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Cell Adhesion Molecules

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Table of Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1

Products at a Glance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2

Selectins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4

Integrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6

Immunoglobulin Superfamily Members . . . . . . . . . . . . . . . . . . . . . . . . . .10

Cadherins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12

Product Listing/Ordering Information . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16

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either as a stand-alone product or as a component of another product. Any

use of this product other than the permitted use without the express written

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Introduction

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Adhesion molecules enable cells tocontact and specifically interactwith each other, a requirement of allmulticellular organisms. Specializedcell-cell and cell-matrix interactionsallow communication between cellsand the surrounding environmentand are crucial for development andfunctional activity. Several differentfamilies of receptors mediate theseinteractions. The families of celladhesion molecules identified todate include selectins, integrins, Ig superfamily members, and cadherins. (Please refer to Productsat a Glance on page 2) Members of these adhesion receptor familiesare critical in:• embryonic development• differentiation• migration• inflammation• cancer metastasis• wound healing

The mechanisms regulating adhesiveinteractions are complex. A singlecell can express an array of differentadhesion receptors, and a singlereceptor may bind to more than oneligand. Both expression and functional activity of adhesion molecules are influenced by a variety of factors, including thedevelopmental stage of the cell and the presence of activating factors such as specific antigen and inflammatory mediators. In addition, different adhesion receptors may operate successivelyin time. This has been well demonstrated for leukocyte extravasation into sites of inflammation, in which adhesionmolecules from the selectin, integrin, and immunoglobulinreceptor families work successively as part of an “adhesion cascade”.

Cover image: Madin-Darby Canine Kidney(MDCK) cells stained with γ -Catenin (c1.15) by immunofluorescent microscopy.

This review presents a brief summary of the structure and function of the members of theselectin, integrin, Ig superfamily and cadherin families of adhesion molecules. In addition, it providesan up-to-date listing of BDBiosciences products useful forstudying cell adhesion from themRNA level to the cellular level.


Adhesion Products at a Glance

Monoclonal Antibodies to Adhesion Molecules

Adhesion Molecule CD Mouse Rat Human

SelectinsE-selectin CD62E 10E9.6 68-5H11L-selectin CD62L MEL-14 HRL1, HRL2 Dreg 56, SK11P-selectin CD62P RB40.34, Polyclonal Polyclonal AK-4, Polyclonal, GA6

Integrinsα1 CD49a Ha31/8 Ha31/8 SR84α2 (VLA-2α) CD49b HMα2, Ha1/29 Ha1/29 12F1-H6, AK-7, 2α3 (VLA-3α) CD49c 42 42 C3 II.1, P1B5α4 CD49d R1-2, 9C10 (MFR4.B), SG31 MRα4-1 9F10α5 CD49e 5H10-27 (MFR5), HMα5-1 HMα5-1 VC5, IIA1, 1α6 CD49f GoH3 GoH3α IEL CD103 2E7, M290αL CD11a 2D7, M17/4 WT.1 G43-25B, HI111, G25.2, 27αM CD11b M1/70 WT.5 ICRF44, D12αM/αX CD11b/c OX-42αV CD51 H9.2B8, RMV-7, 21 21 21αX (gp150) CD11c HL3 B-ly6, SHCL-3α IIb CD41 MWReg30 HIP2β1 CD29 9EG7, KMI6, Ha2/5, HMβ1-1, 18 Ha2/5, HMβ1-1, 18 MAR4, HUTS-21, mAb13, 18β2 (gp95) CD18 GAME-46, C71/16, M18/2 WT.3 6.7, L130β3 (gpIIIa) CD61 2C9.G2 F11, 2C9.G2 VI-PL2, RUU-PL7F12, 1α IIbβ3 (gpIIb/IIIa) CD41/CD61 HIP8αVβ3 (vitronectin R) CD51/CD61 23C6β4 CD104 346-11A, 7 439-9B, 450-11A, 450-9DαVβ5 P1F6β7 M293, FIB27 FIB504, FIB27α4β7 (LPAM-1) DATK32

Immunoglobulin SuperfamilyBCM1 CD48 HM48-1 Tü14SBL-CAM CD22 Cy34.1 HIB22, SHCL-1ICAM-1 CD54 3E2 1A29 HA58, LB-2ICAM-2 CD102 3C4 (mIC2/4)ICAM-3 CD50 TU41LFA-2 CD2 RM2-5 OX-34 RPA-2.10, S5.2LFA-3 CD58 1C3, L306MCAM MUC-18 1N-CAM CD56 12F8, N-CAM 13, 12F11 12F8, N-CAM 13, 12F11 B159, MY31, NCAM 16.2Neurothelin CD147 HIM6PECAM-1 CD31 390, MEC 13.3 TLD-3A12 WM59, L133.1RNCAM RB-8 NCAM 44 44 44VCAM-1 CD106 429 (MVCAM.A) MR106 51-10C9

CadherinsCadherin-5 (VE-Cadherin) CD144 11D4.1 75, 55-7H1E-Cadherin 34 34E-Cadherin 36 36 36M-Cadherin 5 5N-Cadherin 32 32 32, NCAD2P-Cadherin 56 56 56R-Cadherin 48 48Desmoglein 62 62 62

Cateninsα-Catenin 5 5 5β-Catenin 14 14 14γ-Catenin 15 15 15pp120/p120Cas 98 98 98


Monoclonal Antibodies to Adhesion Molecules, continued

Adhesion Molecule CD Mouse Rat Human

OthersCLA HECA-452Endoglin CD105 MJ7/18 266,35Fibrinogen 2C2-G7Fibronectin 10 10 2B6-D4, 10gpIx CD42a ALMA.16gpIba CD42b HIP1gpIV CD36 CB38 (NL07)LAMP-1 CD107a 1D4B H4A3LAMP-2 CD107b ABL-93 H4B4Leukosialin CD43 S7, 1B11 HIS17 1G10, L60MAdCAM-1 MECA-367, MECA-89Mucosialin CD34 RAM34 581OX-40 Antigen CD134 OX-40 ACT35Pgp-1, H-CAM CD44/CD44H IM7, KM114, TM-1 OX-49 G44-26, L178PNAd (CD62L Ligand) MECA-79PSGL-1 (CD62P Ligand) CD162 2PH1 KPL-1P-selectin-IgG Fusion Protein Sialyl Lewis X CD15s 2H5 2H5Syndecan-1 CD138 281-2

For antibody formats and catalog numbers, please refer to product listing on page 13.

RiboQuant™ Integrin Multi-Probe Template Sets Size Cat. No.hITG-1: α1, α2, α3, α4, α5, α6, α7, α8, α9, αAv, αB 10 rxn 45695PhITG-2: α IEL, β4,α4, β5, αA6, β6, β7, β8, αv 10 rxn 45696PhITG-3: αA2b, αd, α l, αm, αx, β2, β3, β7 β8, βv 10 rxn 45697P

Also availableRiboQuant™ In-Vitro Transcription Kit 25 rxn 45004KRiboQuant™ RPA Kit 200 samples 45014K

Purified Extracellular Matrix Proteins*

Protein Source (species) Size Cat. No.Collagen I bovine 30 mg 35 4231Collagen I human 0.25 mg 35 4243Collagen I rat tail 100 mg 35 4236

1 g 35 6236Collagen III human 0.25 mg 35 4244Collagen IV human .25 mg 35 4245Collagen IV mouse 1 mg 35 4233

10 mg 35 6233Collagen V human 0.25 mg 35 4246Fibronectin human 1 mg 35 4008

5 mg 35 600825 mg 35 6009

Laminin mouse 1 mg 35 4232Ultrapure Laminin mouse 1 mg 35 4239Vitronectin human 0.25 mg 35 4238

*To order these purified ECM proteins and related products, please call your local BD Biosciences Repersentative.

Selectins constitute a family of carbohydrate-binding cell adhesionmolecules comprised of three relatedcell surface molecules: L-selectin(CD62L), P-selectin (CD62P), andE-selectin (CD62E). Each of theselectins has a similar structurecomposed of an extracellular N-terminal calcium-dependent C-type lectin domain, a single epidermal growth factor-typedomain and a variable number ofconsensus repeats with sequencessimilar to those in complement regulatory proteins. Additionally,the selectins have a transmembraneregion followed by a short cytoplasmic domain (Figure 1).

Expression

L-selectin expression is limited tohematopoietic cells (reviewed in 1).It is constitutively expressed on themajority of B cells, thymocytes andnaive T cells, but not on most memory T cells. As shown in Figure 2, expression of L-selectin(CD62L) is reduced on lymph nodeT cells with an activated/memoryphenotype (CD3+ CD25+ CD44high).L-selectin is expressed duringmyeloid differentiation and is present on most mature neutrophilsand monocytes. Activation of lymphocytes through antigen receptors or activation of neutrophils by chemokines results in a rapid and transient increase in L-selectin binding affinity for ligand (2). Following activation, lymphocytes and neutrophils undergo a reversible loss of L-selectin from the cell surfacedue to endoproteolytic cleavage (1).

P-selectin is stored preformed inWeibel-Palade bodies of endothelialcells and granules of platelets (3).Following activation with inflam-matory agents, it is rapidly mobilized to the cell surface (4) (Figure 3). Expression of P-selectin at the cell surface is transient and decreases substantially within minutes.

E-selectin expression is largelyrestricted to activated endothelialcells. Expression of E-selectin onvascular endothelium is induced byLPS and by cytokines such as IL-1or TNF-α, and the inductionrequires de novo mRNA and protein synthesis (5). Soluble formsof L-, P-, and E-selectin can be detected in plasma and, in somecases, alterations in plasma levels ofselectins have been associated withdisease (reviewed in 6).

Ligands

Due to the fact that selectins contain domains homologous to C-type lectins, analysis of selectinbinding to ligand has focused mainly on carbohydrate recognitionby the lectin domains (reviewed in 7).Although the detailed structure ofselectin ligands has not been determined, it is known that allthree selectins can bind sialyl LewisX-type (sLeX) and sialyl Lewis A-type (sLeA) structures. Mouse L-selectin has been shown to bindGlyCAM-1, MAdCAM-1, andCD34 in vitro. Each of these ligandsis heavily glycosylated and has sulfated, sialylated, and fucosylatedO-linked carbohydrate side chains


Figure 3. Expression of P-selectin(CD62P) is upregulated on activatedperipheral blood platelets. Humanperipheral blood platelets were activated with thrombin. Unstimulated(A) or thrombin-activated platelets (B)were stained with with anti-CD62P-PE(AK-4) (solid line) or an isotype control(dashed line) and analyzed by flowcytometry.

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Figure 2. L-selectin (CD62L) is notexpressed on most CD3+ CD25+

CD44high cells. Mouse lymph nodecells were stained with mAbs to CD3(145-2C11), CD25 (PC61), CD44 (IM7)and CD62L (MEL-14). Results of staining CD3+ CD25+ cells with anti-CD44 (solid line) or an isotype control(dotted line) are shown in Panel A.The gates in panel A were used toshow CD62L expression on CD3+ CD25+

CD44low (dotted line) and CD3+ CD25+

CD44high (solid line) cells

Figure 1. Selectin Structure. Each selectin is composed of an amino terminal C-type lectin domain(Lectin), an epidermal growth factor-like domain (EGF), a variable number of complement regulatoryprotein-like domains (CRP), a transmembrane domain (TM), and a short cytoplasmic domain.

A

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Lectin EGF CRP TM


that are essential for L-selectin binding. GlyCAM-1 and CD34were originally identified on thehigh endothelial venules of lymphnodes (7). In addition, CD34 isexpressed on hematopoietic progenitor cells in the bone marrowand endothelial cells throughout thebody, and GlyCAM is secreted inmilk. However, when expressed insites outside the lymph nodes, bothCD34 and GlyCAM lack the specific carbohydrate modificationsrequired for L-selectin binding.

P-selectin binds to the glycoproteinP-selectin ligand-1 (PSGL-1,CD162) (8) (Figure 4). PSGL-1 is asialomucin that must be specificallysialylated, fucosylated, and sulfatedto bind to P-selectin. Although mostresting neutrophils, monocytes andlymphocytes express PSGL-1, very few (10-20%) express the functionally active form (8,9).

E-selectin ligand-1 (ESL-1) is themajor ligand for E-selectin. ESL-1 isbroadly expressed, but only myeloidand lymphoid cells express a glyco-sylated form that is functionallyactive (10). E-selectin has also beenshown to bind to PSGL-1, althoughwith lower affinity than the P-selectin/PSGL-1 interaction (11).

Function

Selectins function in the initial step of recruitment of leukocytes (primarily neutrophils) to the site of an inflammatory reaction. Loosetethering to the endothelium resultsin a decrease in leukocyte velocityand rolling along the blood vesselwall (Figure 5A). Leukocyte rollingin most vessels begins within

minutes following tissue injury, andnumerous studies have indicatedthat these interactions are primarilymediated by selectins. The rapidtransport of P-selectin from intra-cellular granules to the plasma membrane is thought to contributeto the early stage of rolling, while L- and E-selectin are involved insubsequent stages.

The physiologic importance ofselectin-mediated adhesion is clearly demonstrated in the clinicalsyndrome called leukocyte adhesiondeficiency type-II (LAD-II). LAD-IIresults from a defect in the synthesisof fucosylated carbohydrates, whichinclude E- and P-selectin ligands(12). In this rare disorder, patientshave defects in neutrophil rollingand extravasation, and they sufferfrom recurrent, severe bacterialinfections (13). More recently,“knockout” mice deficient in eachof the selectins have been described(reviewed in 1). Study of these micehas added to our understanding ofthe role of selectins in inflammation.

Figure 4. Anti-mouse PSGL-1 (CD162) mAb2PH1 blocks adhesion of activated mousespleen cells to immobilized P-selectin-Igfusion protein. Cells were activated with Con A and then cultured in wells coated withBSA or with P-selectin-Ig (Cat. No. 28111A).Prior to culture, 2PH1 antibody was added tothe cells or anti-P-selectin antibody (RB40.34)was added to the coated wells. Percent cellbinding was determined after 2 hours.

Figure 5. Leukocyte migration. (A) Rolling. Selectins mediate the loose adherence of the leukocytes to endothelial cells of the vessel walls.Chemoattractants interact with receptor molecules on the leukocyte surface leading to activation of integrins. B) Attachment/Arrest. Integrins bind tointercellular adhesion molecules (ICAMs) leading to stronger adhesion of leukocytes to the endothelium. C) Transendothelial migration. Leukocytesresponding to a chemoattractant concentration gradient squeeze through the endothelial cell junction (diapedesis).

A. Rolling

B. AttachmentC. Transendothelial

Migration

Integrins


Integrins are a family of cell surfacereceptors that mediate interactionswith extracellular matrix components and with other cells.All integrins are heterodimers composed of non-covalently linked α and β subunits of approximately1,100 and 750 amino acids, respectively (reviewed in 14)(Figure 6).

The integrins can be divided intodistinct subfamilies based on βsubunit association. Originally, integrins were classified into threefamilies: the β1 integrins or very late

activation antigens (VLA) (15), theβ2 integrins or LeuCAMs, and theβ3 integrins or cytoadhesins. Due tothe identification of additional βsubunits and the discovery that certain α subunits can associatewith more that one β chain, the current classification scheme is lessrigid. Currently, at least 8 differentβ and 16 different α chains havebeen identified (Figure 7). Thesereceptors bind to a variety of extracellular matrix and cell adhe-sion molecules, as shown in Table I.

Abbreviations: collagen (CN), fibrinogen (FG), fibronectin (FN), intercellular adhesion molecule(ICAM), laminin (LN), mucosal addressin cell adhesion molecule-1 (MadCAM-1), vitronectin (VN)

Table I. Integrins and Ligands

Integrins Ligands/Counter receptorsα1β1 LN, CNα2β1 LN, CN, FNα3β1 CN, LN, FN, epiligrinα4β1 FN, VCAM-1, invasinα5β1 FN, CNα6β1 LNα7β1 LNα8β1 FN, VN, tenascinα9β1 tenascinαvβ1 VN, FNαvβ3 VN, FN, FG, von Willebrand factor,

thrombospondin, CN, tenascinα IIbβ3 FG, FN, von Willebrand factor, VN,

thrombospondin, CN α6β4 LNαvβ5 VNαvβ6 FN, tenascinα4β7 FN, MAdCAM-1, VCAM-1α IELβ7 E-Cadherinαvβ8 VNαLβ2 ICAM-1, -2, -3αMβ2 ICAM-1, FG, iC3b, Factor XαXβ2 FG, iC3b, ICAM-1, LPSαdβ2 ICAM-3

Figure 6. General structure of the integrinfamily. Each integrin receptor is composedof an α and a β subunit which are noncovalently linked. The α chain containsseveral divalent cation binding sites (M2+).The β chain contains a series of cysteine-rich repeats in the extracellular domain.The ligand binding region is made up of sequences from both the α and the β subunits.

Figure 7. Integrin α and β subunit heterodimers.

Ligand Binding Area

β1 IntegrinsThe β1 integrins comprise thelargest subfamily of integrins andare expressed on a wide variety ofcells. Although resting leukocytescan express detectable levels of β1 integrins including α1 - α6β1,expression is dramatically upregulated by cell activation(reviewed in 16) (Figure 8).Expression of β1 can also be developmentally regulated. Forexample, the level of cell surfaceα4β1 on thymocytes decreases as the cells mature (17) (Figure 9).

Most β1 integrins adhere to extracellular matrix (ECM) components (Table I). The ECM is a complex assortment of proteinsand carbohydrates found in spacesbetween cells. It provides strengthand physical support in tissues andplays an important role in regulating cell activities. (PurifiedECM proteins available from BDBiosciences are listed in Products at a Glance on page 3). The α4β1integrin is unusual in that it canbind to both fibronectin and vascular cell adhesion molecule-1(VCAM-1). The interaction of α4β1with VCAM-1 mediates lymphocytebinding to activated endothelialcells. In addition to their role inleukocyte adhesion, β1 integrinsplay a critical role in embryonicdevelopment (reviewed in 18).

β2 Integrins

The β2 subunit (CD18) has beendemonstrated to form heterodimerswith 4 different α chains, αL(CD11a), αM (CD11b), αX (CD11c),and αd (reviewed in 19) (Figure 7).Unlike the other integrin subfami-lies, the expression of β2 integrins is restricted to leukocytes.

LFA-1 (αLβ2) is expressed on lymphocytes, granulocytes, monocytes, and macrophages, and the level of expression isincreased upon activation (20).LFA-1 binds to ICAM-1 (CD54),ICAM-2 (CD102) and ICAM-3(CD50). The interaction of LFA-1with its ligands plays a critical role in a wide rage of functions,including T and B cell responses adhesion of leukocytes to endothelial cells (reviewed in 14).

Mac-1 (αMβ2) is expressed at high levels on monocytes and granulocytes and at lower levels ona subset of T cells (reviewed in 21).Activation of monocytes and granulocytes by inflammatory stimuli leads to mobilization ofintracellular stores of Mac-1 and arapid increase in its cell surfaceexpression. Mac-1 binds to the iC3bcomplement component, fibrinogen,factor X and ICAM-1. Interactionof Mac-1 with iC3b mediatesphagocytosis of opsonized targets.Mac-1 is also involved in thetransendothelial migration of monocytes and neutrophils.p150,95 (αXβ2) is expressed mainlyby dendritic cells, monocytes,macrophages, and granulocytes, but it is also found at lower levelson NK cells and activated T cells.αXβ2 binds to iC3b, ICAM-1, fibrinogen, and bacterial lipopolysaccharide. Interaction ofαXβ2 with, as yet, unidentified ligandsis important in monocyte and neutrophil adhesion to inflamedendothelium (22) and may beinvolved in cytotoxic T cell activity(23).

Figure 8. Expression of CD49e (α5 integrin) is upregulated on activated T lymphocytes. BALB/csplenocytes were stained with eitheranti-mouse CD49e-PE (5H10-27) (solidlines) or an isotype control (R35-95)(dashed lines). Cells were eitherunstimulated (A) or activated by culturing in the presence of 4 µg/mlCon A for 48 hours prior to staining(B). Splenocytes were analyzed by twocolor flow cytometry. Propidiumiodide was used to exclude dead cells.


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The more recently identified αdβ2integrin is expressed at high levelson macrophages in the red pulp ofthe spleen and on foam cells in aortic fatty streaks (24). It isexpressed at lower levels on subsetsof peripheral blood leukocytes. The αdβ2 integrin binds to ICAM-3,but not ICAM-1 or VCAM-1 (24).

β3 Integrins

The β3 integrin subunit (CD61)forms heterodimers with αIIb(CD41) and with αv (CD51)(reviewed in 25). The αIIbβ3receptor is constitutively expressedon platelets. While αIIbβ3 on unstimulated platelets can bind tofibrinogen only, αIIbβ3 on activatedplatelets is capable of binding to fibrinogen, von Willebrand factor,fibronectin, vitronectin and thrombospondin.

Adhesion mediated by αIIbβ3 plays acritical role in platelet aggregationand activation. Platelet activation isaccompanied by a conformationalchange in αIIbβ3 (26), and ligandbinding induces a further conformational change (27).

The αvβ3 receptor is expressed on avariety of both hematopoietic andnon-hematopoietic cells includingendothelial cells, monocytes,macrophages, neutrophils, platelets,some activated lymphocytes,smooth muscle cells, osteoclasts,and tumor cells. It binds to vitronectin, fibrinogen, fibronectin,von Willebrand factor and thrombospondin (25). αvβ3 isinvolved in platelet and leukocytebinding to endothelium.


Figure 9. CD49d (α4 integrin)expression is downregulated asthymocytes mature. BALB/c thymocyteswere stained with fluorochrome-labeled monoclonal antibodiesspecific for CD4 (RM4-5), CD8 (53-6.7), and CD49d (R1-2). For dataanalysis, gates were set to include CD4-CD8- (A), CD4+CD8+ (B) orCD4+CD8- (C) populations. For eachgated population, histograms show the staining pattern generated with anti-CD49d (solid line) compared to an isotype control (dashed line).

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Integrins, Continued

β4-β8 Integrins

β4 integrin (CD104) forms a heterodimer with the α6 subunit(CD49f) which binds to laminin(28). It is expressed on epithelialcells (29), subsets of endothelialcells (30) and subsets of immature thymocytes in the mouse (31). As shown in Figure 7, the β5 (32), β6 (33) and β8 (34) subunits all formheterodimers with the αv subunit.The β7 subunit can combine with α4and αIEL subunits (35). The α4β7heterodimer is expressed on NKcells, eosinophils and most mature lymphocytes (36), and it can bind to fibronectin, VCAM-1 andMAdCAM-1 (37). The αIELβ7integrin is expressed by the majority of intraepithelial lymphocytes and interacts with E-cadherin on the surface of mucosal epithelial cells (38).

Function

Integrins have a well defined role inthe movement of leukocytes intosites of inflammation. Following theinitial phase of rolling mediated byselectins, the flow of leukocytes isslowed further by the interaction of integrins with intercellular adhesion molecules (ICAMs)expressed on activated endothelialcells (Figure 5B). As integrins generally do not bind ligand unlessthey are in an activated state, the cells must first receive a stimulusthat activates the integrin. The stimulus may be provided bychemokines, crosslinking ofleukoycte receptors such as CD2and CD3, or signals induced bybinding to molecules such as E- and P- selectin on the surface of the endothelial cells (reviewed in 39).

Recent studies suggest thatchemokines, in particular, are amajor factor in activation of inte-grin-mediated adhesion to endothe-lium and subsequent leukocytearrest. The PharMingen catalogdescribes available chemokine products.

Firm adhesion of activated leukocytes to endothelial cells ismediated by both β1 and β2subfamilies of integrin receptors.Adhesion of neutrophils to endothelial cells is mediated primarily by the interaction of β2integrins LFA-1 (αLβ2) and Mac-1(αMβ2) with ICAM-1 and ICAM-2expressed by endothelial cells. Inaddition, adhesive interactionsmediated by β1 integrins can contribute to leukocyte extravasation. The interaction ofα4β1 integrin with VCAM-1expressed on activated endothelialcells contributes to emigration oflymphocytes, monocytes, basophils,and eosinophils (reviewed in 39).

The importance of β2 integrin-mediated adhesion in vivo is illustrated by the leukocyte adhesiondeficiency type I syndrome (LAD-I)in which there is either partial ortotal absence of β2 integrins onleukocytes. Patients with this inherited condition suffer fromsevere, recurrent bacterial and fungal infections. Their neutrophilsexhibit rolling, but do not adhere to endothelial tissue and fail to emigrate from the blood stream to sites of inflammation (40). Similar defects in neutrophil migration are observed in ICAM-1 deficient mice (41,42).


The immunoglobulin (Ig) superfamily is composed of cell surface molecules that containimmunoglobulin-like domains.There are over 100 members of his superfamily, and a number ofthem play an important role in cell adhesion. Each Ig superfamily member contains a variable numberof immunoglobulin-like domainscomposed of 70 to 100 amino acidresidues organized into two anti-parallel β sheets. In most cases,these sheets are stabilized by disulphide bonds. Although the tertiary structures of the domainsare very similar among the differentmembers of this superfamily, the primary structures are highlyvariable.

ICAM-1 (CD54)Intercellular adhesion molecule-1(ICAM-1) is a single chain 80-114 kDa protein with five Ig-likedomains, a single transmembraneregion, and a short cytoplasmicdomain (43). It can bind to LFA-1,Mac-1, fibrinogen, hyaluronan, andCD43 (reviewed in 44). Restingleukocytes express little or nodetectable ICAM-1, but expressionis induced following activation(reviewed in 45). Resting endothe-lial cells have low levels of ICAM-1,and activation with inflammatorycytokines such as IL-1, IFN-γ, andTNF-α results in increased expression on endothelial cells inaddition to induction on epithelialand mesenchymal cells (45). ICAM-1functions as a major cell-cell adhesion molecule in inflammation.In addition, human ICAM-1 is utilized as a receptor for the majorgroup of rhinoviruses (46) and has been identified as an in vitro

receptor for binding of Plasmodiumfalciparum infected erythrocytes to postcapillary venular endothelium (47).

ICAM-2 (CD102)ICAM-2 (55-65 kDa) has two Ig-like domains (48,49). Resting lymphocytes and monocytes, but not neutrophils, express lowlevels of cell surface ICAM-2.Immunohistochemical analysis indicates high expression of ICAM-2 on endothelium and onfollicular dendritic cells in lymphnode germinal centers (50). In contrast to the pattern of expressionobserved for ICAM-1, ICAM-2 isnot upregulated on leukocytes orcultured endothelium followingstimulation with inflammatorymediators (48,50). Ligands recog-nized by ICAM-2 include LFA-1(51)and Mac-1(52). The precise role of ICAM-2 is not understood, but it isthought to be important in recirculation of leukocytes throughuninflamed tissue endothelium (53).

ICAM-3 (CD50)ICAM-3 is a 120-160 kDa moleculeand, like ICAM-1, it contains five Igdomains (54). It is constitutivelyexpressed at high levels on leukocytes (Figure 10), but, in contrast to ICAM-1 and ICAM-2, it is not found on most endothelialcells (55). ICAM-3 binds to LFA-1,but not Mac-1 (56). The interactionof ICAM-3 with LFA-1 is thoughtto be involved in the initial bindingof T cells to antigen presenting cells.The mouse homolog of ICAM-3 hasnot yet been identified.


Immunoglobulin SuperfamilyMembers Involved in Cell Adhesion

Figure 10. Expression of ICAM-3 (CD50)on epidermal Langerhans cells. The section of human skin was stained withanti-human ICAM-3 (clone TU41).

Figure 11. Expression of CD2 on periarteriolar T lymphocytes in humanspleen. The section of human spleenwas stained with anti-human CD2(clone RPA2.10)


LFA-2 (CD2)Leukocyte function associated molecule-2 (LFA-2) is a 50 kDamolecule with two Ig-like domains.Its structure and function have beenrecently reviewed (57). In humansand rats LFA-2 is restricted to thymocytes, T cells and NK cells(Figure 11), while in the mouse it isalso expressed on B cells. Inhumans, LFA-2 binds to LFA-3, and in the mouse and rat CD48 isthe major ligand. Binding of LFA-2to its ligands contributes to adhesion between T cells and antigen presenting cells or targetcells. In addition, LFA-2 can transmit activation signals to thelymphocyte, and there is evidencethat these signals may synergize in T cell activation.

LFA-3 (CD58)LFA-3 is similar to LFA-2 in structure in that it also contains twoIg-like domains (reviewed in 45).LFA-3 can exist in either transmem-brane or glycosyl-phosphatidylinosi-tol linked forms. It is expressed on avariety of cells including leukocytes,endothelial cells, epithelial cells, erythrocytes and fibroblasts. As discussed above, it binds to CD2.No LFA-3 homologue has beenidentified in the mouse or the rat.

NCAM (CD56)Neural cell adhesion molecule(NCAM) exists in various isoforms (120-180 kDa), includingboth transmembrane and glycosyl-phosphatidylinositol linked forms.The different isoforms are generatedby alternative splicing and by post-translational modifications. NCAMis expressed on neural tissue andmuscle cells and is transiently

expressed on many cells duringembryogenesis. In humans, but notmice or rats, it is also expressed onNK cells and a subset of T cells.NCAM is involved in homotypicbinding and has also been demonstrated to interact with collagen, heparin/heparan sulfate,and chondroitin sulfate proteogly-cans. NCAM mediates cell-cell andcell-matrix interactions and isthought to be involved in control ofneuronal development. The role ofNCAM expression on human lymphocytes has not yet been clearly defined.

PECAM-1 (CD31)CD31 is a 120-130 kDa cell surfacemolecule with six Ig-like domains. It is present on platelets, some leukocytes, and at higher levels inthe intercellular junctions ofendothelial cells (reviewed in 58).CD31 is expressed on the endothelium of all vessel types andis a useful marker of blood vessels(Figure 12). Among leukocytesCD31 can be expressed by monocytes and neutrophils, as wellas by unique subsets of T lympho-cytes, particularly naive CD8+ Tcells. Bone marrow stem cells andtransformed cell lines of the myeloidand megakaryocytic lineage alsoexpress CD31. CD31 can interact inhomotypic binding and also withCD38 and the αvβ3 integrin (58-60).Antibodies to CD31 interfere withformation of endothelial cell junctions and block neutrophil andmonocyte chemotaxis (61). Evidencesuggests that CD31 is required for neutrophil and monocyte trans-migration in vivo. In both in vitroand in vivo studies, CD31 has beendemonstrated to play a role in

transendothelial migration of neutrophils and monocytes which is independent of adhesive interactions on the lumenal surface(61) (Figure 5C).

VCAM-1 (CD106)Vascular cell adhesion molecule(VCAM-1) (110 kDa) has seven Ig-like domains (reviewed in 62).Expression is induced on endothelialcells by inflammatory mediators suchas IL-1 and TNF-α. VCAM-1 is alsoexpressed on some macrophages,dendritic cells, bone marrow stromal cells, synovial cells ininflamed joints, and muscle cells.VCAM-1 is recognized by the integrins α4β1 (VLA-4) and α4β7and supports the extravasation ofleukocytes, particularly at sites ofinflammation. In addition, VCAM-1can participate in adhesion outsidethe vasculature, including binding oflymphocytes to dendritic cells andbone marrow stromal cells.

Figure 12. Expression of PECAM-1 (CD31) on ratendothelial cells. The frozen section of rat spleenwas stained with anti-rat CD31 (TLD-3A12).

Cadherins are a superfamily ofadhesion receptors expressed by allcells that form solid tissues. Theymediate homotypic interactions inzonula adherens, tight junctions,gap junctions, and desmosomes.One cell type can express multiplecadherins, and the expression pattern is cell-type specific. The cadherins superfamily can be subdivided into classical cadherinstypes I and II, desmosomal cadherins, protocadherins, andother proteins related to cadherins(63). Classical cadherins contain alarge N-terminal extracellularregion consisting of repeated βbarrel domains that contain Ca2+

binding sites. The C-terminus consists of a transmembrane regionand a cytoplasmic domain, throughwhich cadherins interact withcatenins, cytoplasmic proteins thatconnect cadherins to cytoskeletalcomponents (64). Classical cadherins possess a conserved cytoplasmic domain that interactswith either β or γ catenin which, in turn, binds to α catenin(reviewed in 65). α catenin is anactin binding protein which linksthe cadherin-catenin complex to thecytoskeleton. This intracellularanchorage is required for functionalcadherin-mediated cell adhesion.

Type I classical cadherins include E-, N-, and P- cadherins. E-cadherinis found in most epithelial tissuesand is required for many aspects ofepithelial morphogenesis (Figure 13). Reduced E-cadherinexpression correlates with the invasiveness and metastatic potential of human tumors, suggesting that E-cadherin dysfunction can contribute to progression of carcinomas (reviewed in 66). In addition tomediating homophilic binding, E-cadherin can bind to the integrinαIELβ7. N-cadherin is expressed on

endothelial cells (67), neural cellsand some muscle tissue and hasbeen shown to have neurite growthpromoting activity (reviewed in 63).P-cadherin is expressed in embryonic tissue and in the placenta. Expression of P-cadherinduring embryogenesis is developmentally regulated andappears to differ between mice andhumans (reviewed in 68).

The type II classical cadherinsinclude more recently described cadherins 5 through 12 (63).Cadherin 5, also known as VE-cadherin, is restricted to endothelialcells (Figure 14) and may be important in angiogenesis and control of vascular permeability(reviewed in 69).

Desmoglein and desmocollin arecadherins associated with cell-celljunctions called desmosomes. Thesecadherins interact with a cytoplasmic plaque consisting ofdesmoplakin and plakoglobin (γ-catenin), which are attached tokeratin intermediate filaments.

Protocadherins are the most diversegroup of cadherins. They often contain more than five extracellularrepeats and their cytoplasmicdomains differ in homology and sizecompared to the other cadherins(reviewed in 70) . Although theirintracellular domains have not been shown to interact with cytoplasmic adhesion proteins or to associate with intracellular filament systems, protocadherinsbind Ca2+ and can mediate weakintercellular interactions.

Please refer to Products at a Glanceon page 2 for BD Biosciences antibodies specific for cadherins and catenins.

Cadherins


Figure 13. Expression of E-cadherin on humancells. WiDr adenocarcinoma cells were stainedwith E-Cadherin (clone 36) by immunofluores-cent microscopy.

Figure 14. Expession of VE-Cadherin (CD144) on rat endothelial cells. The frozen section ofmouse heart was stained with anti-mouse VE-Cadherin (11D4.1).

PharMingen and Transduction Laboratories have a complete portfolio ofproducts related to cell adhesion molecules, including:

• Chemokines

• Signal Transduction Molecules

• Inflammatory Cytokines

• Cytokine and

Chemokine Receptors


Product Listing

Antibodies to Mouse Adhesion Molecules

Specificity Clone NA/LE™ Purified Biotin FITC PE APC, HRP, TRITC,CyChrome™

Selectinsmouse E-selectin 10E9.6 09520D 09521D 09522D 09525Bmouse L-selectin MEL-14 01260D 01261D 01262D 01264D 01265B 01269A (APC)mouse P-selectin RB40.34 09480D 09481D 09482D 09484Dhuman P-selectin (x reacts w/mouse) Polyclonal 09361A

Integrinsmouse α1 chain Ha31/8 22620D 22621Dmouse α2 chain HMα2 09790D 09791D 09794A 09795Arat α2 chain (x reacts w/mouse) Ha1/29 22611D 22614Dmouse α3 chain 42 V76720mouse α4 chain R1-2 01270D 01271D 01272A 01274D 01275Bmouse α4 chain 9C10 01730D 01731D 01732A 01734Dmouse α4 chain SG31 28270D 28271A 28272A 28275Amouse α5 chain 5H10-27 01740D 01741D 01742A 01745Amouse α5 chain HMα5-1 01881Dmouse α6 chain GoH3 33771A 33774X 33775Xmouse α IEL chain 2E7 09031A 09032A 09034Amouse α IEL chain M290 09310D 09311A 09312A 09314A 09315Amouse αL chain 2D7 01201D 01202A 01204D 01205Amouse αL chain M17/4 01840D 01841A 01842A 01844Dmouse αM chain M1/70 01710D 01711A 01712A 01714A 01715A 01719A (APC)mouse αV chain H9.2B8 01520D 01521D 01522A 01525Amouse αV chain RMV-7 28350D 28351Ahuman αV chain (x reacts w/mouse) 21 C75120mouse αX chain HL3 09701D 09702D 09704A 09705Amouse α IIb chain MWReg30 09911D 09914Dmouse β1 chain 9EG7 09351Dmouse β1 chain KMI6 09461Arat β1 chain (x reacts w/mouse) Ha2/5 22630D 22631D 22632D 22634Dmouse β1 chain HMβ1-1 09871Dhuman β1 chain (x reacts w/mouse) 18 I41720mouse β2 chain GAME-46 28040D 28041Amouse β2 chain C71/16 01661A 01662A 01664D 01665Amouse β2 chain M18/2 01850D 01851Amouse β3 chain 2C9.G2 01860D 01861D 01862D 01864D 01865Bmouse β4 chain 346-11A 09491Dhuman β4 chain (x reacts w/mouse) 7 I86220mouse β7 chain M293 09321D 09322A 09324A 09325Amouse β7 chain FIB27 09750D 09751Amouse LPAM-1 DATK32 09741A 09745B

Immunoglobulin Superfamilymouse BCM1 HM48-1 09170D 09171A 09174A 09175Amouse Lyb-8.2 Cy34.1 01981A 01982D 01984A 01985Bmouse ICAM-1 3E2 01540D 01541D 01542D 01544D 01545Dmouse ICAM-2 3C4 01800D 01801D 01802A 01804Amouse LFA-2 RM2-5 01171D 01172D 01174D 01175Bmouse N-CAM 12F8 60221Amouse N-CAM N-CAM 13 60211Amouse N-CAM 12F11 60201Amouse PECAM-1 390 09330D 09331A 09332A 09334Amouse PECAM-1 MEC 13.3 01950D 01951A 01952D 01954D 01955Bmouse RNCAM 44 R79220mouse VCAM-1 429 01810D 01811D 01812D 01814D

Green indicates Transduction Laboratories products.


Product ListingAntibodies to Mouse Adhesion Molecules, Continued

Specificity Clone NA/LE™ Purified Biotin FITC PE APC, HRP, TRITC, CyChrome™

Cadherinshuman E-Cadherin 36 C20820mouse M-Cadherin 5 C79620human N-Cadherin 32 C70320human P-Cadherin 56 C24120mouse R-Cadherin 48 C38020mouse VE-Cadherin 11D4.1 28091Dhuman Desmoglein 62 D28120

Cateninsmouse α-Catenin 5 C21620mouse β-Catenin 14 C19220 C19224 C19225 (HRP)human γ-Catenin 15 C26220mouse pp120/p120Cas 98 P17920 P17924 P17926 (TRITC)

Othersmouse Endoglin MJ7/18 09761Dhuman Fibronectin 10 F14420mouse LAMP-1 1D4B 09671D 09674Dmouse LAMP-2 ABL-93 09681A 09684Amouse Leukosialin S7 01601D 01602D 01604D 01605Bmouse Leukosialin 1B11 09691A 09694A 09695Amouse MAdCAM-1 MECA-367 09720D 09721Dmouse MAdCAM-1 MECA-89 09731D 09732Dmouse CD34 RAM34 09431D 09432D 09434Dmouse Pgp-1 IM7 01220D 01221D 01222D 01224D 01225A 01229A (APC)

01228A (CyChrome™)mouse Pgp-1 KM114 09410D 09411Amouse Pgp-1 TM-1 28151D 28154Dmouse PNAd, Carbohydrate epitope MECA-79 09961Dmouse PSGL-1 28111Amouse PSGL-1 2PH1 28170D 28171D 28175Bmouse Syndecan-1 281-2 09341D 09342D 09345B

Antibodies to Rat Adhesion Molecules

Selectinsrat L-selectin HRL1 22471A 22472A 22474D 22475Brat L-selectin (non-blocking) HRL2 22481Ahuman P-selectin (x reacts w/rat) Polyclonal 09361A

Integrinsrat α1 chain Ha31/8 22620D 22621Drat α2 chain Ha1/29 22611Dmouse α3 chain (x reacts w/rat) 42 V76720rat α4 chain MRa4-1 01871D 01874Amouse α5 chain (x reacts w/rat) HMα5-1 01881Drat αL chain WT.1 22541A 22544D 22545B rat αM chain WT.5 22531D 22532D 22534Drat αM/αX chain OX-42 22080D 22081D 22082D 22084D 22085Bhuman αV chain (x reacts w/rat) 21 C75120rat β1 chain Ha2/5 22630D 22631D 22632D 22634Dmouse β1 chain (x reacts w/rat) HMβ1-1 09871Dhuman β1 chain (x reacts w/rat) 18 I41720rat β2 chain WT.3 22520D 22521D 22524Drat β3 chain F11 22440D 22441D 22444Drat β3 chain 2C9.G2 01860D 01861D 01862D 01864D 01865B

Green indicates BD Transduction Laboratories products.


Product ListingAntibodies to Rat Adhesion Molecules, Continued

Specificity Clone NA/LE™ Purified Biotin FITC PE APC, HRP, TRITC, CyChrome™

Immunoglobulin Superfamilyrat ICAM-1 1A29 22490D 22491D 22492D 22494D 22495Brat LFA-2 OX-34 22001D 22004D 22005Brat PECAM-1 TLD-3A12 22710D 22711D 22712D 22715Amouse RNCAM (x reacts w/rat) 44 R79220rat VCAM-1 MR106 22681D 22685A

Cadherinshuman E-Cadherin (x reacts w/rat) 34 C37020human E-Cadherin (x reacts w/rat) 36 C20820mouse M-Cadherin (x reacts w/rat) 5 C79620human N-Cadherin (x reacts w/rat) 32 C70320human P-Cadherin (x reacts w/rat) 56 C24120mouse R-Cadherin (x reacts w/rat) 48 C38020human Desmoglein (x reacts w/rat) 62 D28120

Cateninsmouse α-Catenin (x reacts w/rat) 5 C21620mouse β-Catenin (x reacts w/rat) 14 C19220 C19224 C19225 (HRP)human γ-Catenin (x reacts w/rat) 15 C26220mouse pp120/p120Cas (x reacts w/rat) 98 P17920 P17924 P17926 (TRITC)

Othershuman Fibronectin (x reacts w/rat) 10 F14420rat Leukosialin HIS17 22101D 22102Drat OX-40 Antigen OX-40 22041A 22042D 22044Drat Pgp-1 OX-49 22111D 22114D 22115Bhuman Sialyl Lewis X (x reacts w/rat) 2H5 33601A 33604X

Antibodies to Human Adhesion Molecules

Selectinshuman E-selectin 68-5H11 33361A 33362Ahuman L-selectin Dreg 56 32230D 32231A 32234X 32235X 32239X (APC)

32238X (CyChrome™)human L-selectin SK11 37481Bhuman P-selectin AK-4 31791A 31794X 31795Xhuman P-selectin Polyclonal 09361Ahuman P-selectin GA6 37321B

Integrinshuman α1 SR84 37711A 37714X 37715Xhuman α1 chain 12F1-H6 33441A 33445Xhuman α2 chain AK-7 31420D 31421A 31424Xhuman α2 chain (VLA-2α) 2 V75320human α3 chain C3 II.1 36611A 36615Xhuman α3 chain P1B5 36911Ahuman α4 chain 9F10 31470D 31471A 31475X 31479X (APC)human α5 chain VC5 33370D 33371A 33372Xhuman α5 chain IIA1 33220D 33221A 33222X 33225Xhuman α5 chain 1 I55220mouse α6 chain (x reacts w/human) GoH3 33771A 33774X 33775Xhuman αL chain G43-25B 30420D 30421A 30424X 30425Xhuman αL chain HI111 30440D 30441A 30444X 30445Xhuman αL chain G25.2 37341Bhuman αL chain (LFA-1α) 27 L65320human αM chain ICRF44 (44) 30450D 30451A 30452X 30455X 30459X (APC)

30458X (CyChrome™)human αM chain D12 37351B

Product Listing

Antibodies to Human Adhesion Molecules, Continued


Integrins, Continued

human αV chain 21 C75120human αX chain B-ly6 30480D 30481A 30485Xhuman αX chain SHCL-3 37361Bhuman αIIb chain HIP2 31091A 31094Xhuman β1 chain MAR.4 30861A 30865X 30868X (CyChrome™)human β1 chain mAb13 37551Bhuman β1 chain HUTS-21 36740D 36741A 36745Xhuman β1 chain 18 I41720human β2 chain 6.7 35651A 35654X 35655X 35658X (CyChrome™)human β2 chain L130 36901A 36904Xhuman β3 chain VI-PL2 33821A 33824X 33825Xhuman β3 chain RUU-PL7F12 37561Bhuman β3 chain 1 I81720human αvβ3 23C6 31561A 31564Xhuman αIIb/β3 HIP8 31081A 31084X 31085X 31089X (APC)

31088X (CyChrome™)human β4 chain 439-9B 33691A 33695Xhuman β4 chain (cytoplasmic domain) 450-11A 33711Ahuman β4 chain 450-9D 33701Ahuman β4 chain 7 I86220human αVβ5 P1F6 37151Amouse β7 chain FIB27 09750D 09751Dmouse β7 chain FIB504 35811A 35815X

Immunoglobulin Superfamilyhuman BCM1 Tü145 33851A 33854X 33855Xhuman CD22 HIB22 30711A 30714X 30718X (CyChrome™)human CD22 SHCL-1 37371Bhuman ICAM-1 HA58 31620D 31621A 31625X 31629X (APC)

31628X (CyChrome™)human ICAM-1 LB-2 37461Bhuman ICAM-3 TU41 36011A 36014Xhuman LFA-2 RPA-2.10 30050D 30051A 30052X 30054X 30055X 30058X (CyChrome™)human LFA-2 S5.2 37331Bhuman LFA-3 1C3 35611A 35614X 35615Xhuman LFA-3 L306 36891A 36895Xhuman MCAM 1 M85020NCAM 12F11 60201ANCAM 12F8 60221Ahuman N-CAM 5G3 15551Ahuman N-CAM (CD56) B159 31660D 31661A 31662X 31665X 31669X (APC)

31668X (CyChrome™)human N-CAM MY31 37491Bhuman N-CAM NCAM16.2 37421Bhuman Neurothelin HIM6 36091A 36094Xhuman PECAM-1 WM59 30881A 30884X 30885Xhuman PECAM-1 L133.1 37411Bmouse RNCAM 44 R79220human VCAM-1 51-10C9 33350D 33351A 33352A 33355X

Cadherinshuman Cadherin-5 75 C26120human VE-cadherin 55-7H1 33411Ahuman E-Cadherin 34 C37020


Green indicates BD Transduction Laboratories products.


Antibodies to Human Adhesion Molecules, Continued


Cadherins, Continued

human E-Cadherin 36 C20820human N-Cadherin 32 C70320human P-Cadherin 56 C24120human Desmoglein 62 D28120

Cateninsmouse α-Catenin 5 C21620mouse β-Catenin 14 C19220 C19224 C19225 (HRP)human γ-Catenin 15 C26220mouse pp120/p120Cas 98 P17920 P17924 P17926 (TRITC)

Othershuman CLA HECA-452 35821A 35824Xhuman Endoglin 266 33551Ahuman Endoglin 35 E90320human Fibrinogen 2C2-G7 35031Ahuman Fibronectin 10 F14420human Fibronectin 2B6-D4 35041Ahuman gpIX ALMA.16 37281A 37284X 37285Xhuman gpIba HIP1 31130D 31131A 31134X 31135Xhuman gpIV CB38 (NL07) 30981A 30984X 30985Xhuman LAMP-1 H4A3 34201A 34202X 34204X 34205X 34208X (CyChrome™)human LAMP-2 H4B4 34211A 34214Xhuman Leukosialin 1G10 31140D 31141A 31144Xhuman Leukosialin L60 37431Bhuman OX-40 ACT35 34461A 34464X 34465Xhuman Pgp-1 G44-26 31211A 31212X 31214X 31215X 31219X (APC)human Pgp-1 L178 37451Bhuman PSGL-1 KPL-1 36770Dhuman Sialyl Lewis X (CD15s) 2H5 33601A 33604X

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