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Adhesion molecules in diagnosis and therapy of respiratory disease
Respiratory Medicine (1992) 86, 455-457
Adhesion molecules in diagnosis and therapy of respiratory disease Communication between cells is of fundamental importance in the development and maintenance of inflammatory and immune responses. Two principle mechanisms are involved in these cell-to-cell interactions. The first communication system is maintained by soluble protein factors such as cytokines (e.g. interleukins, colony-stimulating factors, interferons) and lipid mediators (e.g. platelet activating factor, leukotrienes). The second mechanism comprises the interaction between molecular structures on the membrane surface of leucocytes called receptors and molecules on the surface of target cells (ligands). These two systems are closely linked and interdependent since soluble factors can clearly enhance or induce cell-cell interactions, and cell-cell interactions can control the response of cells to inflammatory mediators (l). The biological function of the intercellular communication is not only to induce functions of inflammatory cells but also to provide the basis for a selective and specific mechanism of leucocyte migration into the affected tissue towards the trigger of the immune response. Surface molecules involved herein are generally referred to as adhesion molecules. Three main groups of surface adhesion receptors are recognized (2). The first is the integrin receptor family. This group consists of at least fourteen a/fl heterodimeric transmembrane glycoproteins, which are further divided into three subfamilies on the basis of structurally distinct fl chains. (a) The fl~ or 'very late activation' (VLA) subfamily comprising six members (VLA-I to -6). These adhesion molecules are widely distributed in tissues and interact with the extracellular matrix such as laminin, fibronectin or collagen. Their biological significance has been related to wound healing, cell migration during embryogenesis and eosinophil adherence to endothelial cells (3). (b) In the f12subfamily, also referred to as leucocyte integrins, to date three members have been identified that structurally belong to the CDI I/CD18 heterodimer complex: the 'lymphocyte function associated antigen-1' (LFA1; CD 11a/CD 18) binds to the 'intercellular adhesion molecules' 1 and 2 (ICAM-I and ICAM-2); Mac-1 (CD1 lb/CDI8) binds to the ligand iC3b; and p150,95 (CDI Ic/CDI8) to an, as yet, unknown ligand. These molecules are exclusively expressed on leucocytes, and are mainly involved in immune adherence. (c) The f13or cytoadhesion subfamily has two members, designated VNR and platelet glycoprotein IIb/IIIa which bind to fibronectin, vitronectin, fibrinogen and the von 0954-6111/92/060455 + 03 $08.00/0
Willebrand factor. These molecules are functionally related to the VLA molecules mentioned above. The second group of cell surface adhesion molecules, known as selectins, include the 'endothelial cell adhesion molecule- 1' (ELAM- 1), the 'leucocyte adhesion molecule' (LAM-1 or Mel-14) and the 'plateletactivation-dependent granule-external membrane protein' (PADG-EM). Members of this family are expressed on leucocytes and endothelial cells, and are believed to be involved in leucocyte adhesion to endothelium during inflammatory immune reactions and coagulation. Finally, the third group of adhesion receptors is the immunoglobulin supergene family. These molecules react with antigens (T-cell receptor CD3, surface immunoglobulins) and antigen-independent receptors such as CD2 (CD58) that binds to 'lymphocyte function associated molecule-3' (LFA-3). Interacting cells are able to express both adhesion receptors and ligands. By definition, the activated cell of the interacting couple carries the adhesion receptor whereas its non-stimulated counterpart expresses the ligand. However, intercellular adhesion between two cells can be achieved by more than one distinct receptor-ligand interaction. Finally, an adhesive effect can be achieved via different mechanisms. For instance, eosinophil-dependent adherence, similar to that of neutrophils, involves activation of the leucocyte adhesion complex CDI I/CDI8, as judged by the inhibitory effect of CD18 mAb (4-6). On the other hand, endothelial-dependent adherence of eosinophils is only partially inhibited by CDI8 mAb, suggesting involvement of a second, CD 18-independent adhesive mechanism (4-6). An important inherent characteristic of adhesion receptor expression is its high variability due to numerous extracellular and intercellular factors. For instance, binding of T-lymphocytes to matrix proteins augments activation via the CD3 component of the antigen receptor (7). In addition, cytokines as welI as PAF enhance the binding of eosinophils, to vascular endothelium via activation of both endothelial cells (8,9) and leucocytes (5,6). Other factors known to upregulate the expression of adhesion molecules include differentiation of T-lymphocytes, T-cell activation and viral infection. While much still remains to be elucidated about the underlying mechanisms of communication between cells, increased understanding of the interaction of this © 1992 Bailli~re Tindall
456
Editorial
diverse group of surface molecules leads to the question as to whether these surface structures could be used as parameters in the diagnosis and treatment of disease? Several recent studies employing immunohistochemical and flow cytometrical techniques in human diseases have focused on this possibility. In the liver, for instance, expression of ICAM-1 is increased on hepatocytes in acute and viral hepatitis (10) and during liver allograft rejection (11). Increased I C A M - I expression has also been observed on cerebral vascular endothelium in viral encephalitis and multiple-sclerosis plaques (12), on thyroid epithelial cells in autoimmune thyroiditis (13), and on keratocytes in various inflammatory dermatoses (14). In addition, distribution of ICAM-1 was correlated with the areas of inflammatory tissue damage and infiltrating leucocytes revealed an enhanced expression of LFA-I. Further, ELAM-1 is found on human venular endothelial cells at the sites of acute (15) and chronic inflammation (16). While these investigations require histological biopsies, other studies have found dynamic adhesion receptor expression on blood cells in human disease. In cyclic angioedema, for example, both the spontaneous and in vitro inducible CDI lb expression on eosinophils by P A F increased several-fold, 2 to 3 weeks before a symptomatic relapse (17). Treatment with prednisone not only led to a resolution of the symptoms but also reduced spontaneous and the in vitro inducible CD 11 b expression. In respiratory diseases, C D l l b expression on bronchoalveolar lymphocytes and macrophages seems to be associated with disease activity in sarcoidosis (unpubl. res.). Studies employing endobronchial allergen provocation showed, that bronchoalveolar eosinophils obtained from the antigen challenged segment had an enhanced CDI lb expression while blood cells showed normal values (18). Sputum eosinophils from asthmatics not receiving steroid therapy were found to have considerably elevated levels of CD 11 b, and, in addition, in the majority of the cases, eosinophils expressed I C A M - I and H L A - D R (19). Finally, integrin receptor expression has been reported to be highly variable but tends to be weaker in lung cell carcinoma than in normal epithelium (20). Taken together, these observations indicate that evaluation of adhesion molecules may be a useful adjunct to conventional diagnostic procedures in monitoring disease activity. In addition, these surface molecules may also be helpful in predicting disease behaviour and response to treatment. Do adhesion molecules also have a possible implication in the treatment of inflammatory disease? While there is no human data available to date, results from
animal studies suggest that this may, indeed, be the case. For instance, the use of anti-CDI I/CD18 antibodies has been shown to prevent the migration of leucocytes in acute inflammation (21) and ischaemiareperfusion injury (22). In a primate model of asthma, a monoclonal antibody to ICAM-1, attenuated airway eosinophilia and hyperresponsiveness (9). In the same model, pretreatment of the animals with anti-ELAM- I antibodies blocked both the influx of neutrophils and the late-phase airway obstruction (23). Although caution has to be exercised when extrapolating these results to the situation in humans, these studies at least indicate that blocking of adhesion molecules could represent a new future therapeutic approach. Extensive investigations should provide a clearer idea of whether antibodies against adhesion molecules will gain a therapeutic significance in inflammatory disease of the lung. C. KROEGELAND H. MATTHYS Department o f Pneumology Medical Clinic Albert-Ludwigs-University Hugstetter Str. 55. D-7800 Freiburg Germany References
I. Natthan C, Sporn M. Cytokines in context. J Cell Biol 1991; 113: 981-986. 2. Larson RS, Springer TA. Structure and function of leucocyte integrins. Immunol Rev 1990; 114: 181-217. 3. Bochner BS, Luscinskas FW, Gimbrone MA et al. Adhesion of human basophils, eosinophils, and neutrophils to interleukin-l-activated human vascular endothelial cells: contribution of endothelial cell adhesion molecules. J Exp Med 1991; 173: 1553-1556. 4. Dobrina A, Schwartz BR, Carlos TM, Ochs HD, Beatty PG, Harlan JM. CDll/CDl8-independent neutrophil adherence to inducible endothelial-leucocyte adhesion molecules (ELAM) in vitro. Immunology 1989; 67: 502-508. 5. Kimani G, Tonnesen MG, Henson PM. Stimulation of eosinophil adherence to human vascular endothelial cells in vitro by platelet activating factor. Jlmmuno11988; 140: 3161-3166. 6. Lamas AM, Mulroney CM, Schleimer XX. Studies on the adhesive interaction between human eosinophils and cultured vascular endothelial cells. J Immunol 1988; 140: 1500-1505. 7. Carrerra AC, Rincon M, Sanchez-Madrid F, LopezBotet M, de Landazuri MO. Triggering of co-mitogenic signals in T cell proliferation by anti-LFA-1 (CDI8/ CDlla), LFA-3, and CD7 monoclonal antibodies. J lmmuno11988; 141: 1919-1924. 8. Dobrina A, Menegazzi R, Carlos TM et al. Mechanisms of eosinophil adherence to cultured vascular endothelial cells. Eosinophils bind to the cytokine-induced endothelial vascular cell adhesion molecule-1 via the very late activation antigen-4 integrin receptor. J Clin Invest 1991; 88: 20-26.
Editorial
9. Wegner CD, Gundel RH, Reilly P, Haynes N, Letts LG, Rothlein R. Intercellular adhesion molecules-I (ICAMI) in the pathogenesis of asthma. Science 1990; 247: 456-459. 10. Volpes R, Van Den Oord J J, Desmet VJ. Immunohistochemical study of adhesion molecules in liver inflammation. Hepathology 1990; I2: 59-65. 11. Adams DH, Hubscher SG, Shaw J, Rothlein R, Neuberger JM. Intercellular adhesion molecule 1 on liver allografts during rejection. Lancet 1989; ii: 1122-1125. 12. Sobel RA, Mitchell ME, Fondren G. Intercellular adhesion molecule- I (ICAM- I ) in cellular immune reactions in human central nervous system. Am J Pathol 1990; 136: 1309-1316. 13. Weetman AP, Cohen S, Makgoba MW, Borysiewicz LK. Expression ofan intercellular adhesion molecule, ICAM1, by human thyroid cells. J Endocrinol 1989; 122: 185-191. 14. NickoloffBJ, Griffiths CEM, Barker JNWN. The role of adhesion molecules, chemotactic factors and cytokines in inflammatory and neoplastic skin disease- 1990 update. J blvest Dermatol 1990; 94:151 S- 157S. 15. Cotran RS, Gimbrone MA, Bevilaqua MP, Mendrick DL, Pober JS. Induction and detection of a human endothelial activation antigen in vivo. J Exp Med 1986; 164: 661-666. 16. Picker LJ, Kishimoto TK, Smith CW, Warnock RA, Butcher EC. ELAM-I is an adhesion molecule for skinhoming T-cells. Nature 1992 (in press).
457
17. Bochner BS, Krishnaswami G, Friedman B et al. Cyclic angioedema associated with eosinophil activation and increased serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF). J Allergy Clin Irnmuno11992 (in press). 18. Kroegel C, Liu MC, Lichtenstein LM, Bochner BS. Antigen-induced eosinophil activation and recruitment in the lower airways. J Allergy Clin lmmunol 1991; 87: 303. 19. Hansel TT, Braunstein JB, Blaser K, Bruynzeel PLB, Virchow JC, Jr, Virchow C, Sr. Sputum eosinophils from asthmatics express ICAM-I and HLA-DR. Clin Exp lmmunol 1991; 86:271-277. 20. Damjanovich L, Albelda, SM, Metre SA, Buck CA. Distribution of integrin cell adhesion receptors in normal and malignant lung tissue. Am J Respir Cell Mol Biol 1992; 6: 197-206. 21. Carlos TM, Harlan JM. Membrane proteins involved in phagocyte adherence to endothelium. Immunol Rev 1990; 114: 5-28. 22. Arnout MA. Leucocyte adhesion molecule deficiency: its structural basis, pathophysiology and implications for modulating the inflammatory response. Immunol Rev 1990; 114: 145-180. 23. Gundel RH, WegnerCD, Torcellini CA et al. Endothelial leucocyte adhesion molecule-I (ELAM-I) mediates antigen-induced acute airway inflammation and latephase airway obstruction in monkeys. J Clin Invest 1991; 88:1407-141 I.
Adhesion molecules in diagnosis and therapy of respiratory disease Communication between cells is of fundamental importance in the development and maintenance of inflammatory and immune responses. Two principle mechanisms are involved in these cell-to-cell interactions. The first communication system is maintained by soluble protein factors such as cytokines (e.g. interleukins, colony-stimulating factors, interferons) and lipid mediators (e.g. platelet activating factor, leukotrienes). The second mechanism comprises the interaction between molecular structures on the membrane surface of leucocytes called receptors and molecules on the surface of target cells (ligands). These two systems are closely linked and interdependent since soluble factors can clearly enhance or induce cell-cell interactions, and cell-cell interactions can control the response of cells to inflammatory mediators (l). The biological function of the intercellular communication is not only to induce functions of inflammatory cells but also to provide the basis for a selective and specific mechanism of leucocyte migration into the affected tissue towards the trigger of the immune response. Surface molecules involved herein are generally referred to as adhesion molecules. Three main groups of surface adhesion receptors are recognized (2). The first is the integrin receptor family. This group consists of at least fourteen a/fl heterodimeric transmembrane glycoproteins, which are further divided into three subfamilies on the basis of structurally distinct fl chains. (a) The fl~ or 'very late activation' (VLA) subfamily comprising six members (VLA-I to -6). These adhesion molecules are widely distributed in tissues and interact with the extracellular matrix such as laminin, fibronectin or collagen. Their biological significance has been related to wound healing, cell migration during embryogenesis and eosinophil adherence to endothelial cells (3). (b) In the f12subfamily, also referred to as leucocyte integrins, to date three members have been identified that structurally belong to the CDI I/CD18 heterodimer complex: the 'lymphocyte function associated antigen-1' (LFA1; CD 11a/CD 18) binds to the 'intercellular adhesion molecules' 1 and 2 (ICAM-I and ICAM-2); Mac-1 (CD1 lb/CDI8) binds to the ligand iC3b; and p150,95 (CDI Ic/CDI8) to an, as yet, unknown ligand. These molecules are exclusively expressed on leucocytes, and are mainly involved in immune adherence. (c) The f13or cytoadhesion subfamily has two members, designated VNR and platelet glycoprotein IIb/IIIa which bind to fibronectin, vitronectin, fibrinogen and the von 0954-6111/92/060455 + 03 $08.00/0
Willebrand factor. These molecules are functionally related to the VLA molecules mentioned above. The second group of cell surface adhesion molecules, known as selectins, include the 'endothelial cell adhesion molecule- 1' (ELAM- 1), the 'leucocyte adhesion molecule' (LAM-1 or Mel-14) and the 'plateletactivation-dependent granule-external membrane protein' (PADG-EM). Members of this family are expressed on leucocytes and endothelial cells, and are believed to be involved in leucocyte adhesion to endothelium during inflammatory immune reactions and coagulation. Finally, the third group of adhesion receptors is the immunoglobulin supergene family. These molecules react with antigens (T-cell receptor CD3, surface immunoglobulins) and antigen-independent receptors such as CD2 (CD58) that binds to 'lymphocyte function associated molecule-3' (LFA-3). Interacting cells are able to express both adhesion receptors and ligands. By definition, the activated cell of the interacting couple carries the adhesion receptor whereas its non-stimulated counterpart expresses the ligand. However, intercellular adhesion between two cells can be achieved by more than one distinct receptor-ligand interaction. Finally, an adhesive effect can be achieved via different mechanisms. For instance, eosinophil-dependent adherence, similar to that of neutrophils, involves activation of the leucocyte adhesion complex CDI I/CDI8, as judged by the inhibitory effect of CD18 mAb (4-6). On the other hand, endothelial-dependent adherence of eosinophils is only partially inhibited by CDI8 mAb, suggesting involvement of a second, CD 18-independent adhesive mechanism (4-6). An important inherent characteristic of adhesion receptor expression is its high variability due to numerous extracellular and intercellular factors. For instance, binding of T-lymphocytes to matrix proteins augments activation via the CD3 component of the antigen receptor (7). In addition, cytokines as welI as PAF enhance the binding of eosinophils, to vascular endothelium via activation of both endothelial cells (8,9) and leucocytes (5,6). Other factors known to upregulate the expression of adhesion molecules include differentiation of T-lymphocytes, T-cell activation and viral infection. While much still remains to be elucidated about the underlying mechanisms of communication between cells, increased understanding of the interaction of this © 1992 Bailli~re Tindall
456
Editorial
diverse group of surface molecules leads to the question as to whether these surface structures could be used as parameters in the diagnosis and treatment of disease? Several recent studies employing immunohistochemical and flow cytometrical techniques in human diseases have focused on this possibility. In the liver, for instance, expression of ICAM-1 is increased on hepatocytes in acute and viral hepatitis (10) and during liver allograft rejection (11). Increased I C A M - I expression has also been observed on cerebral vascular endothelium in viral encephalitis and multiple-sclerosis plaques (12), on thyroid epithelial cells in autoimmune thyroiditis (13), and on keratocytes in various inflammatory dermatoses (14). In addition, distribution of ICAM-1 was correlated with the areas of inflammatory tissue damage and infiltrating leucocytes revealed an enhanced expression of LFA-I. Further, ELAM-1 is found on human venular endothelial cells at the sites of acute (15) and chronic inflammation (16). While these investigations require histological biopsies, other studies have found dynamic adhesion receptor expression on blood cells in human disease. In cyclic angioedema, for example, both the spontaneous and in vitro inducible CDI lb expression on eosinophils by P A F increased several-fold, 2 to 3 weeks before a symptomatic relapse (17). Treatment with prednisone not only led to a resolution of the symptoms but also reduced spontaneous and the in vitro inducible CD 11 b expression. In respiratory diseases, C D l l b expression on bronchoalveolar lymphocytes and macrophages seems to be associated with disease activity in sarcoidosis (unpubl. res.). Studies employing endobronchial allergen provocation showed, that bronchoalveolar eosinophils obtained from the antigen challenged segment had an enhanced CDI lb expression while blood cells showed normal values (18). Sputum eosinophils from asthmatics not receiving steroid therapy were found to have considerably elevated levels of CD 11 b, and, in addition, in the majority of the cases, eosinophils expressed I C A M - I and H L A - D R (19). Finally, integrin receptor expression has been reported to be highly variable but tends to be weaker in lung cell carcinoma than in normal epithelium (20). Taken together, these observations indicate that evaluation of adhesion molecules may be a useful adjunct to conventional diagnostic procedures in monitoring disease activity. In addition, these surface molecules may also be helpful in predicting disease behaviour and response to treatment. Do adhesion molecules also have a possible implication in the treatment of inflammatory disease? While there is no human data available to date, results from
animal studies suggest that this may, indeed, be the case. For instance, the use of anti-CDI I/CD18 antibodies has been shown to prevent the migration of leucocytes in acute inflammation (21) and ischaemiareperfusion injury (22). In a primate model of asthma, a monoclonal antibody to ICAM-1, attenuated airway eosinophilia and hyperresponsiveness (9). In the same model, pretreatment of the animals with anti-ELAM- I antibodies blocked both the influx of neutrophils and the late-phase airway obstruction (23). Although caution has to be exercised when extrapolating these results to the situation in humans, these studies at least indicate that blocking of adhesion molecules could represent a new future therapeutic approach. Extensive investigations should provide a clearer idea of whether antibodies against adhesion molecules will gain a therapeutic significance in inflammatory disease of the lung. C. KROEGELAND H. MATTHYS Department o f Pneumology Medical Clinic Albert-Ludwigs-University Hugstetter Str. 55. D-7800 Freiburg Germany References
I. Natthan C, Sporn M. Cytokines in context. J Cell Biol 1991; 113: 981-986. 2. Larson RS, Springer TA. Structure and function of leucocyte integrins. Immunol Rev 1990; 114: 181-217. 3. Bochner BS, Luscinskas FW, Gimbrone MA et al. Adhesion of human basophils, eosinophils, and neutrophils to interleukin-l-activated human vascular endothelial cells: contribution of endothelial cell adhesion molecules. J Exp Med 1991; 173: 1553-1556. 4. Dobrina A, Schwartz BR, Carlos TM, Ochs HD, Beatty PG, Harlan JM. CDll/CDl8-independent neutrophil adherence to inducible endothelial-leucocyte adhesion molecules (ELAM) in vitro. Immunology 1989; 67: 502-508. 5. Kimani G, Tonnesen MG, Henson PM. Stimulation of eosinophil adherence to human vascular endothelial cells in vitro by platelet activating factor. Jlmmuno11988; 140: 3161-3166. 6. Lamas AM, Mulroney CM, Schleimer XX. Studies on the adhesive interaction between human eosinophils and cultured vascular endothelial cells. J Immunol 1988; 140: 1500-1505. 7. Carrerra AC, Rincon M, Sanchez-Madrid F, LopezBotet M, de Landazuri MO. Triggering of co-mitogenic signals in T cell proliferation by anti-LFA-1 (CDI8/ CDlla), LFA-3, and CD7 monoclonal antibodies. J lmmuno11988; 141: 1919-1924. 8. Dobrina A, Menegazzi R, Carlos TM et al. Mechanisms of eosinophil adherence to cultured vascular endothelial cells. Eosinophils bind to the cytokine-induced endothelial vascular cell adhesion molecule-1 via the very late activation antigen-4 integrin receptor. J Clin Invest 1991; 88: 20-26.
Editorial
9. Wegner CD, Gundel RH, Reilly P, Haynes N, Letts LG, Rothlein R. Intercellular adhesion molecules-I (ICAMI) in the pathogenesis of asthma. Science 1990; 247: 456-459. 10. Volpes R, Van Den Oord J J, Desmet VJ. Immunohistochemical study of adhesion molecules in liver inflammation. Hepathology 1990; I2: 59-65. 11. Adams DH, Hubscher SG, Shaw J, Rothlein R, Neuberger JM. Intercellular adhesion molecule 1 on liver allografts during rejection. Lancet 1989; ii: 1122-1125. 12. Sobel RA, Mitchell ME, Fondren G. Intercellular adhesion molecule- I (ICAM- I ) in cellular immune reactions in human central nervous system. Am J Pathol 1990; 136: 1309-1316. 13. Weetman AP, Cohen S, Makgoba MW, Borysiewicz LK. Expression ofan intercellular adhesion molecule, ICAM1, by human thyroid cells. J Endocrinol 1989; 122: 185-191. 14. NickoloffBJ, Griffiths CEM, Barker JNWN. The role of adhesion molecules, chemotactic factors and cytokines in inflammatory and neoplastic skin disease- 1990 update. J blvest Dermatol 1990; 94:151 S- 157S. 15. Cotran RS, Gimbrone MA, Bevilaqua MP, Mendrick DL, Pober JS. Induction and detection of a human endothelial activation antigen in vivo. J Exp Med 1986; 164: 661-666. 16. Picker LJ, Kishimoto TK, Smith CW, Warnock RA, Butcher EC. ELAM-I is an adhesion molecule for skinhoming T-cells. Nature 1992 (in press).
457
17. Bochner BS, Krishnaswami G, Friedman B et al. Cyclic angioedema associated with eosinophil activation and increased serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF). J Allergy Clin Irnmuno11992 (in press). 18. Kroegel C, Liu MC, Lichtenstein LM, Bochner BS. Antigen-induced eosinophil activation and recruitment in the lower airways. J Allergy Clin lmmunol 1991; 87: 303. 19. Hansel TT, Braunstein JB, Blaser K, Bruynzeel PLB, Virchow JC, Jr, Virchow C, Sr. Sputum eosinophils from asthmatics express ICAM-I and HLA-DR. Clin Exp lmmunol 1991; 86:271-277. 20. Damjanovich L, Albelda, SM, Metre SA, Buck CA. Distribution of integrin cell adhesion receptors in normal and malignant lung tissue. Am J Respir Cell Mol Biol 1992; 6: 197-206. 21. Carlos TM, Harlan JM. Membrane proteins involved in phagocyte adherence to endothelium. Immunol Rev 1990; 114: 5-28. 22. Arnout MA. Leucocyte adhesion molecule deficiency: its structural basis, pathophysiology and implications for modulating the inflammatory response. Immunol Rev 1990; 114: 145-180. 23. Gundel RH, WegnerCD, Torcellini CA et al. Endothelial leucocyte adhesion molecule-I (ELAM-I) mediates antigen-induced acute airway inflammation and latephase airway obstruction in monkeys. J Clin Invest 1991; 88:1407-141 I.