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J Exp Med. 1995 Mar 1; 181(3): 1197–1203.
PMCID: PMC2191943

Monocyte migration to arthritis in the rat utilizes both CD11/CD18 and very late activation antigen 4 integrin mechanisms


In human and experimental models of arthritis, blood monocytes migrate into the inflamed synovium and joint space. The mechanisms required for monocyte migration across the vascular endothelium in joints is poorly defined. Radiolabeled rat blood monocytes were used to measure monocyte migration to the inflamed joints of rats with adjuvant arthritis, and the role of monocyte adhesion molecules was analyzed. Monocyte accumulation in the inflamed joints was maximal 14-21 d after immunization with adjuvant, when arthritis had fully developed. Blocking mAbs to lymphocyte function-associated antigen 1 (LFA-1), Mac- 1, and very late activation antigen 4 (VLA-4) were used to evaluate the role of these integrins in the migration. Migration to the joints was not inhibited by treatment of the animals with mAb to LFA-1, Mac-1, or VLA-4 alone, and was partially (50%) inhibited in only the most arthritic joint, the talar joint, by the combination of mAb to LFA-1 plus Mac-1. In contrast, this combination inhibited migration to dermal inflammation induced by C5ades Arg, endotoxin, tumor necrosis factor alpha, and polyinosine-cytosine by 60-70%. When mAbs to LFA-1 and VLA-4 were combined, migration to all the inflamed joints was strongly inhibited (80-98%, depending on the joint). Treatment with the combination of the three mAbs to LFA-1, Mac-1, and VLA-4 completely eliminated monocyte migration to all joints and dermal inflammation. The results show that 51Cr blood monocytes can be used to quantify monocyte migration to arthritic joints in the rat. LFA-1 alone or VLA-4 alone is sufficient to mediate most of this migration, and either LFA-1 or VLA-4 is required for monocyte migration to joint inflammation. These results indicate that both the VLA-4 and LFA-1 integrins should be therapeutic targets for suppression of monocyte infiltration of joints in arthritis.

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Selected References

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  • Movat HZ, Cybulsky MI. Neutrophil emigration and microvascular injury. Role of chemotaxins, endotoxin, interleukin-1 and tumor necrosis factor alpha. Pathol Immunopathol Res. 1987;6(3):153–176. [PubMed]
  • Bevilacqua MP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol. 1993;11:767–804. [PubMed]
  • Pober JS, Cotran RS. Cytokines and endothelial cell biology. Physiol Rev. 1990 Apr;70(2):427–451. [PubMed]
  • Hakkert BC, Kuijpers TW, Leeuwenberg JF, van Mourik JA, Roos D. Neutrophil and monocyte adherence to and migration across monolayers of cytokine-activated endothelial cells: the contribution of CD18, ELAM-1, and VLA-4. Blood. 1991 Nov 15;78(10):2721–2726. [PubMed]
  • Zvaifler NJ. The immunopathology of joint inflammation in rheumatoid arthritis. Adv Immunol. 1973;16(0):265–336. [PubMed]
  • Breedveld FC, Trentham DE. Progress in the understanding of inducible models of chronic arthritis. Rheum Dis Clin North Am. 1987 Dec;13(3):531–544. [PubMed]
  • Taurog JD, Argentieri DC, McReynolds RA. Adjuvant arthritis. Methods Enzymol. 1988;162:339–355. [PubMed]
  • Mainardi CL. Biochemical mechanisms of articular destruction. Rheum Dis Clin North Am. 1987 Aug;13(2):215–233. [PubMed]
  • Springer TA. Adhesion receptors of the immune system. Nature. 1990 Aug 2;346(6283):425–434. [PubMed]
  • Arnaout MA. Structure and function of the leukocyte adhesion molecules CD11/CD18. Blood. 1990 Mar 1;75(5):1037–1050. [PubMed]
  • Smith CW, Marlin SD, Rothlein R, Toman C, Anderson DC. Cooperative interactions of LFA-1 and Mac-1 with intercellular adhesion molecule-1 in facilitating adherence and transendothelial migration of human neutrophils in vitro. J Clin Invest. 1989 Jun;83(6):2008–2017. [PMC free article] [PubMed]
  • Arfors KE, Lundberg C, Lindbom L, Lundberg K, Beatty PG, Harlan JM. A monoclonal antibody to the membrane glycoprotein complex CD18 inhibits polymorphonuclear leukocyte accumulation and plasma leakage in vivo. Blood. 1987 Jan;69(1):338–340. [PubMed]
  • Issekutz AC, Issekutz TB. The contribution of LFA-1 (CD11a/CD18) and MAC-1 (CD11b/CD18) to the in vivo migration of polymorphonuclear leucocytes to inflammatory reactions in the rat. Immunology. 1992 Aug;76(4):655–661. [PMC free article] [PubMed]
  • Rosen H. Role of CR3 in induced myelomonocytic recruitment: insights from in vivo monoclonal antibody studies in the mouse. J Leukoc Biol. 1990 Nov;48(5):465–469. [PubMed]
  • Chuluyan HE, Issekutz AC. VLA-4 integrin can mediate CD11/CD18-independent transendothelial migration of human monocytes. J Clin Invest. 1993 Dec;92(6):2768–2777. [PMC free article] [PubMed]
  • Meerschaert J, Furie MB. Monocytes use either CD11/CD18 or VLA-4 to migrate across human endothelium in vitro. J Immunol. 1994 Feb 15;152(4):1915–1926. [PubMed]
  • Winn RK, Harlan JM. CD18-independent neutrophil and mononuclear leukocyte emigration into the peritoneum of rabbits. J Clin Invest. 1993 Sep;92(3):1168–1173. [PMC free article] [PubMed]
  • Issekutz AC, Issekutz TB. Quantitation and kinetics of blood monocyte migration to acute inflammatory reactions, and IL-1 alpha, tumor necrosis factor-alpha, and IFN-gamma. J Immunol. 1993 Aug 15;151(4):2105–2115. [PubMed]
  • Williams JH, Jr, Moser KM, Ulich T, Cairo MS. Harvesting the noncirculating pool of polymorphonuclear leukocytes in rats by hetastarch exchange transfusion (HET): yield and functional assessment. J Leukoc Biol. 1987 Nov;42(5):455–462. [PubMed]
  • Issekutz TB. Inhibition of lymphocyte endothelial adhesion and in vivo lymphocyte migration to cutaneous inflammation by TA-3, a new monoclonal antibody to rat LFA-1. J Immunol. 1992 Nov 15;149(10):3394–3402. [PubMed]
  • Issekutz TB, Wykretowicz A. Effect of a new monoclonal antibody, TA-2, that inhibits lymphocyte adherence to cytokine stimulated endothelium in the rat. J Immunol. 1991 Jul 1;147(1):109–116. [PubMed]
  • Issekutz TB. Inhibition of in vivo lymphocyte migration to inflammation and homing to lymphoid tissues by the TA-2 monoclonal antibody. A likely role for VLA-4 in vivo. J Immunol. 1991 Dec 15;147(12):4178–4184. [PubMed]
  • Issekutz TB, Issekutz AC. T lymphocyte migration to arthritic joints and dermal inflammation in the rat: differing migration patterns and the involvement of VLA-4. Clin Immunol Immunopathol. 1991 Dec;61(3):436–447. [PubMed]
  • Issekutz AC, Issekutz TB. A major portion of polymorphonuclear leukocyte and T lymphocyte migration to arthritic joints in the rat is via LFA-1/MAC-1-independent mechanisms. Clin Immunol Immunopathol. 1993 Jun;67(3 Pt 1):257–263. [PubMed]
  • Fernandez HN, Henson PM, Otani A, Hugli TE. Chemotactic response to human C3a and C5a anaphylatoxins. I. Evaluation of C3a and C5a leukotaxis in vitro and under stimulated in vivo conditions. J Immunol. 1978 Jan;120(1):109–115. [PubMed]
  • Hemler ME. VLA proteins in the integrin family: structures, functions, and their role on leukocytes. Annu Rev Immunol. 1990;8:365–400. [PubMed]
  • Carlos T, Kovach N, Schwartz B, Rosa M, Newman B, Wayner E, Benjamin C, Osborn L, Lobb R, Harlan J. Human monocytes bind to two cytokine-induced adhesive ligands on cultured human endothelial cells: endothelial-leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1. Blood. 1991 May 15;77(10):2266–2271. [PubMed]
  • Tamatani T, Kotani M, Miyasaka M. Characterization of the rat leukocyte integrin, CD11/CD18, by the use of LFA-1 subunit-specific monoclonal antibodies. Eur J Immunol. 1991 Mar;21(3):627–633. [PubMed]
  • Carlos TM, Schwartz BR, Kovach NL, Yee E, Rosa M, Osborn L, Chi-Rosso G, Newman B, Lobb R, Rosso M, et al. Vascular cell adhesion molecule-1 mediates lymphocyte adherence to cytokine-activated cultured human endothelial cells. Blood. 1990 Sep 1;76(5):965–970. [PubMed]
  • Koch AE, Burrows JC, Haines GK, Carlos TM, Harlan JM, Leibovich SJ. Immunolocalization of endothelial and leukocyte adhesion molecules in human rheumatoid and osteoarthritic synovial tissues. Lab Invest. 1991 Mar;64(3):313–320. [PubMed]
  • Morales-Ducret J, Wayner E, Elices MJ, Alvaro-Gracia JM, Zvaifler NJ, Firestein GS. Alpha 4/beta 1 integrin (VLA-4) ligands in arthritis. Vascular cell adhesion molecule-1 expression in synovium and on fibroblast-like synoviocytes. J Immunol. 1992 Aug 15;149(4):1424–1431. [PubMed]
  • Johnson BA, Haines GK, Harlow LA, Koch AE. Adhesion molecule expression in human synovial tissue. Arthritis Rheum. 1993 Feb;36(2):137–146. [PubMed]
  • Firestein GS. Cytokines in autoimmune diseases. Concepts Immunopathol. 1992;8:129–160. [PubMed]
  • Pulido R, Elices MJ, Campanero MR, Osborn L, Schiffer S, García-Pardo A, Lobb R, Hemler ME, Sánchez-Madrid F. Functional evidence for three distinct and independently inhibitable adhesion activities mediated by the human integrin VLA-4. Correlation with distinct alpha 4 epitopes. J Biol Chem. 1991 Jun 5;266(16):10241–10245. [PubMed]

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