Cellular Adhesion in Inflammation

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Cellular Adhesion in Inflammation

Presented by Suvanee Charoenlap, MD.

August22, 2014

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Cellular Adhesion in Inflammation

  1. 1. Cellular Adhesion in Inflammation Suvanee Charoenlap, M.D.
  2. 2. Outline •Introduction •Characteristic and function of cellular adhesion molecules •Human disease associated with adhesion molecule deficiency •Adhesion molecules in Human Allergic Inflammation
  3. 3. Introduction •Inflammation : a reaction to injury or infection •Leukocyte- endothelial interactions = a major event in the inflammatory process Tissue resident cells •Mast cells •Dendritic cells •Macrophages Peripheral blood leukocytes •Neutrophils •Eosinophils •Basophils •T-cells •Mononuclear cells
  4. 4. MIGRATION OF IMMUNE CELLS LYMPHOCYTE HOMING AND RECIRCULATION Janeway, C. (2001). Immunobiology: The immune system in health and disease.
  5. 5. The main functions served by leukocyte migration from blood into tissues Abul K. Abbas, et al.Cellular and Molecular Immunology 7th EDITION
  6. 6. The main functions served by leukocyte migration from blood into tissues Abul K. Abbas, et al.Cellular and Molecular Immunology 7th EDITION
  7. 7. The main functions served by leukocyte migration from blood into tissues Abul K. Abbas, et al.Cellular and Molecular Immunology 7th EDITION
  8. 8. Cell adhesion molecules (CAMs)  Promote cell-cell and cell-matrix interactions •Selectins •Integrins •Immunoglobulin gene superfamily members •Others : Galectins, Cadherins, and CD44 Cell adhesion molecules (CAMs)
  9. 9. The cascade model of leukocyte extravasation Blood flow Selectins Chemokines •Integrins •Ig gene Superfamily
  10. 10. Adhesion molecules Cells Ligand on endothelial cells Extravasation stage L-selection (CD62L) Naïve T lymphocytes, other leukocytes GlyCAM-1, CD34, MadCAM-1 Tethering/Rolling PSGL-1 Neutrophils E-selectin (CD26E), P-selectin (CD62P) Tethering/Rolling LFA-1 (β2 Integrin, CD11a/CD18) Activated T lymphocytes , other leukocytes ICAM-1 (CD54), ICAM-2 (CD102) Tight adhesion VLA-4 (β1 Integrin, CD49d/CD28) Activated T lymphocytes , monocytes, neutrophils, eosinophils, basophils VCAM-1 (CD106), Fibronectin Tight adhesion Mac-1 (CD11b/CD18) Neutrophils, Monocytes, Macrophages ICAM-1, iC3b, fibronectin Tight adhesion LPAM-1 (β7 integrin) Effector T lymphocytes VCAM-1, MadCAM-1, fibronectin Adhesion
  11. 11. Selectins and Selectin Ligands
  12. 12. Selectins •Bind to specific sugar determinants on the surfaces of adjacent cells and act as adhesion counter receptors. •L- selectin (CD62L) •E- selectin (CD62E) •P- selectin (CD62P)
  13. 13. The extracellular domains of the three selectins  share significant homology All three selectins use the lectin domain to mediate adhesion
  14. 14. L-Selectin •Expressed on the tips of the microvilli of most leukocytes •Mediates leukocyte margination and tethering to endothelium under conditions of shear stress associated with blood flow •Irreversibly and rapidly shed from the leukocyte cell surface by endogenous membrane-bound proteases.
  15. 15. E-Selectin •The expression of E-selectin is restricted to activated endothelial cells. •IL-1, TNF-α or bacterial endotoxin  Activate •Expression of E-selectin can be potentiated by IFN-γ and inhibited by TGF-β •Supports adhesion of neutrophils and subsets of T cells but not eosinophils in vivo •In vitro Baseline levels by 24 hours. Endothelial expression levels peaking at 4 to 6 hours
  16. 16. P-Selectin •Expressed by activated endothelium and activated platelets •Stored preformed in intracellular granules •Stimulated with : C5a, histamine, thrombin, or LTC4 and IL-13 Alter leukocyte cellular functions •superoxide production •integrin-mediated phagocytosis •production of cytokines and chemokines Leukocyte interaction with endothelial
  17. 17. Selectins Tissue distribution Ligands L-selectin (LAM-1, CD62L) Neutrophils, monocytes, T cells (naive and central memory), B cells (naive) Sialyl Lewis X/PNAd on GlyCAM-1, CD34, MadCAM-1, others; endothelium (HEV) E-selectin (ELAM-1, CD62E) Endothelium activated by cytokines (TNF, IL-1) Sialyl Lewis X (e.g., CLA-1) on glycoproteins; neutrophils, monocytes, T cells (effector, memory) P-selectin (PADGEM, CD62P) Endothelium & platelet activated by cytokines (TNF, IL-1), histamine, or thrombin Sialyl Lewis X on PSGL-1 and other glycoproteins; neutrophils, monocytes, T cells (effector, memory) Selectins and Selectin Ligands Abul K. Abbas, et al.Cellular and Molecular Immunology 7th EDITION
  18. 18. ENZYMES INVOLVED IN SELECTIN LIGAND SYNTHESIS •Golgi-resident glycosyltransferases –Sialyltransferases –Fucosyltransferases (FucT) •FucT-IV and FucT-VII important for : leukocyte synthesis of Sialyl-LewisX (sLe x )
  19. 19. SELECTIN-DEFICIENT MICE: INSIGHTS INTO THE ROLE OF SELECTINS IN ALLERGIC INFLAMMATION •P-selectin–deficient mice decreased airway hyperreactivity (AHR) attenuated influx of eosinophils and lymphocytes in bronchoalveolar lavage (BAL) •L-selectin– deficient mice a marked decrease in AHR and a mild attenuation of T cell recruitment in BAL in a mouse model of asthma. •E-selectin more important in the adhesion of neutrophils to endothelium than in the adhesion of eosinophils to endothelium. Broide DH, et al. Blood 1998;91:2847-56. Fiscus LC, et al. J Allergy Clin Immunol 2001;107:1019-24. Sriramarao P, et al. J Immunol 1996;157: 4672-80.
  20. 20. SELECTIN LIGAND–DEFICIENT MICE: INSIGHTS INTO THE ROLE OF SELECTIN LIGANDS IN INFLAMMATION •Support for a critical role for glycosyltransferases during leukocyte trafficking in vivo •Mice deficient in FucT-VII a significantly increased peripheral blood leukocyte count due to an almost complete absence of leukocyte rolling in inflamed venules. •FucT-VII appears to be more important than FucT-IV in leukocyte adhesion to endothelium. Homeister JW, et al. Immunity 2001;15: 115-26. Maly P, et al. Cell 1996;86: 643-53.
  21. 21. HUMAN GENETIC DISEASES ASSOCIATED WITH SELECTIN LIGAND DEFICIENCY : INSIGHTS INTO THE ROLE OF SELECTINS IN INFLAMMATION •Genetic defects in fucose metabolism a defect in the Golgi-associated guanosine diphosphate- fucose transporter (GFTP) in patients with LAD-II impaired leukocyte sLe x synthesis Etzioni A, Alon R. Curr Opin Allergy Clin Immunol 2004;4:485-90. McDowall A, et al. J Clin Invest 2003;111:51-60.
  22. 22. TARGETING SELECTINS IN HUMAN ALLERGIC INFLAMMATION •A single intravenous dose of a pan-selectin antagonist TBC1269 administered 15 minutes before allergen challenge  inhibit the early and late asthmatic responses in mild asymptomatic asthmatics. •Inhaled TBC1269  significantly reduced allergen-induced late phase asthmatic reactions by approximately 50% compared with placebo in mild asthmatics  no effect on the early asthmatic response Avila PC, et al. Clin Exp Allergy 2004;34:77-84.
  23. 23. Integrins
  24. 24. •A large family of structurally related, noncovalently linked α and β heterodimeric cell adhesion receptors. •The mammalian genome comprises 18 α and 8 β subunit genes Integrins
  25. 25. Integrins DAVID H. BROIDE, P. SRIRAMARAO, . Middleton's Allergy: Principles & Practice, 8th ed 56 cysteine residues a key recognition site for integrin-binding activity
  26. 26. INTEGRIN EXPRESSION AND LIGANDS •Most integrins interact with multiple ligands •A single integrin ligand (ECM proteins and other CAMs) can interact with multiple integrins. •Cells relevant to allergic disease: eosinophils and basophils : α4 (α4β1 and α4β7) and β2 (αLβ2, αMβ2, αXβ2, αDβ2) integrins •Eosinophils express α6β1, Basophils express α5β1 •Endothelial cells express β1 integrins (α2β1, α3β1, α5β1, and α6β1) •Respiratory epithelial cells express α9β1, αvβ1, α6β4, αvβ5, and αvβ6
  27. 27. Ligands and distribution of integrins Gang Niu, Xiaoyuan Chen. Theranostics 2011; 1:30-47.
  28. 28. Ligands and distribution of integrins Gang Niu, Xiaoyuan Chen. Theranostics 2011; 1:30-47. VLA-4
  29. 29. Ligands and distribution of integrins Gang Niu, Xiaoyuan Chen. Theranostics 2011; 1:30-47. LFA-1
  30. 30. Integrins Tissue distribution Ligands LFA-1 (CD11aCD18) Neutrophils, monocytes, T cells (naive, effector, memory) ICAM-1 (CD54), ICAM-2 (CD102); endothelium (upregulated when cytokine activated) Mac-1 (CD11bCD18) Monocytes, Macrophages, dendritic cells ICAM-1 (CD54), ICAM-2 (CD102); endothelium (upregulated when cytokine activated) VLA-4 (CD49aCD29) Monocytes, T cells (naive, effector, memory) VCAM-1 (CD106); endothelium (upregulated when cytokine activated) α4β7 (CD49dCD29) Monocytes, T cells (gut homing, naive, effector,memory) VCAM-1 (CD106), MadCAM-1; endothelium in gut and gut-associated lymphoid tissues Integrins and Integrin Ligands Abul K. Abbas, et al.Cellular and Molecular Immunology 7th EDITION
  31. 31. Integrin activation Abul K. Abbas, et al.Cellular and Molecular Immunology 7th EDITION CD44, CD47, CD98, and tetraspanins regulate the conformational switch of integrins  ability to microcluster and anchor to actin cytoskeleton. •Chemokines •GPCRs
  32. 32. INTEGRIN SIGNALING •Integrins function as bidirectional signaling molecules. –“outside-in” signaling : influence cell proliferation, differentiation, migration, gene transcription, and apoptosis. –“inside-out” signaling : is important in a key step in the adhesion of leukocytes to endothelium.
  33. 33. Shattil SJ. Nat Rev Mol Cell Biol.2010 Apr;11(4):288-300.
  34. 34. TARGETING INTEGRINS IN HUMAN ALLERGIC INFLAMMATION •Targeting of the integrin αIIbβ3 : Abciximab, Eptifibatide, or Tirofiban Treatment of acute coronary syndromes Prevention of myocardial infarction after percutaneous coronary interventions for approximately 10 years.
  35. 35. •VLA-4 (very late antigen 4, α4β1) •based on promising results of studies with VLA-4 antagonists in inhibiting airway responsiveness in animal models of asthma TARGETING INTEGRINS IN HUMAN ALLERGIC INFLAMMATION Abraham WM, et al. J Clin Invest 1994;93:776-87. Henderson WR, et al. J Clin Invest 1997; 100:3083-92.
  36. 36. Effect of IVL745, a VLA-4 antagonist, on allergen-induced bronchoconstriction in patients with asthma •16 adult patients with mild to moderate atopic asthma were treated with either the VLA-4 antagonist (IVL745) or placebo twice daily by inhalation for 7 days before an inhalation allergen challenge Norris V, et al. J Allergy Clin Immunol 2005;116: 761-7 The VLA-4 antagonist did not inhibit the early or the late asthmatic response
  37. 37. Norris V, et al. J Allergy Clin Immunol 2005;116: 761-7 modestly suppress the 7-day sputum eosinophil count by approximately 50%
  38. 38. The effect of a single inhaled dose of a VLA-4 antagonist on allergen-induced airway responses and airway inflammation in patients with asthma •a single inhaled dose of the VLA-4 antagonist GW559090X was used to determine whether it could protect against allergen-induced changes in airway responses in 15 patients with mild intermittent asthma. Ravensberg AJ, et al. Allergy 2006;61:1097-103. The VLA-4 antagonist did not inhibit the early phase or the late phase response to inhalation allergen challenge
  39. 39. •Natalizumab binds to α4 •Inhibits the interaction between –α4β1 and VCAM-1 –α4β7 and MadCAM-1 Natalizumab for Relapsing Multiple Sclerosis and Crohn disease
  40. 40. DAVID H. BROIDE, P. SRIRAMARAO, . Middleton's Allergy: Principles & Practice, 8th ed
  41. 41. A Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis Miller DH, et al. N Engl J Med 2003;348: 15-23. Natalizumab blocks leukocyte trafficking across the blood-brain barrier and thereby reduces inflammation within multiple sclerosis lesions.
  42. 42. Natalizumab for Active Crohn’s Disease Ghosh S, et al. N Engl J Med 2003;348:24-32. Natalizumab may function by inhibiting T lymphocytes that induce cytokines and chemokines needed to sustain neutrophil recruitment
  43. 43. Human studies in asthma have also evaluated targeting of β2 integrins expressed by leukocytes •Efalizumab is a humanized anti-αL monoclonal antibody (mAb) that targets leukocyte CD11a, the α subunit of lymphocyte function-associated antigen 1 (LFA-1). •Inhibits binding of The α chain of αLβ2 (CD11a/CD18 or LFA-1) to intercellular adhesion molecule 1 (ICAM-1) expressed by blood vessels
  44. 44. DAVID H. BROIDE, P. SRIRAMARAO, . Middleton's Allergy: Principles & Practice, 8th ed
  45. 45. The effects of an anti-CD11a mAb, efalizumab, on allergen-induced airway responses and airway inflammation in subjects with atopic asthma Gauvreau GM, et al. J Allergy Clin Immunol 2003;112: 331-8. Efalizumab did not inhibit the early or late phase fall in FEV1 after allergen challenge
  46. 46. Immunoglobulin Gene Superfamily
  47. 47. Immunoglobulin Gene Superfamily
  48. 48. DAVID H. BROIDE, P. SRIRAMARAO, . Middleton's Allergy: Principles & Practice, 8th ed
  49. 49. Immunoglobulin Gene Superfamily Ligand for Expression Stimulation by ICAM-1 (CD54) LFA-1, fibrinogen, rhinovirus ,MAC-1 endothelial cells ,leukocytes, epithelial cells, and fibroblasts cytokines (e.g., IL-1, TNF-α, IFN-γ) bacterial endotoxin ICAM-2 (CD102) LFA-1 endothelial cells , mononuclear cells, basophils, mast cells, and platelets unaffected by cytokines ICAM-3 (CD50) LFA-1, CD18 all leukocytes , mast cells, langerhans cells, endothelium ICAM-3 cross-linking Immunoglobulin Gene Superfamily
  50. 50. Immunoglobulin Gene Superfamily Ligand for Expression Stimulation by VCAM-1 (CD106) VLA-4 (α4β1) and αDβ2 integrin endothelium, macrophages, dendritic cells, astrocytes, BM stromal cells, and respiratory epithelial cell lines. IL-1, TNF-α, or bacterial endotoxin IL-4 or IL-13 PECAM-1 (CD31) PECAM expressed by endothelial cells (homotypic binding), αvβ3 integrin, CD31,CD38 endothelial cells , leukocytes (role in transendothelial migration) , Platelets MAdCAM-1 α4/ß7 Mucosal endothelium Immunoglobulin Gene Superfamily
  51. 51. TARGETING IMMUNOGLOBULIN GENE SUPERFAMILY MEMBERS IN HUMAN ALLERGIC INFLAMMATION •Targeting one of the IgSF members (ICAM-1) have been used in clinical trials in : Rheumatoid arthritis, Transplant rejection, and Stroke •R6.5 (BIRR-1, enlimomab) (a murine IgG2a mAb to human ICAM-1) Proved to be beneficial in reducing disease activity in a subset of patients with rheumatoid arthritis. Adverse effects such as fever (50%) and cutaneous reactions (22% pruritus; 9% urticaria) were frequent, and leukopenia was also noted.
  52. 52. GALECTINS : a family of β-galactose–recognizing proteins that exhibit a conserved carbohydrate-recognition domain (CRD) of approximately 130 amino acids DAVID H. BROIDE, P. SRIRAMARAO, . Middleton's Allergy: Principles & Practice, 8th ed
  53. 53. Galectin-3 functions as an adhesion molecule to support eosinophil rolling and adhesion Rao SP, et al. J Immunol 2007;179:7800-7.
  54. 54. CADHERINS : Transmembrane proteins that mediate intercellular adhesion in epithelial and endothelial cells •E-, N-, P-, T- and VE-cadherins, protocadherins, seven-transmembrane cadherin, and FAT-family cadherin. •Endothelium and Epithelium  maintaining tissue integrity, cell-cell recognition, signaling, communication, growth, and angiogenesis.
  55. 55. E-cadherin •Maintenance of epithelial integrity •Immunologic function of the airway epithelium : Regulation of epithelial junctions, proliferation, differentiation, and production of growth factors and proinflammatory mediators •Vascular permeability, leukocyte extravasation, and angiogenesis Nawijn MC. Trends Immunol 2011;32:248-55
  56. 56. CD44 •CD44 is expressed on a majority of immune cells •a variety of biologic processes : lymphopoiesis, angiogenesis, wound healing, leukocyte extravasation at inflammatory sites, and tumor metastasis. •ligand for CD44 is hyaluronan
  57. 57. Baaten, et al. Frontiers in Immunology ; Vol 3, 2012
  58. 58. Baaten, et al. Frontiers in Immunology ; Vol 3, 2012
  59. 59. A role for CD44 in an antigen induced murine model of pulmonary eosinophilia •IL-3, IL-5, and GM-CSF increase CD44 expression on eosinophils •Administration of an anti-CD44 mAb prevented both lymphocyte and eosinophil accumulation in the lung, reducing AHR in mouse models of asthma. Katoh S, et al. J Clin Invest 2003; 111:1563-70.
  60. 60. Leukocyte Adhesion to the Extracellular Matrix in Tissues •Leukocytes express adhesion receptors that allow them to bind to ECM proteins (e.g., fibronectin, laminin, vitronectin, tenascin, collagen)  the β1 integrin family •α4β1 integrins (VLA-4) : Eosinophils, Basophils and mast cells bind to Fibronectin •In vivo studied  administration of α4 integrin antibodies to sensitized rats inhibits mast cell activation and prevents acute allergic airway responses. •Eosinophils can also bind to laminin through α6 integrins.
  61. 61. Regulation of Adhesion Molecule Expression
  62. 62. 2 – 6 hr. Preformed P-selectin is rapidly expressed within 30 minutes after stimulation with histamine E-selectin (4 to 6 hours) DAVID H. BROIDE, P. SRIRAMARAO, . Middleton's Allergy: Principles & Practice, 8th ed resident cells
  63. 63. 8 – 24 hr. ICAM-1 and VCAM-1 (8 to 24 hours) TNF and IL-1 induce E-selectin, ICAM-1, VCAM-1 IL-4 and IL-13 are selective for VCAM-1 DAVID H. BROIDE, P. SRIRAMARAO, . Middleton's Allergy: Principles & Practice, 8th ed
  64. 64. Regulation of Adhesion Molecule Expression Cytokines  regulate adhesion molecule expression on •Endothelium •Circulating leukocytes : inducing their upregulation, shedding, or change in affinity. Eosinophils IL-3, IL-5, or GM-CSF •augments adhesion molecule function •induces L-selectin shedding and CD11b upregulation •enhances chemoattractant-induced adhesion responses and transendothelial migration
  65. 65. Human Disease Associated with Adhesion Molecule Deficiency
  66. 66. Human Disease Associated with Adhesion Molecule Deficiency
  67. 67. LAD-I Of the LAD syndromes, LAD-I is most common Cause A genetic defect in the β2 subunit (CD18) of the integrin (21q22.3) Inheritance AR Result Impaired surface expression of β2 integrin on neutrophils Hallmarks •Delayed separation of the umbilical cord •Recurrent severe bacterial infection without pus formation •Marked leukocytosis •Absent or markedly decreased CD18 expression on the leukocyte surface.
  68. 68. LAD-II LAD-II is an even more rare condition Cause A defect in a Golgi-associated GFTP protein Inheritance AR Result A generalized defect in fucose metabolism a defect in the selectin-mediated rolling phase Hallmarks •Recurrent infection •Growth and mental retardation •Lack of expression of the fucose-containing structures (CD15s, also known as sialyl- Lewis x) and the red blood cell H antigen
  69. 69. LAD-III LAD-III syndrome is also very rare Cause mutations in the FERMT3 gene (11q13.1), Defects in integrin (β1, β2, and β3) activation signaling by physiologic inside-out stimuli Inheritance AR Result Integrin signals do not enhance •platelet aggregation •neutrophil adhesion to ICAM-1 or fibronectin. Hallmarks •Severe recurrent infections •Bleeding tendency •Marked leukocytosis with •normal expression of CD18 •normal expression of CD15s
  70. 70. Adhesion Molecules in Human Allergic Inflammation
  71. 71. ALLERGEN CHALLENGE STUDIES IN THE SKIN Leung DYM, et al.J Clin Invest 1991;87:1805-9. Intradermal injection with allergen induces endothelial cells in the skin to express E-selectin and VCAM-1 and also increases endothelial expression of ICAM-1.
  72. 72. •IL-13  important for VCAM-1 expression and eosinophil recruitment in the skin. •An important role for IL-1 and TNF in inducing E-selectin expression in skin endothelial cells was suggested from studies. Leung DYM, et al.J Clin Invest 1991;87:1805-9. ALLERGEN CHALLENGE STUDIES IN THE SKIN Ying S, et al. J Immunol 1997;158:5050-7.
  73. 73. Subcutaneous administration of a TNF receptor 2-Fc fusion protein (etanercept) •Induced a modest 16% reduction in the immediate cutaneous response to allergen challenge •No effect on the size, symptoms, or cellular features of the late phase response ALLERGEN CHALLENGE STUDIES IN THE SKIN Conner E,et al. J Allergy Clin Immunol 2008;121:258-60.
  74. 74. ALLERGIC RHINITIS •Increases in levels of nasal mucosa VCAM-1 were observed 24 hours after local intranasal allergen challenge •The number of infiltrating eosinophils correlating with the extent and intensity of VCAM-1 staining Lee B-J, et al. J Allergy Clin Immunol 1994;94: 1006-16.
  75. 75. Patients with allergic rhinitis were pretreated with intranasal beclomethasone •Allergen-induced symptoms and superficial mucosal eosinophils were reduced •The number of infiltrating submucosal eosinophils or on endothelial VCAM-1 expression  no effect Baroody FM, et al. Am J Respir Crit Care Med 1998;157:899-906. Intranasal Beclomethasone Reduces Allergen-induced Symptoms and Superficial Mucosal Eosinophilia without Affecting Submucosal Inflammation
  76. 76. Local nasal allergen provocation of subjects with allergic rhinitis •Both nasal and bronchial eosinophilia in association with increased expression of ICAM-1, VCAM-1, and E- selectin on nasal and bronchial blood vessels •Nasal challenge –endothelial activation –eosinophil recruitment at multiple levels throughout the airway ALLERGIC RHINITIS Braunstahl GJ, et al. J Allergy Clin Immunol 2001;107:469-76
  77. 77. •In patients with perennial rhinitis –Nasal tissue detected increased expression of ICAM-1 and VCAM-1, but not E-selectin, compared with nonallergic control subjects. •Seasonal exposure to pollen –Increases in nasal epithelial cell expression of ICAM-1 –Increased numbers of eosinophils, neutrophils, and metachromatic cells. •In nasal polyps –P-selectin and VCAM-1  eosinophil recruitment. –Studies have also implicated TNF-α  inducer of VCAM-1 in the nasal mucosa. ALLERGIC RHINITIS
  78. 78. ASTHMA •Endobronchial allergen challenge –Increases endothelial VCAM-1 staining and epithelial ICAM-1 staining, which correlates significantly with eosinophil influx •Increased levels of soluble forms of E-selectin, ICAM-1, and VCAM-1 in BAL fluids in asthmatics after allergen challenge Bentley AM, et al. J Allergy Clin Immunol 1993;92:857-68. Wilson SJ, et al. Am J Respir Crit Care Med 2001;164: 1047-52.
  79. 79. VCAM-1 staining of airways from asthmatic patients before and after 8 weeks of treatment with inhaled budesonide or formoterol •Only the budesonide-treated subjects had a reduction in VCAM-1 expression. •Both treatments reduced eosinophil numbers. In another study : prednisone  reduced levels of soluble E-selectin in BAL fluid ASTHMA Wilson SJ, et al. Am J Respir Crit Care Med 2001;164: 1047-52. Liu MC, et al. J Allergy Clin Immunol 2001;108:29-38.
  80. 80. EOSINOPHILIC ESOPHAGITIS Pediatric patients with eosinophilic esophagitis Increased levels of VCAM-1 staining of blood vessels Aceves SS,et al. J Allergy Clin Immunol 2007;119:206-12.
  81. 81. ATOPIC DERMATITIS In patients with atopic dermatitis The endothelial expression of ICAM-1 and VCAM-1 is increased in the healthy-appearing skin (nonlesional skin) and markedly increased in the lesional skin, compared with normal individuals •Several studies have demonstrated a positive correlation of serum levels of soluble ICAM-1 and VCAM-1 with atopic dermatitis disease activity. Jung K, et al. Allergy 1996;51:452-60. Wuthrich B, et al. Allergy 1995;50:88. Koide M, et al. J Dermatol 1997;24:88-93.
  82. 82. Summary •Advances in understanding of the cellular and molecular pathways –Molecular causes of immunodeficiencies. –Potential adhesion-based therapeutic targets in asthma and allergy. •Clinical studies have demonstrated the potential benefit of adhesion-based therapies : Multiple sclerosis, Crohn disease, and Psoriasis  Require further study
  83. 83. Thank you
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