaneous injections of the humanized anti-{alpha}L mAb efalizumab exhibited significant improvement in their psoriasis compared with controls for all endpoints [125 126 127 ]. Efalizumab was approved by the U.S. FDA in October 2003 for the treatment of chronic, moderate-to-severe plaque psoriasis [166 ]. For psoriatic arthritis, however, preliminary results from a Phase II trial using efalizumab failed to demonstrate any clinical benefit [128 ].

RA
RA is a chronic, inflammatory condition, primarily affecting the joints, which can lead to debilitating destruction of cartilage and bone. As with other immune disorders, leukocytes are believed to be critical effectors of tissue injury in arthritis, and blockade of {alpha}4ß1/VCAM-1 and {alpha}Lß2/ICAM-1 interactions has demonstrated efficacy in animal models (e.g., ref. [167 ] and reviewed in ref. [168 ]).

Phase I/II trials were conducted in early and refractory RA using a murine anti-ICAM-1 mAb. Although the studies were not placebo-controlled, the majority of patients responded to treatment with greater apparent efficacy in early versus refractory disease [169 , 170 ]. A Phase II trial of the humanized anti-{alpha}Lß2 mAb efalizumab in moderate-to-severe RA was terminated, as there was no overall benefit compared with control [129 ]. A randomized, placebo-controlled trial of an antisense oligodeoxynucleotide to ICAM-1 in the treatment of severe RA did not show significant efficacy at the primary endpoint [130 ].

Transplant
Graft survival in solid organ transplant has improved as immunosuppressive therapy has evolved. However, rejection remains an important post-transplant complication. Transplanted organs and organs undergoing rejection show leukocyte accumulation and increased expression of IgSF ligands [171 , 172 ], and leukocyte integrin antagonists have shown efficacy in animal models of graft rejection (e.g., refs. [19 , 173 174 175 ]). There have been several clinical trials of adhesion blockade in clinical transplantation. There was a reduction of graft failure by a murine mAb to {alpha}Lß2 after human leukocyte antigen nonidentical bone marrow transplantation in children [176 ]. In patients receiving partially incompatible bone marrow transplants, a high rate of engraftment was achieved by the use of anti-{alpha}Lß2 and anti-CD2 antibodies, but there was a high incidence of lethal infections and relapses as a result of long-lasting immunodeficiency [177 ]. However, a Phase II trial of a murine anti-{alpha}Lß2 mAb odulimomab in renal transplant showed no difference in the incidence and severity of acute rejection in the first 3 months compared with treatment with rabbit antithymocyte globulin [133 ]. A Phase III trial of this drug also showed little efficacy [134 ]. Short-term induction therapy with the murine anti-ICAM-1 mAb enlimomab after cadaveric renal transplantation did not reduce the rate of acute rejection or delayed onset of graft function [135 ]. In a Phase I/II dose-finding study of the humanized anti-{alpha}Lß2 mAb efalizumab in patients receiving cadaveric or living donor kidneys, there was a worrisome occurrence of post-transplant lymphoproliferative disease in several patients receiving the high dose, presumably reflecting potent immunosuppresion [178 ].

Emigrated leukocytes are also the effectors of graft-versus-host disease (GVHD) [179 , 180 ]. Blockade of leukocyte integrins was shown to ameliorate experimental GVHD (e.g., refs. [181 , 182 ]). In a small clinical trial, an anti-{alpha}Lß2 antibody was effective in treatment of steroid-resistant, acute GVHD [183 ], and the murine anti-{alpha}Lß2 mAb odulimomab has been used in France for prevention of GVHD [18 ].


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CONCLUSION
 
Antiadhesion therapy directed at leukocyte integrins and their IgSF ligands has demonstrated efficacy in multiple preclinical models of inflammatory and immune diseases. Although positive results in clinical trials have been somewhat elusive, the field has been buoyed by recent successes with recombinant, humanized mAb to {alpha}L in psoriasis and to {alpha}4 in MS and inflammatory bowel disease. Humanized, anti-integrin antibodies are being tested in other indications, and multiple companies are pursuing development of small molecule ligand mimetic antagonists. Insights into integrin structure and inside-out and outside-in signaling will also likely lead new therapies. The future of leukocyte integrin antagonist therapy is exciting, promising a new class of therapeutics with the potential to impact a broad spectrum of human diseases.


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ACKNOWLEDGEMENTS
 
This work was supported by U.S. Public Health Service Grants HL18645 (J. M. H.) and DK007662 (K. Y.).

Received August 17, 2004; revised September 13, 2004; accepted October 4, 2004.


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REFERENCES
 
    1
  1. . National Center for Health Statistics (2003) 2001 National hospital discharge survey http://www.cdc.gov/nchs/data/ad/ad332.pdf. Accessed August 14, 2004.
    2. 2
  2. Nathan, C. (2002) Points of control in inflammation Nature 420,846-852[CrossRef][Medline]
    3. 3
  3. Butcher, E. C. (1991) Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity Cell 67,1033-1036[CrossRef][Medline]
    4. 4
  4. Springer, T. A. (1995) Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration Annu. Rev. Physiol. 57,827-872[CrossRef][Medline]
    5. 5
  5. Carlos, T. M., Harlan, J. M. (1994) Leukocyte-endothelial adhesion molecules Blood 84,2068-2101[Abstract/Free Full Text]
    6. 6
  6. McIntyre, T. M., Prescott, S. M., Weyrich, A. S., Zimmerman, G. A. (2003) Cell-cell interactions: leukocyte-endothelial interactions Curr. Opin. Hematol. 10,150-158[CrossRef][Medline]
    7. 7
  7. von Andrian, U. H., Mackay, C. R. (2000) T-cell function and migration. Two sides of the same coin N. Engl. J. Med. 343,1020-1034[Free Full Text]
    8. 8
  8. Cornejo, C. J., Winn, R. K., Harlan, J. M. (1997) Anti-adhesion therapy Adv. Pharmacol. 39,99-142
    9. 9
  9. Humphries, M. J., McEwan, P. A., Barton, S. J., Buckley, P. A., Bella, J., Paul Mould, A. (2003) Integrin structure: heady advances in ligand binding, but activation still makes the knees wobble Trends Biochem. Sci. 28,313-320[CrossRef][Medline]
    10. 10
  10. Carman, C. V., Springer, T. A. (2003) Integrin avidity regulation: are changes in affinity and conformation underemphasized? Curr. Opin. Cell Biol. 15,547-556[CrossRef][Medline]
    11. 11
  11. Xiong, J. P., Stehle, T., Goodman, S. L., Arnaout, M. A. (2003) New insights into the structural basis of integrin activation Blood 102,1155-1159[Abstract/Free Full Text]
    12. 12
  12. Shimaoka, M., Springer, T. A. (2003) Therapeutic antagonists and conformational regulation of integrin function Nat. Rev. Drug Discov. 2,703-716[CrossRef][Medline]
    13. 13
  13. Crouch, M. A., Nappi, J. M., Cheang, K. I. (2003) Glycoprotein IIb/IIIa receptor inhibitors in percutaneous coronary intervention and acute coronary syndrome Ann. Pharmacother. 37,860-875[Abstract/Free Full Text]
    14. 14
  14. Lepor, N. E. (2002) Use of glycoprotein IIb/IIIa receptor inhibitors in acute coronary syndromes Rev. Cardiovasc. Med. 3(Suppl. 1),S3-S12
    15. 15
  15. Lin, K. C., Castro, A. C. (1998) Very late antigen 4 (VLA4) antagonists as anti-inflammatory agents Curr. Opin. Chem. Biol. 2,453-457[CrossRef][Medline]
    16. 16
  16. Jackson, D. Y. (2002) {alpha} 4 integrin antagonists Curr. Pharm. Des. 8,1229-1253[CrossRef][Medline]
    17. 17
  17. Yusuf-Makagiansar, H., Anderson, M. E., Yakovleva, T. V., Murray, J. S., Siahaan, T. J. (2002) Inhibition of LFA-1/ICAM-1 and VLA-4/VCAM-1 as a therapeutic approach to inflammation and autoimmune diseases Med. Res. Rev. 22,146-167[CrossRef][Medline]
    18. 18
  18. Ulbrich, H., Eriksson, E. E., Lindbom, L. (2003) Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease Trends Pharmacol. Sci. 24,640-647[CrossRef][Medline]
    19. 19
  19. Dedrick, R. L., Bodary, S., Garovoy, M. R. (2003) Adhesion molecules as therapeutic targets for autoimmune diseases and transplant rejection Expert Opin. Biol. Ther. 3,85-95[CrossRef][Medline]
    20. 20
  20. Tamkun, J. W., DeSimone, D. W., Fonda, D., Patel, R. S., Buck, C., Horwitz, A. F., Hynes, R. O. (1986) Structure of integrin, a glycoprotein involved in the transmembrane linkage between fibronectin and actin Cell 46,271-282[CrossRef][Medline]
    21. 21
  21. Hynes, R. O. (2002) Integrins: bidirectional, allosteric signaling machines Cell 110,673-687[CrossRef][Medline]
    22. 22
  22. Takagi, J., Springer, T. A. (2002) Integrin activation and structural rearrangement Immunol. Rev. 186,141-163[CrossRef][Medline]
    23. 23
  23. Kilshaw, P. J. (1999) {alpha}Eß7 Mol. Pathol. 52,203-207[Abstract]
    24. 24
  24. Danen, E. H., Sonnenberg, A. (2003) Integrins in regulation of tissue development and function J. Pathol. 201,632-641[CrossRef][Medline]
    25. 25
  25. Hogg, N., Bates, P. A. (2000) Genetic analysis of integrin function in man: LAD-1 and other syndromes Matrix Biol 19,211-222[CrossRef][Medline]
    26. 26
  26. Wehrle-Haller, B., Imhof, B. A. (2003) Integrin-dependent pathologies J. Pathol. 200,481-487[CrossRef][Medline]
    27. 27
  27. Nurden, A. T., Caen, J. P. (1974) An abnormal platelet glycoprotein pattern in three cases of Glanzmann’s thrombasthenia Br. J. Haematol. 28,253-260[Medline]
    28. 28
  28. Phillips, D. R., Agin, P. P. (1977) Platelet membrane defects in Glanzmann’s thrombasthenia. Evidence for decreased amounts of two major glycoproteins J. Clin. Invest. 60,535-545
    29. 29
  29. Roos, D., Law, S. K. (2001) Hematologically important mutations: leukocyte adhesion deficiency Blood Cells Mol. Dis. 27,1000-1004[CrossRef][Medline]
    30. 30
  30. Bunting, M., Harris, E. S., McIntyre, T. M., Prescott, S. M., Zimmerman, G. A. (2002) Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving ß 2 integrins and selectin ligands Curr. Opin. Hematol. 9,30-35[CrossRef][Medline]
    31. 31
  31. Springer, T. A., Thompson, W. S., Miller, L. J., Schmalstieg, F. C., Anderson, D. C. (1984) Inherited deficiency of the Mac-1, LFA-1, p150,95 glycoprotein family and its molecular basis J. Exp. Med. 160,1901-1918[Abstract/Free Full Text]
    32. 32
  32. Kuijpers, T. W., Van Lier, R. A., Hamann, D., de Boer, M., Thung, L. Y., Weening, R. S., Verhoeven, A. J., Roos, D. (1997) Leukocyte adhesion deficiency type 1 (LAD-1)/variant. A novel immunodeficiency syndrome characterized by dysfunctional ß2 integrins J. Clin. Invest. 100,1725-1733[Medline]
    33. 33
  33. Harris, E. S., Shigeoka, A. O., Li, W., Adams, R. H., Prescott, S. M., McIntyre, T. M., Zimmerman, G. A., Lorant, D. E. (2001) A novel syndrome of variant leukocyte adhesion deficiency involving defects in adhesion mediated by ß1 and ß2 integrins Blood 97,767-776[Abstract/Free Full Text]
    34. 34
  34. McDowall, A., Inwald, D., Leitinger, B., Jones, A., Liesner, R., Klein, N., Hogg, N. (2003) A novel form of integrin dysfunction involving ß1, ß2, and ß3 integrins J. Clin. Invest. 111,51-60[CrossRef][Medline]
    35. 35
  35. Alon, R., Aker, M., Feigelson, S., Sokolovsky-Eisenberg, M., Staunton, D. E., Cinamon, G., Grabovsky, V., Shamri, R., Etzioni, A. (2003) A novel genetic leukocyte adhesion deficiency in subsecond triggering of integrin avidity by endothelial chemokines results in impaired leukocyte arrest on vascular endothelium under shear flow Blood 101,4437-4445[Abstract/Free Full Text]
    36. 36
  36. Alon, R., Etzioni, A. (2003) LAD-III, a novel group of leukocyte integrin activation deficiencies Trends Immunol 24,561-566[CrossRef][Medline]
    37. 37
  37. Vidal, F., Aberdam, D., Miquel, C., Christiano, A. M., Pulkkinen, L., Uitto, J., Ortonne, J. P., Meneguzzi, G. (1995) Integrin ß 4 mutations associated with junctional epidermolysis bullosa with pyloric atresia Nat. Genet. 10,229-234[CrossRef][Medline]
    38. 38
  38. Pulkkinen, L., Kimonis, V. E., Xu, Y., Spanou, E. N., McLean, W. H., Uitto, J. (1997) Homozygous {alpha}6 integrin mutation in junctional epidermolysis bullosa with congenital duodenal atresia Hum. Mol. Genet. 6,669-674[Abstract/Free Full Text]
    39. 39
  39. Pulkkinen, L., Rouan, F., Bruckner-Tuderman, L., Wallerstein, R., Garzon, M., Brown, T., Smith, L., Carter, W., Uitto, J. (1998) Novel ITGB4 mutations in lethal and nonlethal variants of epidermolysis bullosa with pyloric atresia: missense versus nonsense Am. J. Hum. Genet. 63,1376-1387[CrossRef][Medline]
    40. 40
  40. Hayashi, Y. K., Chou, F. L., Engvall, E., Ogawa, M., Matsuda, C., Hirabayashi, S., Yokochi, K., Ziober, B. L., Kramer, R. H., Kaufman, S. J., Ozawa, E., Goto, Y., Nonaka, I., Tsukahara, T., Wang, J. Z., Hoffman, E. P., Arahata, K. (1998) Mutations in the integrin {alpha}7 gene cause congenital myopathy Nat. Genet. 19,94-97[CrossRef][Medline]
    41. 41
  41. Pegoraro, E., Cepollaro, F., Prandini, P., Marin, A., Fanin, M., Trevisan, C. P., El-Messlemani, A. H., Tarone, G., Engvall, E., Hoffman, E. P., Angelini, C. (2002) Integrin {alpha} 7 ß 1 in muscular dystrophy/myopathy of unknown etiology Am. J. Pathol. 160,2135-2143[Abstract/Free Full Text]
    42. 42
  42. McEver, R. P. (2002) Selectins: lectins that initiate cell adhesion under flow Curr. Opin. Cell Biol. 14,581-586[CrossRef][Medline]
    43. 43
  43. Hogg, N., Leitinger, B. (2001) Shape and shift changes related to the function of leukocyte integrins LFA-1 and Mac-1 J. Leukoc. Biol. 69,893-898[Abstract/Free Full Text]
    44. 44
  44. Schmidt, A. M., Yan, S. D., Yan, S. F., Stern, D. M. (2001) The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses J. Clin. Invest. 108,949-955[CrossRef][Medline]
    45. 45
  45. Chavakis, T., Bierhaus, A., Al-Fakhri, N., Schneider, D., Witte, S., Linn, T., Nagashima, M., Morser, J., Arnold, B., Preissner, K. T., Nawroth, P. P. (2003) The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment J. Exp. Med. 198,1507-1515[Abstract/Free Full Text]
    46. 46
  46. Schenkel, A. R., Mamdouh, Z., Muller, W. A. (2004) Locomotion of monocytes on endothelium is a critical step during extravasation Nat. Immunol. 5,393-400[CrossRef][Medline]
    47. 47
  47. Muller, W. A., Weigl, S. A., Deng, X., Phillips, D. M. (1993) PECAM-1 is required for transendothelial migration of leukocytes J. Exp. Med. 178,449-460[Abstract/Free Full Text]
    48. 48
  48. Ostermann, G., Weber, K. S., Zernecke, A., Schroder, A., Weber, C. (2002) JAM-1 is a ligand of the ß(2) integrin LFA-1 involved in transendothelial migration of leukocytes Nat. Immunol. 3,151-158[CrossRef][Medline]
    49. 49
  49. Zen, K., Babbin, B. A., Liu, Y., Whelan, J. B., Nusrat, A., Parkos, C. A. (2004) JAM-C is a component of desmosomes and a ligand for CD11b/CD18-mediated neutrophil transepithelial migration Mol. Biol. Cell 15,3926-3937[Abstract/Free Full Text]
    50. 50
  50. Schenkel, A. R., Mamdouh, Z., Chen, X., Liebman, R. M., Muller, W. A. (2002) CD99 plays a major role in the migration of monocytes through endothelial junctions Nat. Immunol. 3,143-150[CrossRef][Medline]
    51. 51
  51. Feng, D., Nagy, J. A., Pyne, K., Dvorak, H. F., Dvorak, A. M. (1998) Neutrophils emigrate from venules by a transendothelial cell pathway in response to fMLP J. Exp. Med. 187,903-915[Abstract/Free Full Text]
    52. 52
  52. Berlin, C., Bargatze, R. F., Campbell, J. J., von Andrian, U. H., Szabo, M. C., Hasslen, S. R., Nelson, R. D., Berg, E. L., Erlandsen, S. L., Butcher, E. C. (1995) {alpha} 4 integrins mediate lymphocyte attachment and rolling under physiologic flow Cell 80,413-422[CrossRef][Medline]
    53. 53
  53. Alon, R., Kassner, P. D., Carr, M. W., Finger, E. B., Hemler, M. E., Springer, T. A. (1995) The integrin VLA-4 supports tethering and rolling in flow on VCAM-1 J. Cell Biol. 128,1243-1253[Abstract/Free Full Text]
    54. 54
  54. Salas, A., Shimaoka, M., Kogan, A. N., Harwood, C., von Andrian, U. H., Springer, T. A. (2004) Rolling adhesion through an extended conformation of integrin {alpha}Lß2 and relation to {alpha}I and ß1-like domain interaction Immunity 20,393-406[CrossRef][Medline]
    55. 55
  55. DeGrendele, H. C., Estess, P., Picker, L. J., Siegelman, M. H. (1996) CD44 and its ligand hyaluronate mediate rolling under physiologic flow: a novel lymphocyte-endothelial cell primary adhesion pathway J. Exp. Med. 183,1119-1130[Abstract/Free Full Text]
    56. 56
  56. Salmi, M., Jalkanen, S. (2001) VAP-1: an adhesin and an enzyme Trends Immunol 22,211-216[CrossRef][Medline]
    57. 57
  57. Mizgerd, J. P., Meek, B. B., Kutkoski, G. J., Bullard, D. C., Beaudet, A. L., Doerschuk, C. M. (1996) Selectins and neutrophil traffic: margination and Streptococcus pneumoniae-induced emigration in murine lungs J. Exp. Med. 184,639-645[Abstract/Free Full Text]
    58. 58
  58. Wong, J., Johnston, B., Lee, S. S., Bullard, D. C., Smith, C. W., Beaudet, A. L., Kubes, P. (1997) A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature J. Clin. Invest. 99,2782-2790[Medline]
    59. 59
  59. Kuijper, P. H., Gallardo Torres, H. I., van der Linden, J. A., Lammers, J. W., Sixma, J. J., Koenderman, L., Zwaginga, J. J. (1996) Platelet-dependent primary hemostasis promotes selectin- and integrin-mediated neutrophil adhesion to damaged endothelium under flow conditions Blood 87,3271-3281[Abstract/Free Full Text]
    60. 60
  60. Weber, C., Springer, T. A. (1997) Neutrophil accumulation on activated, surface-adherent platelets in flow is mediated by interaction of Mac-1 with fibrinogen bound to {alpha}IIbß3 and stimulated by platelet-activating factor J. Clin. Invest. 100,2085-2093[Medline]
    61. 61
  61. Kirchhofer, D., Riederer, M. A., Baumgartner, H. R. (1997) Specific accumulation of circulating monocytes and polymorphonuclear leukocytes on platelet thrombi in a vascular injury model Blood 89,1270-1278[Abstract/Free Full Text]
    62. 62
  62. Kubes, P. (2002) The complexities of leukocyte recruitment Semin. Immunol. 14,65-72[CrossRef][Medline]
    63. 63
  63. Languino, L. R., Plescia, J., Duperray, A., Brian, A. A., Plow, E. F., Geltosky, J. E., Altieri, D. C. (1993) Fibrinogen mediates leukocyte adhesion to vascular endothelium through an ICAM-1-dependent pathway Cell 73,1423-1434[CrossRef][Medline]
    64. 64
  64. Simon, D. I., Chen, Z., Xu, H., Li, C. Q., Dong, J., McIntire, L. V., Ballantyne, C. M., Zhang, L., Furman, M. I., Berndt, M. C., Lopez, J. A. (2000) Platelet glycoprotein Ib {alpha} is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18) J. Exp. Med. 192,193-204[Abstract/Free Full Text]
    65. 65
  65. Santoso, S., Sachs, U. J., Kroll, H., Linder, M., Ruf, A., Preissner, K. T., Chavakis, T. (2002) The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1 J. Exp. Med. 196,679-691[Abstract/Free Full Text]
    66. 66
  66. Cunningham, S. A., Rodriguez, J. M., Arrate, M. P., Tran, T. M., Brock, T. A. (2002) JAM2 interacts with {alpha}4ß1. Facilitation by JAM3 J. Biol. Chem. 277,27589-27592[Abstract/Free Full Text]
    67. 67
  67. Taooka, Y., Chen, J., Yednock, T., Sheppard, D. (1999) The integrin {alpha}9ß1 mediates adhesion to activated endothelial cells and transendothelial neutrophil migration through interaction with vascular cell adhesion molecule-1 J. Cell Biol. 145,413-420[Abstract/Free Full Text]
    68. 68
  68. Herwald, H., Cramer, H., Morgelin, M., Russell, W., Sollenberg, U., Norrby-Teglund, A., Flodgaard, H., Lindbom, L., Bjorck, L. (2004) M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage Cell 116,367-379[CrossRef][Medline]
    69. 69
  69. Ridley, A. J., Schwartz, M. A., Burridge, K., Firtel, R. A., Ginsberg, M. H., Borisy, G., Parsons, J. T., Horwitz, A. R. (2003) Cell migration: integrating signals from front to back Science 302,1704-1709[Abstract/Free Full Text]
    70. 70
  70. Imhof, B. A., Aurrand-Lions, M. (2004) Adhesion mechanisms regulating the migration of monocytes Nat. Rev. Immunol. 4,432-444[CrossRef][Medline]
    71. 71
  71. Yang, G. X., Hagmann, W. K. (2003) VLA-4 antagonists: potent inhibitors of lymphocyte migration Med. Res. Rev. 23,369-392[CrossRef][Medline]
    72. 72
  72. Lindbom, L., Werr, J. (2002) Integrin-dependent neutrophil migration in extravascular tissue Semin. Immunol. 14,115-121[CrossRef][Medline]
    73. 73
  73. Rossetti, G., Collinge, M., Bender, J. R., Molteni, R., Pardi, R. (2002) Integrin-dependent regulation of gene expression in leukocytes Immunol. Rev. 186,189-207[CrossRef][Medline]
    74. 74
  74. Rose, D. M., Han, J., Ginsberg, M. H. (2002) {alpha}4 integrins and the immune response Immunol. Rev. 186,118-124[CrossRef][Medline]
    75. 75
  75. Stupack, D. G., Cheresh, D. A. (2002) Get a ligand, get a life: integrins, signaling and cell survival J. Cell Sci. 115,3729-3738[Abstract/Free Full Text]
    76. 76
  76. Miyamoto, Y. J., Andruss, B. F., Mitchell, J. S., Billard, M. J., McIntyre, B. W. (2003) Diverse roles of integrins in human T lymphocyte biology Immunol. Res. 27,71-84[CrossRef][Medline]
    77. 77
  77. Abraham, W. M., Sielczak, M. W., Ahmed, A., Cortes, A., Lauredo, I. T., Kim, J., Pepinsky, B., Benjamin, C. D., Leone, D. R., Lobb, R. R., et al (1994) {alpha}4-integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep J. Clin. Invest. 93,776-787
    78. 78
  78. Henderson, W. R., Jr, Chi, E. Y., Albert, R. K., Chu, S. J., Lamm, W. J., Rochon, Y., Jonas, M., Christie, P. E., Harlan, J. M. (1997) Blockade of CD49d ({alpha}4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma J. Clin. Invest. 100,3083-3092[Medline]
    79. 79
  79. de Fougerolles, A. R., Sprague, A. G., Nickerson-Nutter, C. L., Chi-Rosso, G., Rennert, P. D., Gardner, H., Gotwals, P. J., Lobb, R. R., Koteliansky, V. E. (2000) Regulation of inflammation by collagen-binding integrins {alpha}1ß1 and {alpha}2ß1 in models of hypersensitivity and arthritis J. Clin. Invest. 105,721-729[Medline]
    80. 80
  80. Krieglstein, C. F., Cerwinka, W. H., Sprague, A. G., Laroux, F. S., Grisham, M. B., Koteliansky, V. E., Senninger, N., Granger, D. N., de Fougerolles, A. R. (2002) Collagen-binding integrin {alpha}1ß1 regulates intestinal inflammation in experimental colitis J. Clin. Invest. 110,1773-1782[CrossRef][Medline]
    81. 81
  81. Ray, S. J., Franki, S. N., Pierce, R. H., Dimitrova, S., Koteliansky, V., Sprague, A. G., Doherty, P. C., de Fougerolles, A. R., Topham, D. J. (2004) The collagen binding {alpha}1ß1 integrin VLA-1 regulates CD8 T cell-mediated immune protection against heterologous influenza infection Immunity 20,167-179[CrossRef][Medline]
    82. 82
  82. Abraham, W. M., Ahmed, A., Serebriakov, I., Carmillo, A. N., Ferrant, J., de Fougerolles, A. R., Garber, E. A., Gotwals, P. J., Koteliansky, V. E., Taylor, F., Lobb, R. R. (2004) A monoclonal antibody to {alpha}1ß1 blocks antigen-induced airway responses in sheep Am. J. Respir. Crit. Care Med. 169,97-104[Abstract/Free Full Text]
    83. 83
  83. Krissansen, G. W., Elliott, M. J., Lucas, C. M., Stomski, F. C., Berndt, M. C., Cheresh, D. A., Lopez, A. F., Burns, G. F. (1990) Identification of a novel integrin ß subunit expressed on cultured monocytes (macrophages). Evidence that one {alpha} subunit can associate with multiple ß subunits J. Biol. Chem. 265,823-830[Abstract/Free Full Text]
    84. 84
  84. Engleman, V. W., Nickols, G. A., Ross, F. P., Horton, M. A., Griggs, D. W., Settle, S. L., Ruminski, P. G., Teitelbaum, S. L. (1997) A peptidomimetic antagonist of the {alpha}(v)ß3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo J. Clin. Invest. 99,2284-2292[Medline]
    85. 85
  85. Arroyo, A. G., Yang, J. T., Rayburn, H., Hynes, R. O. (1996) Differential requirements for {alpha}4 integrins during fetal and adult hematopoiesis Cell 85,997-1008[CrossRef][Medline]
    86. 86
  86. Arroyo, A. G., Taverna, D., Whittaker, C. A., Strauch, U. G., Bader, B. L., Rayburn, H., Crowley, D., Parker, C. M., Hynes, R. O. (2000) In vivo roles of integrins during leukocyte development and traffic: insights from the analysis of mice chimeric for {alpha} 5, {alpha} v, and {alpha} 4 integrins J. Immunol. 165,4667-4675[Abstract/Free Full Text]
    87. 87
  87. Koopman, G., Keehnen, R. M., Lindhout, E., Newman, W., Shimizu, Y., van Seventer, G. A., de Groot, C., Pals, S. T. (1994) Adhesion through the LFA-1 (CD11a/CD18)-ICAM-1 (CD54) and the VLA-4 (CD49d)-VCAM-1 (CD106) pathways prevents apoptosis of germinal center B cells J. Immunol. 152,3760-3767[Abstract]
    88. 88
  88. Hirsch, E., Iglesias, A., Potocnik, A. J., Hartmann, U., Fassler, R. (1996) Impaired migration but not differentiation of haematopoietic stem cells in the absence of ß1 integrins Nature 380,171-175[CrossRef][Medline]
    89. 89
  89. Potocnik, A. J., Brakebusch, C., Fassler, R. (2000) Fetal and adult hematopoietic stem cells require ß1 integrin function for colonizing fetal liver, spleen, and bone marrow Immunity 12,653-663[CrossRef][Medline]
    90. 90
  90. Scott, L. M., Priestley, G. V., Papayannopoulou, T. (2003) Deletion of {alpha}4 integrins from adult hematopoietic cells reveals roles in homeostasis, regeneration, and homing Mol. Cell. Biol. 23,9349-9360[Abstract/Free Full Text]
    91. 91
  91. Papayannopoulou, T., Craddock, C., Nakamoto, B., Priestley, G. V., Wolf, N. S. (1995) The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen Proc. Natl. Acad. Sci. USA 92,9647-9651[Abstract/Free Full Text]
    92. 92
  92. Papayannopoulou, T., Priestley, G. V., Nakamoto, B. (1998) Anti-VLA4/VCAM-1-induced mobilization requires cooperative signaling through the kit/mkit ligand pathway Blood 91,2231-2239[Abstract/Free Full Text]
    93. 93
  93. Papayannopoulou, T., Priestley, G. V., Nakamoto, B., Zafiropoulos, V., Scott, L. M., Harlan, J. M. (2001) Synergistic mobilization of hemopoietic progenitor cells using concurrent ß1 and ß2 integrin blockade or ß2-deficient mice Blood 97,1282-1288[Abstract/Free Full Text]
    94. 94
  94. Matsunaga, T., Takemoto, N., Sato, T., Takimoto, R., Tanaka, I., Fujimi, A., Akiyama, T., Kuroda, H., Kawano, Y., Kobune, M., Kato, J., Hirayama, Y., Sakamaki, S., Kohda, K., Miyake, K., Niitsu, Y. (2003) Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia Nat. Med. 9,1158-1165[CrossRef][Medline]
    95. 95
  95. . Investigators (2001) Use of anti-ICAM-1 therapy in ischemic stroke: results of the enlimomab acute stroke trial Neurology 57,1428-1434[Abstract/Free Full Text]
    96. 96
  96. Mileski, W. J., Burkhart, D., Hunt, J. L., Kagan, R. J., Saffle, J. R., Herndon, D. N., Heimbach, D. M., Luterman, A., Yurt, R. W., Goodwin, C. W., Hansborough, J. (2003) Clinical effects of inhibiting leukocyte adhesion with monoclonal antibody to intercellular adhesion molecule-1 (enlimomab) in the treatment of partial-thickness burn injury J. Trauma 54,950-958[Medline]
    97. 97
  97. Abraham, W. M., Gill, A., Ahmed, A., Sielczak, M. W., Lauredo, I. T., Botinnikova, Y., Lin, K. C., Pepinsky, B., Leone, D. R., Lobb, R. R., Adams, S. P. (2000) A small-molecule, tight-binding inhibitor of the integrin {alpha}(4)ß(1) blocks antigen-induced airway responses and inflammation in experimental asthma in sheep Am. J. Respir. Crit. Care Med. 162,603-611[Abstract/Free Full Text]
    98. 98
  98. Kudlacz, E., Whitney, C., Andresen, C., Duplantier, A., Beckius, G., Chupak, L., Klein, A., Kraus, K., Milici, A. (2002) Pulmonary eosinophilia in a murine model of allergic inflammation is attenuated by small molecule {alpha}4ß1 antagonists J. Pharmacol. Exp. Ther. 301,747-752[Abstract/Free Full Text]
    99. 99
  99. Last-Barney, K., Davidson, W., Cardozo, M., Frye, L. L., Grygon, C. A., Hopkins, J. L., Jeanfavre, D. D., Pav, S., Qian, C., Stevenson, J. M., Tong, L., Zindell, R., Kelly, T. A. (2001) Binding site elucidation of hydantoin-based antagonists of LFA-1 using multidisciplinary technologies: evidence for the allosteric inhibition of a protein-protein interaction J. Am. Chem. Soc. 123,5643-5650[CrossRef][Medline]
    100. 100
  100. Weitz-Schmidt, G., Welzenbach, K., Brinkmann, V., Kamata, T., Kallen, J., Bruns, C., Cottens, S., Takada, Y., Hommel, U. (2001) Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site Nat. Med. 7,687-692[CrossRef][Medline]
    101. 101
  101. Liu, G., Huth, J. R., Olejniczak, E. T., Mendoza, R., DeVries, P., Leitza, S., Reilly, E. B., Okasinski, G. F., Fesik, S. W., von Geldern, T. W. (2001) Novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 2. Mechanism of inhibition and structure-based improvement of pharmaceutical properties J. Med. Chem. 44,1202-1210[CrossRef][Medline]
    102. 102
  102. Welzenbach, K., Hommel, U., Weitz-Schmidt, G. (2002) Small molecule inhibitors induce conformational changes in the I domain and the I-like domain of lymphocyte function-associated antigen-1. Molecular insights into integrin inhibition J. Biol. Chem. 277,10590-10598[Abstract/Free Full Text]
    103. 103
  103. Shimaoka, M., Salas, A., Yang, W., Weitz-Schmidt, G., Springer, T. A. (2003) Small molecule integrin antagonists that bind to the ß2 subunit I-like domain and activate signals in one direction and block them in the other Immunity 19,391-402[CrossRef][Medline]
    104. 104
  104. Harris, E. S., McIntyre, T. M., Prescott, S. M., Zimmerman, G. A. (2000) The leukocyte integrins J. Biol. Chem. 275,23409-23412[Free Full Text]
    105. 105
  105. Dustin, M. L., Bivona, T. G., Philips, M. R. (2004) Membranes as messengers in T cell adhesion signaling Nat. Immunol. 5,363-372[CrossRef][Medline]
    106. 106
  106. Katagiri, K., Ohnishi, N., Kabashima, K., Iyoda, T., Takeda, N., Shinkai, Y., Inaba, K., Kinashi, T. (2004) Crucial functions of the Rap1 effector molecule RAPL in lymphocyte and dendritic cell trafficking Nat. Immunol. 5,1045-1051[CrossRef][Medline]
    107. 107
  107. Giagulli, C., Scarpini, E., Ottoboni, L., Narumiya, S., Butcher, E. C., Constantin, G., Laudanna, C. (2004) RhoA and {zeta} PKC control distinct modalities of LFA-1 activation by chemokines: critical role of LFA-1 affinity triggering in lymphocyte in vivo homing Immunity 20,25-35[CrossRef][Medline]
    108. 108
  108. Guinamard, R., Okigaki, M., Schlessinger, J., Ravetch, J. V. (2000) Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral response Nat. Immunol. 1,31-36[CrossRef][Medline]
    109. 109
  109. Tadokoro, S., Shattil, S. J., Eto, K., Tai, V., Liddington, R. C., de Pereda, J. M., Ginsberg, M. H., Calderwood, D. A. (2003) Talin binding to integrin ß tails: a final common step in integrin activation Science 302,103-106[Abstract/Free Full Text]
    110. 110
  110. Liu, L., Moesner, P., Kovach, N. L., Bailey, R., Hamilton, A. D., Sebti, S. M., Harlan, J. M. (1999) Integrin-dependent leukocyte adhesion involves geranylgeranylated protein(s) J. Biol. Chem. 274,33334-33340[Abstract/Free Full Text]
    111. 111
  111. Gakidis, M. A., Cullere, X., Olson, T., Wilsbacher, J. L., Zhang, B., Moores, S. L., Ley, K., Swat, W., Mayadas, T., Brugge, J. S. (2004) Vav GEFs are required for ß2 integrin-dependent functions of neutrophils J. Cell Biol. 166,273-282[Abstract/Free Full Text]
    112. 112
  112. Newbrough, S. A., Mocsai, A., Clemens, R. A., Wu, J. N., Silverman, M. A., Singer, A. L., Lowell, C. A., Koretzky, G. A. (2003) SLP-76 regulates Fc{gamma} receptor and integrin signaling in neutrophils Immunity 19,761-769[CrossRef][Medline]
    113. 113
  113. Hannon, G. J. (2002) RNA interference Nature 418,244-251[CrossRef][Medline]
    114. 114
  114. Gauvreau, G. M., Becker, A. B., Boulet, L. P., Chakir, J., Fick, R. B., Greene, W. L., Killian, K. J., O’Byrne, P. M., Reid, J. K., Cockcroft, D. W. (2003) 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. 112,331-338[CrossRef][Medline]
    115. 115
  115. . Roche (2004) Asthma: R411 development programme to continue http://www.roche.com/med-cor-2004-05-05. Accessed August 14, 2004.
    116. 116
  116. Ghosh, S., Goldin, E., Gordon, F. H., Malchow, H. A., Rask-Madsen, J., Rutgeerts, P., Vyhnalek, P., Zadorova, Z., Palmer, T., Donoghue, S. (2003) Natalizumab for active Crohn’s disease N. Engl. J. Med. 348,24-32Accessed August 14, 2004.[Abstract/Free Full Text]
    117. 117
  117. . Millennium (2002) Millennium announces phase II data for MLN02 in Crohn’s disease http://www.mlnm.com/media/news/2002/2002-09-16-0.asp.
    118. 118
  118. Yacyshyn, B. R., Chey, W. Y., Goff, J., Salzberg, B., Baerg, R., Buchman, A. L., Tami, J., Yu, R., Gibiansky, E., Shanahan, W. R. (2002) Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, alicaforsen (ISIS 2302), in active steroid-dependent Crohn’s disease Gut 51,30-36[Abstract/Free Full Text]
    119. 119
  119. Schreiber, S., Nikolaus, S., Malchow, H., Kruis, W., Lochs, H., Raedler, A., Hahn, E. G., Krummenerl, T., Steinmann, G. (2001) Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn’s disease Gastroenterology 120,1339-1346[CrossRef][Medline]
    120. 120
  120. . Millennium (2003) In phase II study, Millennium investigational frug MLN02 produced significant improvement in ulcerative colitis remission rates as compared to placebo http://www.mlnm.com/media/news/2003/2003-05-21-0.asp. Accessed August 14, 2004.
    121. 121
  121. Miller, D. H., Khan, O. A., Sheremata, W. A., Blumhardt, L. D., Rice, G. P., Libonati, M. A., Willmer-Hulme, A. J., Dalton, C. M., Miszkiel, K. A., O’Connor, P. W. (2003) A controlled trial of natalizumab for relapsing multiple sclerosis N. Engl. J. Med. 348,15-23[Abstract/Free Full Text]
    122. 122
  122. . All About Multiple Sclerosis (1999) Icos Corp won’t study LeukArrest as chronic MS treatment http://www.mult-sclerosis.org/news/Oct1999/LeukArrestStudyStopped.html. Accessed August 14, 2004.
    123. 123
  123. Baran, K. W., Nguyen, M., McKendall, G. R., Lambrew, C. T., Dykstra, G., Palmeri, S. T., Gibbons, R. J., Borzak, S., Sobel, B. E., Gourlay, S. G., Rundle, A. C., Gibson, C. M., Barron, H. V. (2001) Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study Circulation 104,2778-2783[Abstract/Free Full Text]
    124. 124
  124. Faxon, D. P., Gibbons, R. J., Chronos, N. A., Gurbel, P. A., Sheehan, F. (2002) The effect of blockade of the CD11/CD18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty: the results of the HALT-MI study J. Am. Coll. Cardiol. 40,1199-1204[Abstract/Free Full Text]
    125. 125
  125. Gordon, K. B., Papp, K. A., Hamilton, T. K., Walicke, P. A., Dummer, W., Li, N., Bresnahan, B. W., Menter, A. (2003) Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial JAMA 290,3073-3080[Abstract/Free Full Text]
    126. 126
  126. Lebwohl, M., Tyring, S. K., Hamilton, T. K., Toth, D., Glazer, S., Tawfik, N. H., Walicke, P., Dummer, W., Wang, X., Garovoy, M. R., Pariser, D. (2003) A novel targeted T-cell modulator, efalizumab, for plaque psoriasis N. Engl. J. Med. 349,2004-2013[Abstract/Free Full Text]
    127. 127
  127. Menter, A., Kosinski, M., Bresnahan, B. W., Papp, K. A., Ware, J. E., Jr (2004) Impact of efalizumab on psoriasis-specific patient-reported outcomes. Results from three randomized, placebo-controlled clinical trials of moderate to severe plaque psoriasis J. Drugs Dermatol. 3,27-38[Medline]
    128. 128
  128. . Genentech (2004) Genentech and XOMA announce results of phase II study of Raptiva in psoriatic arthritis patients http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=7287. Accessed August 14, 2004.
    129. 129
  129. . Genentech (2003) Genentech and XOMA discontinue rheumatoid arthritis trial http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=6107. Accessed August 14, 2004.
    130. 130
  130. Maksymowych, W. P., Blackburn, W. D., Jr, Tami, J. A., Shanahan, W. R., Jr (2002) A randomized, placebo-controlled trial of an antisense oligodeoxynucleotide to intercellular adhesion molecule-1 in the treatment of severe rheumatoid arthritis J. Rheumatol. 29,447-453[Abstract/Free Full Text]
    131. 131
  131. Krams, M., Lees, K. R., Hacke, W., Grieve, A. P., Orgogozo, J. M., Ford, G. A. (2003) Acute stroke therapy by inhibition of neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke Stroke 34,2543-2548[Abstract/Free Full Text]
    132. 132
  132. . Stoke Center (2000) Stroke interventions in clinical trials http://www.strokecenter.org/trials/interventiondetail.asp?therapyname=ints/intpage26.htm. Accessed August 14, 2004.
    133. 133
  133. Hourmant, M., Bedrossian, J., Durand, D., Lebranchu, Y., Renoult, E., Caudrelier, P., Buffet, R., Soulillou, J. P. (1996) A randomized multicenter trial comparing leukocyte function-associated antigen-1 monoclonal antibody with rabbit antithymocyte globulin as induction treatment in first kidney transplantations Transplantation 62,1565-1570[CrossRef][Medline]
    134. 134
  134. Matthews, J. B., Ramos, E., Bluestone, J. A. (2002) Clinical trials of transplant tolerance: slow but steady progress Am. J. Transplantation 3,794-803
    135. 135
  135. Salmela, K., Wramner, L., Ekberg, H., Hauser, I., Bentdal, O., Lins, L. E., Isoniemi, H., Backman, L., Persson, N., Neumayer, H. H., Jorgensen, P. F., Spieker, C., Hendry, B., Nicholls, A., Kirste, G., Hasche, G. (1999) A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group Transplantation 67,729-736[Medline]
    136. 136
  136. Vedder, N., Harlan, J., Winn, R., Maier, R., Hoyt, D., Moore, F., Fabian, T., West, M., Peitzman, A., Moore, E., Lewis, F., Malangoni, M., Morris, J., McNabney, K., Heckbert, S., Yu, A., Anardi, D., Peterman, S. (2000) Immunomodulators: inhibitors of adhesion Shock 13(supplement),1[Medline]
    137. 137
  137. Rhee, P., Morris, J., Durham, R., Hauser, C., Cipolle, M., Wilson, R., Luchette, F., McSwain, N., Miller, R. (2000) Recombinant humanized monoclonal antibody against CD18 (rhuMAb CD18) in traumatic hemorrhagic shock: results of a phase II clinical trial. Traumatic Shock Group J. Trauma 49,611-619[Medline]
    138. 138
  138. Calzada, M. J., Zhou, L., Sipes, J. M., Zhang, J., Krutzsch, H. C., Iruela-Arispe, M. L., Annis, D. S., Mosher, D. F., Roberts, D. D. (2004) {alpha}4ß1 integrin mediates selective endothelial cell responses to thrombospondins 1 and 2 in vitro and modulates angiogenesis in vivo Circ. Res. 94,462-470[Abstract/Free Full Text]
    139. 139
  139. Kunsch, C., Luchoomun, J., Grey, J. Y., Olliff, L. K., Saint, L. B., Arrendale, R. F., Wasserman, M. A., Saxena, U., Medford, R. M. (2004) Selective inhibition of endothelial and monocyte redox-sensitive genes by AGI-1067: a novel antioxidant and anti-inflammatory agent J. Pharmacol. Exp. Ther. 308,820-829[Abstract/Free Full Text]
    140. 140
  140. Foster, C. A., Dreyfuss, M., Mandak, B., Meingassner, J. G., Naegeli, H. U., Nussbaumer, A., Oberer, L., Scheel, G., Swoboda, E. M. (1994) Pharmacological modulation of endothelial cell-associated adhesion molecule expression: implications for future treatment of dermatological diseases J. Dermat. 21,847-854
    141. 141
  141. Thiagarajan, R. R., Winn, R. K., Harlan, J. M. (1997) The role of leukocyte and endothelial adhesion molecules in ischemia-reperfusion injury Thromb. Haemost. 78,310-314[Medline]
    142. 142
  142. Vuorte, J., Lindsberg, P. J., Kaste, M., Meri, S., Jansson, S. E., Rothlein, R., Repo, H. (1999) Anti-ICAM-1 monoclonal antibody R6.5 (enlimomab) promotes activation of neutrophils in whole blood J. Immunol. 162,2353-2357[Abstract/Free Full Text]
    143. 143
  143. Winn, R. K., Liggitt, D., Vedder, N. B., Paulson, J. C., Harlan, J. M. (1993) Anti-P-selectin monoclonal antibody attenuates reperfusion injury to the rabbit ear J. Clin. Invest. 92,2042-2047
    144. 144
  144. Vedder, N. B., Winn, R. K., Rice, C. L., Chi, E. Y., Arfors, K. E., Harlan, J. M. (1990) Inhibition of leukocyte adherence by anti-CD18 monoclonal antibody attenuates reperfusion injury in the rabbit ear Proc. Natl. Acad. Sci. USA 87,2643-2646[Abstract/Free Full Text]
    145. 145
  145. Palazzo, A. J., Jones, S. P., Girod, W. G., Anderson, D. C., Granger, D. N., Lefer, D. J. (1998) Myocardial ischemia-reperfusion injury in CD18- and ICAM-1-deficient mice Am. J. Physiol. 275,H2300-H2307
    146. 146
  146. Jolly, S. R., Kane, W. J., Hook, B. G., Abrams, G. D., Kunkel, S. L., Lucchesi, B. R. (1986) Reduction of myocardial infarct size by neutrophil depletion: effect of duration of occlusion Am. Heart J. 112,682-690[CrossRef][Medline]
    147. 147
  147. Iwata, A., Harlan, J. M., Vedder, N. B., Winn, R. K. (2002) The caspase inhibitor z-VAD is more effective than CD18 adhesion blockade in reducing muscle ischemia-reperfusion injury: implication for clinical trials Blood 100,2077-2080[Abstract/Free Full Text]
    148. 148
  148. Cybulsky, M. I., Iiyama, K., Li, H., Zhu, S., Chen, M., Iiyama, M., Davis, V., Gutierrez-Ramos, J. C., Connelly, P. W., Milstone, D. S. (2001) A major role for VCAM-1, but not ICAM-1, in early atherosclerosis J. Clin. Invest. 107,1255-1262[Medline]
    149. 149
  149. Tardif, J. C., Gregoire, J., Schwartz, L., Title, L., Laramee, L., Reeves, F., Lesperance, J., Bourassa, M. G., L’Allier, P. L., Glass, M., Lambert, J., Guertin, M. C. (2003) Effects of AGI-1067 and probucol after percutaneous coronary interventions Circulation 107,552-558[Abstract/Free Full Text]
    150. 150
  150. Rabb, H. A., Olivenstein, R., Issekutz, T. B., Renzi, P. M., Martin, J. G. (1994) The role of the leukocyte adhesion molecules VLA-4, LFA-1, and Mac-1 in allergic airway responses in the rat Am. J. Respir. Crit. Care Med. 149,1186-1191[Abstract]
    151. 151
  151. Bloemen, P. G., Buckley, T. L., van den Tweel, M. C., Henricks, P. A., Redegeld, F. A., Koster, A. S., Nijkamp, F. P. (1996) LFA-1, and not Mac-1, is crucial for the development of hyperreactivity in a murine model of nonallergic asthma Am. J. Respir. Crit. Care Med. 153,521-529[Abstract]
    152. 152
  152. Mileski, W. J., Rothlien, R., Lipsky, P. (1994) Interference with the function of leukocyte adhesion molecules by monoclonal antibodies: a new approach to burn injury Eur. J. Pediatr. Surg. 4,225-230[Medline]
    153. 153
  153. Podolsky, D. K. (2002) Inflammatory bowel disease N. Engl. J. Med. 347,417-429[Free Full Text]
    154. 154
  154. Jones, S. C., Banks, R. E., Haidar, A., Gearing, A. J., Hemingway, I. K., Ibbotson, S. H., Dixon, M. F., Axon, A. T. (1995) Adhesion molecules in inflammatory bowel disease Gut 36,724-730[Abstract/Free Full Text]
    155. 155
  155. Koizumi, M., King, N., Lobb, R., Benjamin, C., Podolsky, D. K. (1992) Expression of vascular adhesion molecules in inflammatory bowel disease Gastroenterology 103,840-847[Medline]
    156. 156
  156. Briskin, M., Winsor-Hines, D., Shyjan, A., Cochran, N., Bloom, S., Wilson, J., McEvoy, L. M., Butcher, E. C., Kassam, N., Mackay, C. R., Newman, W., Ringler, D. J. (1997) Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue Am. J. Pathol. 151,97-110[Abstract]
    157. 157
  157. . Biogen Idec (2004) Elan and Biogen Idec announce results from phase III maintenance trail of ANTEGREN® in Crohn’s disease at digestive disease week http://www.biogen.com/site/019_0.html. Accessed August 14, 2004.
    158. 158
  158. . Biogen Idec (2004) Elan and Biogen Idec announce intention to submit ANTEGREN® for approval for Crohn’s disease in Europe http://www.biogen.com/site/019_0.html. Accessed August 14, 2004.
    159. 159
  159. Hafler, D. A. (2004) Multiple sclerosis J. Clin. Invest. 113,788-794[CrossRef][Medline]
    160. 160
  160. Gordon, E. J., Myers, K. J., Dougherty, J. P., Rosen, H., Ron, Y. (1995) Both anti-CD11a (LFA-1) and anti-CD11b (MAC-1) therapy delay the onset and diminish the severity of experimental autoimmune encephalomyelitis J. Neuroimmunol. 62,153-160[CrossRef][Medline]
    161. 161
  161. Yednock, T. A., Cannon, C., Fritz, L. C., Sanchez-Madrid, F., Steinman, L., Karin, N. (1992) Prevention of experimental autoimmune encephalomyelitis by antibodies against {alpha} 4 ß 1 integrin Nature 356,63-66[CrossRef][Medline]
    162. 162
  162. . Biogen Idec (2004) Biogen Idec and Elan submit biologics license application to the FDA for approval of ANTEGREN®, for multiple sclerosis based on one-year data http://www.biogen.com/site/019_0.html. Accessed August 14, 2004.
    163. 163
  163. . Biogen Idec (2004) Biogen Idec and Elan submit application to the European medicines agency for approval of ANTEGREN® for multiple sclerosis based on one-year data http://www.biogen.com/site/019_0.html. Accessed August 14, 2004.
    164. 164
  164. Nickoloff, B. J., Nestle, F. O. (2004) Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities J. Clin. Invest. 113,1664-1675[CrossRef][Medline]
    165. 165
  165. Jullien, D., Prinz, J. C., Langley, R. G., Caro, I., Dummer, W., Joshi, A., Dedrick, R., Natta, P. (2004) T-cell modulation for the treatment of chronic plaque psoriasis with efalizumab (Raptiva): mechanisms of action Dermatology 208,297-306[CrossRef][Medline]
    166. 166
  166. . Genentech (2003) FDA approves Raptiva (efalizumab) for chronic moderate-to-severe plaque psoriasis http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=6707. Accessed August 14, 2004.
    167. 167
  167. Issekutz, A. C., Ayer, L., Miyasaka, M., Issekutz, T. B. (1996) Treatment of established adjuvant arthritis in rats with monoclonal antibody to CD18 and very late activation antigen-4 integrins suppresses neutrophil and T-lymphocyte migration to the joints and improves clinical disease Immunology 88,569-576[CrossRef][Medline]
    168. 168
  168. Szekanecz, Z., Koch, A. E. (2004) Therapeutic inhibition of leukocyte recruitment in inflammatory diseases Curr. Opin. Pharmacol. 4,423-428[CrossRef][Medline]
    169. 169
  169. Kavanaugh, A. F., Davis, L. S., Nichols, L. A., Norris, S. H., Rothlein, R., Scharschmidt, L. A., Lipsky, P. E. (1994) Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule 1 Arthritis Rheum 37,992-999[Medline]
    170. 170
  170. Kavanaugh, A. F., Davis, L. S., Jain, R. I., Nichols, L. A., Norris, S. H., Lipsky, P. E. (1996) A phase I/II open label study of the safety and efficacy of an anti-ICAM-1 (intercellular adhesion molecule-1; CD54) monoclonal antibody in early rheumatoid arthritis J. Rheumatol. 23,1338-1344[Medline]
    171. 171
  171. Fuggle, S. V., Koo, D. D. (1998) Cell adhesion molecules in clinical renal transplantation Transplantation 65,763-769[CrossRef][Medline]
    172. 172
  172. Tanio, J. W., Basu, C. B., Albelda, S. M., Eisen, H. J. (1994) Differential expression of the cell adhesion molecules ICAM-1, VCAM-1, and E-selectin in normal and posttransplantation myocardium. Cell adhesion molecule expression in human cardiac allografts Circulation 89,1760-1768[Abstract/Free Full Text]
    173. 173
  173. Isobe, M., Suzuki, J., Yagita, H., Okumura, K., Yamazaki, S., Nagai, R., Yazaki, Y., Sekiguchi, M. (1994) Immunosuppression to cardiac allografts and soluble antigens by anti-vascular cellular adhesion molecule-1 and anti-very late antigen-4 monoclonal antibodies J. Immunol. 153,5810-5818[Abstract]
    174. 174
  174. Cavazzana-Calvo, M., Sarnacki, S., Haddad, E., De Coene, C., Calise, D., Yvon, E., Cerf-Bensussan, N., Fischer, A. (1995) Prevention of bone marrow and cardiac graft rejection in an H-2 haplotype disparate mouse combination by an anti-LFA-1 antibody Transplantation 59,1576-1582[Medline]
    175. 175
  175. Sarnacki, S., Auber, F., Cretolle, C., Camby, C., Cavazzana-Calvo, M., Muller, W., Wagner, N., Brousse, N., Revillon, Y., Fischer, A., Cerf-Bensussan, N. (2000) Blockade of the integrin {alpha}Lß2 but not of integrins {alpha}4 and/or ß7 significantly prolongs intestinal allograft survival in mice Gut 47,97-104[Abstract/Free Full Text]
    176. 176
  176. Fischer, A., Friedrich, W., Fasth, A., Blanche, S., Le Deist, F., Girault, D., Veber, F., Vossen, J., Lopez, M., Griscelli, C., et al (1991) Reduction of graft failure by a monoclonal antibody (anti-LFA-1 CD11a) after HLA nonidentical bone marrow transplantation in children with immunodeficiencies, osteopetrosis, and Fanconi’s anemia: a European Group for Immunodeficiency/European Group for Bone Marrow Transplantation report Blood 77,249-256[Abstract/Free Full Text]
    177. 177
  177. Cavazzana-Calvo, M., Bordigoni, P., Michel, G., Esperou, H., Souillet, G., Leblanc, T., Stephan, J. L., Vannier, J. P., Mechinaud, F., Reiffers, J., Vilmer, E., Landman-Parker, J., Benkerrou, M., Baruchel, A., Pico, J., Bernaudin, F., Bergeron, C., Plouvier, E., Thomas, C., Wijdenes, J., Lacour, B., Blanche, S., Fischer, A. (1996) A phase II trial of partially incompatible bone marrow transplantation for high-risk acute lymphoblastic leukaemia in children: prevention of graft rejection with anti-LFA-1 and anti-CD2 antibodies. Societe Francaise de Greffe de Moelle Osseuse Br. J. Haematol. 93,131-138[CrossRef][Medline]
    178. 178
  178. Kuypers, D. R., Vanrenterghem, Y. F. (2004) Monoclonal antibodies in renal transplantation: old and new Nephrol. Dial. Transplant. 19,297-300[Free Full Text]
    179. 179
  179. Reddy, P. (2003) Pathophysiology of acute graft-versus-host disease Hematol. Oncol. 21,149-161[CrossRef][Medline]
    180. 180
  180. Noti, J. D. (2004) Expression and function of the leukocyte integrins in organ transplant rejection Curr. Med. Chem. 11,477-490[CrossRef][Medline]
    181. 181
  181. Harning, R., Pelletier, J., Lubbe, K., Takei, F., Merluzzi, V. J. (1991) Reduction in the severity of graft-versus-host disease and increased survival in allogenic mice by treatment with monoclonal antibodies to cell adhesion antigens LFA-1 {alpha} and MALA-2 Transplantation 52,842-845[Medline]
    182. 182
  182. Tanaka, T., Ohtsuka, Y., Yagita, H., Shiratori, Y., Omata, M., Okumura, K. (1995) Involvement of {alpha}1 and {alpha}4 integrins in gut mucosal injury of graft-versus-host disease Int. Immunol. 7,1183-1189[Abstract/Free Full Text]
    183. 183
  183. Stoppa, A. M., Maraninchi, D., Blaise, D., Viens, P., Hirn, M., Olive, D., Reiffers, J., Milpied, N., Gaspard, M. H., Mawas, C. (1991) Anti-LFA1 monoclonal antibody (25.3) for treatment of steroid-resistant grade III-IV acute graft-versus-host disease Transpl. Int. 4,3-7[CrossRef][Medline]



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