Email updates

Keep up to date with the latest news and content from Arthritis Research & Therapy and BioMed Central.

This article is part of the series Cell-cell interactions in synovitis.

Review

Endothelial cells and immune cell migration

Zoltan Szekanecz1 and Alisa E Koch12

Author Affiliations

1 University of Debrecen Medical and Health Sciences Center, Debrecen, Hungary

2 Northwestern University Medical School, Chicago, USA

For all author emails, please log on.

Arthritis Res 2000, 2:368-373  doi:10.1186/ar114

The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/2/5/368


Received:10 March 2000
Accepted:23 May 2000
Published:3 July 2000

© 2000 Current Science Ltd

Abstract

Leukocyte ingress into the synovium is a key process in the pathogenesis of rheumatoid arthritis and other inflammatory conditions. In this review, the role of endothelial cells in leukocyte extravasation will be discussed, including the role of the most relevant cellular adhesion molecules. These molecules play an important role in mediating leukocyte-endothelial interactions. It is likely that different adhesive pathways are involved in different steps of leukocyte adhesion to and migration through endothelia. Targeting of pathological endothelial function, including leukocyte-endothelial adhesion, may be useful for the future management of inflammatory arthritis.

Keywords:
Adhesion molecules; endothelium; leukocyte migration; rheumatoid arthritis

Introduction

Leukocyte extravasation through the endothelial barrier is important in the pathogenesis of inflammatory disorders such as rheumatoid arthritis (RA). Endothelial cells line the lumina of vessels, thus separating and also connecting the blood and the synovial tissue. It has become clear that, in inflammation, endothelial cells are not only passive bystanders but are active responders to various stimuli (state of activation of leukocytes, exogenous cytokines, endogenous endothelial mediators, and crosstalk between adhesion molecules). Thus endothelia are targets for inflammatory leukocytes and their mediators. In return, endothelial cells themselves produce a number of inflammatory mediators, express cellular adhesion molecules (CAMs) and therefore directly influence the action of leukocytes and the outcome of the inflammatory response [1,2].

Endothelial cells are involved in a number of mechanisms underlying arthritis. Various inflammatory mediators, primarily pro-inflammatory cytokines including tumor necrosis factor (TNF)-α and IL-1β, activate endothelial cells. In response, there is an upregulation of endothelial CAMs in RA, leading to increased leukocyte-endothelial interactions [2,3,4].

In this review we discuss the role of endothelial cells, as well as that of leukocyte-endothelial adhesion and migration in synovial inflammation. First we describe the general characteristics of leukocyte-endothelial adhesion. Then the role of the most relevant CAMs, as well as that of the most important adhesive pathways determined by these CAMs in arthritis is introduced. Finally we discuss potential strategies of targeting these mechanisms.

Leukocyte-endothelial interactions in synovitis

The ingress of leukocytes into the synovium is an active process mediated by a number of CAMs. The cascade of events begins with the adhesion of neutrophils, lymphocytes and monocytes to the specialized, fenestrated synovial endothelium [4,5]. High endothelial venule (HEV)-like microvessels, similar to HEVs in the primary lymphoid organs, are present in the rheumatoid synovial tissue [2,4,5]. Thus the process of leukocyte extravasation into the synovium closely resembles physiological lymphocyte `homing'. After adhesion, leukocytes transmigrate through the vessel wall into the synovium [6**,7**,8,9].

CAMs have been classified into a number of superfamilies. However, most CAMs involved in endothelial adhesion belong to three supergene familes, the integrin, selectin and immunoglobulin families [6**,7**,8,9]. Leukocyte adhesion to endothelial cells occurs in four distinct steps [9,10**] (Table 1):

1. Primary, relatively weak adhesion termed `rolling' occurs within the first 1-2 h. It is mediated by E-, P-and L-selectins and their counter-receptors.

2. Leukocyte activation and triggering occurs next and is due to the interactions between chemokine receptors on leukocytes and proteoglycans on endothelial cells. Platelet-endothelial adhesion molecule (PECAM)-1 (or CD31) and the soluble platelet-activating factor (PAF) are also involved in this step.

3. Activation-dependent, firm adhesion occurs within 4-6 h. This interaction is mediated mostly by α4β1 integrin-vascular cell adhesion molecule (VCAM)-1 and αLβ2 integrin [or lymphocyte function-associated antigen (LFA)-1]-intercellular adhesion molecule (ICAM)-1 interactions.

4. Transendothelial migration or diapedesis occurs when secreted chemokines bind to endothelial heparan sulphate glycosaminoglycans. Chemokines attract endothelium-bound neutrophils and/or mononuclear leukocytes preferentially. Integrins recognizing fibronectin and laminin enable leukocyte extravasation [9,10**]. Leukocyte adhesion to and migration through the vascular endothelium result in the formation of inflammatory infiltrates within the synovium [2,4,5].

Table 1. Distinct steps during leukocyte emigration into the arthritic synovium

Cellular adhesion molecules and pathways in the rheumatoid synovium

Selectins contain an extracellular N-terminal domain related to lectins, an epidermal growth factor-like domain and moieties related to complement regulatory proteins [6**,7**, 8,9]. This superfamily of CAMs includes E-, P- and L-selectin. Among these CAMs, E- and P-selectin are present and cytokine-inducible on endothelial cells; they are therefore markers of endothelial activation in inflammation [4,6**,7**,11]. E- and P-selectin ligands, such as E-selectin ligand (ESL)-1, P-selectin ligand (PSGL)-1 and cutaneous leukocyte antigen (CLA), contain sialylated glycan motifs [12,13,14]. E-selectin mediates the adhesion of neutrophils and, to a smaller extent, eosinophils, monocytes and some memory T cells to endothelia [15]. E-selectin has been associated with dermal and pulmonary inflammation in animal models [16,17]. We and others found an abundant expression of E-selectin in the synovial tissues [18*,19]. P-selectin is constitutively present on the membrane of endothelial Weibel-Palade bodies and is involved in neutrophil and monocyte adhesion to endothelium[6**,7**,20,21*]. Because the upregulation of P-selectin expression on endothelia occurs within seconds, this CAM is thought to be involved in the very early phases of adhesion [22]. We demonstrated P-selectin expression on RA synovial endothelial cells [23].

Integrins are αβ heterodimers and are classified into families with respect to their commonβ subunits (β18) [6**,7**,8,9]. Among these CAMs, β1 and β3 integrins are expressed on endothelial cells. These integrins (α1-9β1, αVβ3) mediate cell adhesion to ECM components, including various types of collagen, laminin, fibronectin, fibrinogen, tenascin, vitronectin and thrombospondin [6**,7**,8]. Not only are integrins involved in endothelial cell adhesion to ECM, but sometimes they are able to mediate cell-cell contacts. In the latter situation, integrins bind to CAMs belonging to the immunoglobulin superfamily. The two most relevant receptor-counter-receptor pairs are α4β1 integrin recognizing VCAM-1 and β2 integrins (LFA-1 and Mac-1) binding to ICAM-1 and ICAM-3 [6**,7**,24]. We and others have demonstrated the abundant expression of endothelial integrins in synovial inflammation [4,5,23,24,25,26].

VCAM-1, a ligand for the integrins α4β1 and α4β7, is constitutively expressed on resting endothelial cells but its expression is markedly upregulated by IL-1, TNF-α and IL-4 [4,27]. Abundant VCAM-1 expression has been associated with inflammatory infiltrates [28]. We and others have reported the expression of VCAM-1 on synovial endothelial cells, and also on macrophages in RA [4,18*,29].

ICAM-1 serves as a ligand for the β2 integrins LFA-1(αLβ2), Mac-1 (αMβ2) and p150,95 (αXβ2) [6**,7**,8,9].ICAM-1 shows basal expression on endothelial cells; however, its expression can be further stimulated by IL-1, TNF-α and interferon-γ [30*]. In vitro, the maximal expression of ICAM-1 on endothelia is observed later (more than 24h) than that of E-selectin or VCAM-1 [1]. ICAM-1 is highly expressed on endothelial cells in inflammatory sites such as the inflamed synovium in situ [4,16,18*].

Other CAMs mediating endothelial cell adhesion to cells in the inflamed synovium include LFA-3, PECAM-1 (CD31), CD44, CD66, vascular adhesion protein (VAP)-1, endoglin, ICAM-3 and possibly others [4,5,6**,7**,8, 31,32,33,34]. LFA-3 and its counter-receptor CD2 are members of the immunoglobulin superfamily. Whereas CD2 is a T cell marker, LFA-3 is present on endothelial cells. The CD2/LFA-3 adhesion pathway is involved in various inflammatory responses including synovitis [4,31]. PECAM-1, another member of the immunoglobulin super-gene family, mediates homotypic adhesion by binding to PECAM-1, and heterotypic adhesion by recognizing the αVβ3 integrin [6**,7**,8,35]. PECAM-1 is a marker of activated endothelium; we found it in large quantities in the RA synovium [23,33]. CD44 is a receptor for hyaluronate[6**,7**,8] and is present on activated endothelial cells in inflammation including RA [23,36]. VAP-1 was originally isolated from synovial endothelial cells. The expression of VAP-1 is increased in RA [32]. Endoglin is a receptor for transforming growth factor (TGF)-β1 and TGF-β3, and is involved in endothelial adhesion. We have detected endoglin on most endothelial cells in the RA synovium [34]. ICAM-3 is a leukocyte CAM that is a known ligand for LFA-1. It is absent from resting endothelial cells. However, we could detect ICAM-3 on a portion of RA synovial endothelial cells [24,37], which suggests the possible role of endothelial ICAM-3 in synovitis. Thus a number of CAMs might have a role in leukocyte-endothelial interactions underlying inflammatory synovitis.

In RA, the most important adhesive interactions between leukocytes and endothelial cells are determined by α4β1-VCAM-1, β2 integrin (LFA-1, Mac-1)-ICAM-1 and CD2-LFA-3 interactions, as well as E- and P-selectins, CD44, PECAM-1 and their ligands. These adhesion pathways are summarized in Table 2.

Table 2. The most important leukocyte-endothelial adhesion pathways in rheumatoid arthritis

Leukocyte-endothelial adhesion: a possible target for antirheumatic therapy

There have been several attempts to therapeutically block leukocyte adhesion to endothelium, and thus to control inflammation. Adhesion and the expression of CAMs can be targeted with currently used antirheumatic agents, specific monoclonal antibodies, purified protein or carbohydrate ligands, soluble adhesion molecules, gene therapy or other methods [4]. Leukocyte-endothelial adhesion and adhesion molecules have been targeted in vitro, in animal models of arthritis, and recently in humans.

With regard to studies in vitro, dexamethasone (a glucocorticoid compound) and bucillamine (a D-penicillamine derivative) inhibit T cell adhesion to cultured synovial fibroblasts [38*,39]. Corticosteroids can also suppress TNF-α -induced ICAM-1 expression on these fibroblasts [40]. Gold sodium thiomalate inhibits cytokine-induced VCAM-1 and E-selectin expression on endothelia [41]. Clarithromycin markedly suppresses the upregulated expression of ICAM-1, VCAM-1 and LFA-3 on human synovial fibroblasts [42]. Purified CAM ligands such as integrin-binding peptides block cartilage chondrolysis [43*]. Antisense oligonucleotides block ICAM-1, VCAM-1 and E-selectin expression on endothelial cells [44**].

In animal models, methotrexate blocks leukocyte-endothelial adhesion and leukocyte extravasation [45]. Antibodies against ICAM-1 and the β2 integrin subunit (CD18) inhibited leukocyte ingress into the synovium in rats, and also the development of arthritis in rats and rabbits [46,47*,48]. Anti-ICAM-1 antibody also inhibited murine collagen-induced arthritis [49]. Anti-α4β1 integrin antibodies suppressed leukocyte migration to joints and diminished adjuvant-induced arthritis in rats [48,50*,51]. Anti-CD44 antibodies markedly decreased the severity of murine proteoglycan-induced arthritis [52,53*].

In humans, oral methoxypsoralen combined with intra-articular UV-A irradiation downregulated ICAM-1, VCAM-1 and E-selectin expression in the RA synovium [54]. Gold salts inhibited synovial E-selectin expression in RA [55]. In a recent series of studies, 32 patients with longstanding RA that had been resistant to conventional therapy were treated with anti-ICAM-1 monoclonal antibody; there was a transient improvement in the status of these patients [56**]. An even greater effect of this antibody was observed when treating 10 patients who had early or indolent RA [57]. Anti-cytokine targeting in RA might also influence the production of synovial adhesion molecules. For example, treatment of RA patients with monoclonal antibody against TNF-α resulted in decreased serum levels of soluble ICAM-1 and E-selectin in these patients [58*].

Summary

Leukocyte-endothelial adhesion has a central role in leukocyte extravasation, a key feature of inflammation including arthritis. A number of adhesion molecules, among which are integrins, selectins and immunoglobulins, act in concert and regulate the sequence of distinct steps. According to the four-step model of leukocyte-endothelial interactions, the selectin-dependent leukocyte rolling is followed by integrin-dependent leukocyte activation, firm adhesion and then transmigration. The most important adhesive pathways are determined by receptor-ligand pairs including endothelial E- and P-selectin and their respective sialylated ligands; α4β1 integrin and VCAM-1; and LFA-1 or Mac-1 integrin and ICAM-1. The presence of various CAM pairs and the existence of distinct steps of rolling, activation, adhesion and migration account for the diversity and specificity of leukocyte-endothelial interactions. There have been several attempts to interfere therapeutically with the cellular and molecular mechanisms described above. Most studies have been performed with animal models of various types of inflammation. A limited number of human clinical trials, such as that with anti-ICAM-1 antibody in RA, have given promising results. Specific targeting of pathological endothelial function might be useful for the future management of inflammatory arthritis.

Acknowledgements

This work was supported by National Institutes of Health grants AR-30692, AR-41492 and AI-40987 (AEK); funds from the Veterans' Administration Research Service (AEK); the Gallagher Professorship for Arthritis Research (AEK); grants from the Hungarian National Scientific Research Fund no. T 013239 and F 025813 (ZS), and Medical Research Council Fund no. 314/96 (ZS)

References

  1. Pober JS, Cotran RS: Cytokines and endothelial cell biology.

    Physiol Rev 1990, 70:427-434. PubMed Abstract OpenURL

  2. Cotran RS: Endothelial cells.

    In Textbook of Rheumatology. Edited by Kelley WN, Harris ED, Ruddy S, Sledge CB. Philadelphia: WB Saunders 1993, 327-336. OpenURL

  3. Szekanecz Z, Strieter RM, Koch AE: Cytokines in rheumatoid arthritis: potential targets for pharmacological intervention.

    Drugs Aging 1998, 12:377-390. PubMed Abstract OpenURL

  4. Szekanecz Z, Szegedi G, Koch AE: Cellular adhesion molecules in rheumatoid arthritis. Regulation by cytokines and possible clinical importance.

    J Invest Med 1996, 44:124-135. OpenURL

  5. Haskard DO: Cell adhesion molecules in rheumatoid arthritis.

    Curr Opin Rheumatol 1995, 7:229-234. PubMed Abstract OpenURL

  6. Albelda SM, Buck CA: Integrins and other cell adhesion molecules.

    FASEB J 1990, 4:2868-2880. PubMed Abstract OpenURL

  7. Springer TA: Adhesion receptors of the immune system.

    Nature 1990, 346:425-433. PubMed Abstract | Publisher Full Text OpenURL

  8. Szekanecz Z, Szegedi G: Cell surface adhesion molecules: structure, function, clinical importance.

    Hung Med J 1992, 133:135-142. OpenURL

  9. Carlos TM, Harlan JM: Leukocyte-endothelial adhesion molecules.

    Blood 1994, 84:2068-2101. PubMed Abstract OpenURL

  10. Butcher EC: Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity.

    Cell 1991, 67:1033-1036. PubMed Abstract | Publisher Full Text OpenURL

  11. Ishikawa H, Nishibayashi Y, Kita K, Ohno O, Imura S, Hirata S: Adhesion molecules in the lymphoid cell distribution in rheumatoid synovial membrane.

    Bull Hosp Jt Dis 1993, 53:23-28. PubMed Abstract OpenURL

  12. Walz G, Aruffo A, Kolanus W, Bevilacqua M, Seed B: Recognition by ELAM-1 of the sialyl-Lex determinant on myeloid and tumor cells.

    Science 1990, 250:1132-1135. PubMed Abstract OpenURL

  13. Asa D, Raycroft L, Ma L, et al.: The P-selectin glycoprotein ligand functions as a common human leukocyte ligand for P- and E-selectins.

    J Biol Chem 1995, 270:11662-11670. PubMed Abstract | Publisher Full Text OpenURL

  14. Borges E, Tietz W, Steegmaier M, Moll T, Hallmann R, Hamann A, Vestweber D: P-selectin glycoprotein ligand-1 (PSGL-1) on T helper 1 but not on T helper 2 cells binds to P-selectin and supports migration into inflamed skin.

    J Exp Med 1997, 185:573-578. PubMed Abstract | Publisher Full Text OpenURL

  15. Bochner BS, Luscinskas FW, Gimbrone MA Jr, Newman W, Sterbinsky SA, Derse-Anthony CP, Klunk D, Schleimer RP: Adhesion of human basophils, eosinophils, and neutrophils to interleukin 1-activated human vascular endothelial cells: contributions of endothelial cell adhesion molecules.

    J Exp Med 1991, 173:1553-1557. PubMed Abstract OpenURL

  16. Munro JM, Pober JS, Cotran RS: Tumor necrosis factor and interferon-gamma induce distinct patterns of endothelial activation and associated leukocyte accumulation in skin of Papio anubis.

    Am J Pathol 1989, 135:121-133. PubMed Abstract OpenURL

  17. Mulligan MS, Varani J, Dame MK, Lane CL, Smith CW, Anderson DC, Ward PA: Role of endothelial-leukocyte adhesion molecule 1 (ELAM-1) in neutrophil-mediated lung injury in rats.

    J Clin Invest 1991, 88:1396-1406. PubMed Abstract OpenURL

  18. Koch AE, Burrows JC, Haines GK, Carlos TM, Harlan J, Leibovich SJ: Immunolocalization of leukocyte and endothelial adhesion molecules in human rheumatoid and osteoarthritic synovial tissue.

    Lab Invest 1991, 64:313-320. PubMed Abstract OpenURL

  19. Veale D, Yanni G, Rogers S, Barnes L, Bresnihan B, Fitzgerald O: Reduced synovial membrane macrophage numbers, ELAM-1 expression and lining layer hyperplasia in psoriatic arthritis as compared with rheumatoid arthritis.

    Arthritis Rheum 1993, 36:893-900. PubMed Abstract OpenURL

  20. Lorenzon P, Vecile E, Nardon E, Ferrero E, Harlan JM, Tedesco F, Dobrina A: Endothelial cell E- and P-selectin and vascular cell adhesion molecule-1 function as signaling receptors.

    J Cell Biol 1998, 142:1381-1391. PubMed Abstract | Publisher Full Text OpenURL

  21. Geng JG, Bevilacqua MP, Moore KL, McIntyre TM, Prescott SM, Kim JM, Bliss GA, Zimmerman GA, McEver RP: Rapid neutrophil adhesion to activated endothelium mediated by GMP-140.

    Nature 1990, 343:757-760. PubMed Abstract | Publisher Full Text OpenURL

  22. Lawrence MB, Springer TA: Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins.

    Cell 1991, 65:859-873. PubMed Abstract | Publisher Full Text OpenURL

  23. Johnson B, Haines GK, Harlow LA, Koch AE: Adhesion molecule expression in human synovial tissues.

    Arthritis Rheum 1993, 36:137-146. PubMed Abstract OpenURL

  24. Szekanecz Z, Haines GK, Lin TR, Harlow LA, Goerdt S, Rayan G, Koch AE: Differential distribution of ICAM-1, ICAM-2 and ICAM-3, and the MS-1 antigen in normal and diseased human synovia.

    Arthritis Rheum 1994, 37:221-231. PubMed Abstract OpenURL

  25. Allen CA, Highton J, Palmer DG: Increased expression of p150,95 and CR3 leukocyte adhesion molecules by mononuclear phagocytes in rheumatoid synovial membranes.

    Arthritis Rheum 1989, 32:947-954. PubMed Abstract OpenURL

  26. Laffon A, Garcia-Vicuna R, Humbria A, Postigo AA, Corbi AL, de Landazuri MO, Sanchez-Madrid F: Upregulated expression and function of VLA-4 fibronectin receptors on human activated T cells in rheumatoid arthritis.

    J Clin Invest 1991, 88:546-552. PubMed Abstract OpenURL

  27. Thornhill MH, Haskard DO: IL-4 regulates endothelial cell activation by IL-1, tumor necrosis factor, or IFN-gamma.

    J Immunol 1990, 145:865-872. PubMed Abstract OpenURL

  28. Rice GE, Munro M, Corless C, Bevilacqua MP: Vascular and non-vascular expression of INCAM-110.

    Am J Pathol 1991, 138:385-390. PubMed Abstract OpenURL

  29. Wilkinson LS, Edwards JC, Poston RN, Haskard DO: Expression of vascular cell adhesion molecule-1 in normal and inflamed synovium.

    Lab Invest 1993, 68:82-88. PubMed Abstract OpenURL

  30. Pober JS, Gimbrone MA Jr, Lapierre LA, Mendrick DL, Fiers W, Rothlein R, Springer TA: Overlapping patterns of activation of human endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon.

    J Immunol 1986, 137:1893-1896. PubMed Abstract OpenURL

  31. Hale LP, Martin ME, McCollum DE, Nunley JA, Springer TA, Singer KH, Haynes BF: Immunohistologic analysis of the distribution of cell adhesion molecules within the inflammatory synovial micro-environment.

    Arthritis Rheum 1989, 32:22-30. PubMed Abstract OpenURL

  32. Salmi M, Kalimo K, Jalkanen S: Induction and function of vascular adhesion protein-1 at sites of inflammation.

    J Exp Med 1993, 178:2255-2260. PubMed Abstract OpenURL

  33. Szekanecz Z, Haines GK, Harlow LA, Shah MR, Fong TW, Fu R, Lin SJ, Koch AE: Increased synovial expression of the adhesion molecules CD66a, CD66b and CD31 in rheumatoid and osteoarthritis.

    Clin Immunol Immunopathol 1995, 76:180-186. PubMed Abstract | Publisher Full Text OpenURL

  34. Szekanecz Z, Haines GK, Harlow LA, Shah MR, Fong TW, Fu R, Lin SJ, Rayan G, Koch AE: Increased synovial expression of transforming growth factor (TGF)-β receptor endoglin and TGF-β1 in rheumatoid arthritis: possible interactions in the pathogenesis of the disease.

    Clin Immunol Immunopathol 1995, 76:187-194. PubMed Abstract | Publisher Full Text OpenURL

  35. Piali L, Hammel P, Uherek C, Bachmann F, Gisler RH, Dunon D, Imhof BA: CD31/PECAM-1 is a ligand for alpha v beta 3 integrin involved in adhesion of leukocytes to endothelium.

    J Cell Biol 1995, 130:451-460. PubMed Abstract | Publisher Full Text OpenURL

  36. Haynes BF, Hale LP, Patton KL, Martin ME, McCallum RM: Measurement of an adhesion molecule as an indicator of inflammatory disease activity. Up-regulation of the receptor for hyaluronate (CD44) in rheumatoid arthritis.

    Arthritis Rheum 1991, 34:1434-1443. PubMed Abstract OpenURL

  37. Szekanecz Z, Koch AE: Intercellular adhesion molecule (ICAM)-3 expression on endothelial cells.

    Am J Pathol 1997, 151:313-314. PubMed Abstract OpenURL

  38. Eguchi K, Kawakami A, Nakashima M, Ida H, Sakito S, Matsuoka N, Terada K, Sakai M, Kawabe Y, Fukuda T, et al.: Interferon-alpha and dexamethasone inhibit adhesion of T cells to endothelial cells and synovial cells.

    Clin Exp Immunol 1992, 88:448-454. PubMed Abstract OpenURL

  39. Eguchi K, Kawakami A, Ida H, Nakashima M, Yamashita I, Sakai M, Shimada H, Terada K, Fukuda T, Ishimaru T, et al.: Bucillamine inhibits T cell adhesion to human endothelial cells.

    J Rheumatol 1992, 19:1045-1050. PubMed Abstract OpenURL

  40. Tessier P, Audette M, Cattaruzzi P, McColl SR: Up-regulation by tumour necrosis factor-α of intercellular adhesion molecule 1 expression and function in synovial fibroblasts and its inhibition by glucocorticoids.

    Arthritis Rheum 1993, 36:1528-1539. PubMed Abstract OpenURL

  41. Newman PM, To SS, Robinson BG, Hyland VJ, Schrieber L: Effect of gold sodium thiomalate and its thiomalate component on the in vitro expression of endothelial cell adhesion molecules.

    J Clin Invest 1994, 94:1864-1871. PubMed Abstract OpenURL

  42. Matsuoka N, Eguchi K, Kawakami A, Tsuboi M, Kawabe Y, Aoyagi T, Nagataki S: Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells.

    Clin Exp Immunol 1996, 104:501-508. PubMed Abstract | Publisher Full Text OpenURL

  43. Homandberg GA, Hui F: Arg-Gly-Asp-Ser peptide analogs suppress cartilage chondrolytic activities of integrin-binding and non-binding fibronectin fragments.

    Arch Biochem Biophys 1994, 310:40-48. PubMed Abstract | Publisher Full Text OpenURL

  44. Bennett CF, Condon TP, Grimm S, Chan H, Chiang MY: Inhibition of endothelial cell adhesion molecule expression with antisense oligonucleotides.

    J Immunol 1994, 152:3530-3540. PubMed Abstract OpenURL

  45. Cronstein BN, Naime D, Ostad E: The anti-inflammatory mechanisms of methotrexate.

    J Clin Invest 1993, 92:2675-2682. PubMed Abstract OpenURL

  46. Iigo Y, Takashi T, Tamatani T, Miyasaka M, Higashida T, Yagita H, Okumura K, Tsukada W: ICAM-1-dependent pathway is critically involved in the pathogenesis of adjuvant arthritis in rats.

    J Immunol 1991, 147:4167-4171. PubMed Abstract OpenURL

  47. Jasin HE, Lightfoot E, Davis LS, Rothlein R, Faanes RB, Lipsky PE: Amelioration of antigen-induced arthritis in rabbits treated with monoclonal antibodies to leukocyte adhesion molecules.

    Arthritis Rheum 1992, 35:541-549. PubMed Abstract OpenURL

  48. Issekutz AC, Ayer L, Miyasaka M, Issekutz TB: 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 1996, 88:569-576. PubMed Abstract | Publisher Full Text OpenURL

  49. Kakimoto K, Nakamura T, Ishii K, Takashi T, Iigou H, Yagita H, Okumura K, Onoue K: The effect of anti-adhesion molecule antibody on the development of collagen-induced arthritis.

    Cell Immunol 1992, 142:326-337. PubMed Abstract OpenURL

  50. Barbadillo C, Arroyo A, Salas C, Mulero J, Sanchez-Madrid F, Andreu JL: Anti-integrin immunotherapy in rheumatoid arthritis: protective effect of anti-alpha 4 antibody in adjuvant arthritis.

    Springer Semin Immunopathol 1995, 16:427-436. PubMed Abstract OpenURL

  51. Seiffge D: Protective effects of monoclonal antibody to VLA-4 on leukocyte adhesion and course of disease in adjuvant arthritis in rats.

    J Rheumatol 1996, 23:2086-2091. PubMed Abstract OpenURL

  52. Mikecz K, Dennis K, Shi M, Kim JH: Modulation of hyaluronan receptor (CD44) function in vivo in a murine model of rheumatoid arthritis.

    Arthritis Rheum 1999, 42:659-668. PubMed Abstract | Publisher Full Text OpenURL

  53. Mikecz K, Brennan FR, Kim JH, Glant TT: Anti-CD44 treatment abrogates tissue oedema and leukocyte infiltration in murine arthritis.

    Nature Med 1995, 1:558-563. PubMed Abstract OpenURL

  54. Laing TJ, Ike RW, Griffiths CE, Richardson BC, Grober JS, Keroack BJ, Toth MB, Railan D, Cooper KD: A pilot study of the effect of oral 8-methoxypsoralen and intraarticular ultraviolet light on rheumatoid synovitis.

    J Rheumatol 1995, 22:29-33. PubMed Abstract OpenURL

  55. Corkill MM, Kirkham BW, Haskard DO, Barbatis C, Gibson T, Panayi GS: Gold treatment of rheumatoid arthritis decreases synovial expression of the endothelial leukocyte adhesion receptor ELAM-1.

    J Rheumatol 1991, 18:1453-1460. PubMed Abstract OpenURL

  56. Kavanaugh AF, Davis LS, Nichols LA, Norris SH, Rothlein R, Scharschmidt LA, Lipsky PE: Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule 1.

    Arthritis Rheum 1994, 37:992-999. PubMed Abstract OpenURL

  57. Kavanaugh AF, Davis LS, Jain RI, Nichols LA, Norris SH, Lipsky PE: A phase I/II open label study of the safety and efficacy of an anti-ICAM-1 monoclonal antibody in early rheumatoid arthritis.

    J Rheumatol 1996, 23:1338-1344. PubMed Abstract OpenURL

  58. Paleolog EM, Hunt M, Elliott MJ, Feldmann M, Maini RN, Woody JN: Deactivation of vascular endothelium by monoclonal anti-tumor necrosis factor alpha antibody in rheumatoid arthritis.

    Arthritis Rheum 1996, 39:1082-1091. PubMed Abstract OpenURL