Cellular Adhesion in Inflammation Presented by Suvanee Charoenlap, MD. August22, 2014

1. Cellular Adhesion in Inflammation
Suvanee Charoenlap, M.D.

2. Outline
•Introduction
•Characteristic and function of cellular adhesion molecules
•Human disease associated with adhesion molecule deficiency
•Adhesion molecules in Human Allergic Inflammation

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. MIGRATION OF IMMUNE CELLS LYMPHOCYTE HOMING AND RECIRCULATION
Janeway, C. (2001). Immunobiology: The immune system in health and disease.

5. The main functions served by leukocyte migration from blood into tissues
Abul K. Abbas, et al.Cellular and Molecular Immunology 7th EDITION

6. The main functions served by leukocyte migration from blood into tissues
Abul K. Abbas, et al.Cellular and Molecular Immunology 7th EDITION

7. The main functions served by leukocyte migration from blood into tissues
Abul K. Abbas, et al.Cellular and Molecular Immunology 7th EDITION

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. The cascade model of leukocyte extravasation
Blood flow
Selectins
Chemokines
•Integrins
•Ig gene Superfamily

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. Selectins and Selectin Ligands

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. The extracellular domains of the three selectins
 share significant homology
All three selectins use the lectin domain to mediate adhesion

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. 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. 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. 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. 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. 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. 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. 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. 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. Integrins

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. 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. 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. Ligands and distribution of integrins
Gang Niu, Xiaoyuan Chen. Theranostics 2011; 1:30-47.

28. Ligands and distribution of integrins
Gang Niu, Xiaoyuan Chen. Theranostics 2011; 1:30-47.
VLA-4

29. Ligands and distribution of integrins
Gang Niu, Xiaoyuan Chen. Theranostics 2011; 1:30-47.
LFA-1

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. 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. 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. Shattil SJ. Nat Rev Mol Cell Biol.2010 Apr;11(4):288-300.

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. •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. 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. Norris V, et al. J Allergy Clin Immunol 2005;116: 761-7
modestly suppress the 7-day sputum eosinophil count by approximately 50%

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. •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. DAVID H. BROIDE, P. SRIRAMARAO, . Middleton's Allergy: Principles & Practice, 8th ed

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. 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. 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. DAVID H. BROIDE, P. SRIRAMARAO, . Middleton's Allergy: Principles & Practice, 8th ed

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. Immunoglobulin Gene Superfamily

47. Immunoglobulin Gene Superfamily

48. DAVID H. BROIDE, P. SRIRAMARAO, . Middleton's Allergy: Principles & Practice, 8th ed

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. 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. 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. 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. Galectin-3 functions as an adhesion molecule to support eosinophil rolling and adhesion
Rao SP, et al. J Immunol 2007;179:7800-7.

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. 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. 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. Baaten, et al. Frontiers in Immunology ; Vol 3, 2012

58. Baaten, et al. Frontiers in Immunology ; Vol 3, 2012

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. 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. Regulation of Adhesion Molecule Expression

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. 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. 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. Human Disease Associated with Adhesion Molecule Deficiency

66. Human Disease Associated with Adhesion Molecule Deficiency

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. 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. 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

71. Adhesion Molecules in Human Allergic Inflammation

72. 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.

73. •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.

74. 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.

75. 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.

76. 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

77. 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

78. •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

79. 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.

80. 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.

81. 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.

82. 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.

83. 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

84. Thank you