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`
`Mechanisms of intranasal steroids in the
`management of upper respiratory
`allergic diseases
`Harold S. Nelson, MD Denver, Colo
`
`Intranasal steroids have proved to be the most effective class of
`drugs in reducing the symptoms of allergic rhinitis. This clini-
`cal response reflects the broad anti-inflammatory activity that
`has been demonstrated for corticosteroids. Single doses of topi-
`cal corticosteroids administered before nasal allergen chal-
`lenge block the late-phase reaction, whereas repeated dosing
`with intranasal steroids blocks both the early and the late
`response, as well as the priming phenomenon. Nasal inflamma-
`tion is accomplished through a number of effector cells and
`mechanisms, which in turn are produced by director cells
`through the release of cytokines and chemokines. The anti-
`inflammatory action of corticosteroids is largely effected
`through blocking the synthesis and release of these
`cytokines/chemokines. (J Allergy Clin Immunol
`1999;104:S138-43)
`
`Key words: Intranasal steroids, allergic rhinitis, mechanisms of
`action, cytokines, chemokines
`
`The clinical features of allergic rhinitis result from a
`series of inflammatory events that are induced after aller-
`gen exposure. Intranasal steroids have proved to be the
`most effective class of drugs in reducing the symptoms of
`allergic rhinitis. This clinical response reflects the broad
`anti-inflammatory activity that has been demonstrated for
`corticosteroids. Investigations in patients with allergic
`rhinitis have demonstrated that single doses of topical cor-
`ticosteroids administered before nasal allergen challenge
`block the late-phase reaction, whereas repeated dosing
`with intranasal steroids blocks both the early and the late
`response1,2 as well as the subsequent period of increased
`reactivity to allergen,2 histamine,3 and methacholine4
`challenge known as priming. These findings suggest that
`the corticosteroids are interrupting several pathways of
`the nasal reaction to allergen. Studies of the actions of
`corticosteroids in patients undergoing nasal allergen chal-
`lenge or natural allergen exposure confirm the widespread
`actions of the corticosteroids not only on the effector
`mechanisms of the allergic response in the nose but also
`on the cells that are the directors of this response.
`
`From the Department of Medicine, National Jewish Medical and Research
`Center, and the University of Colorado Health Sciences Center, Denver,
`Colo.
`Supported by an unrestricted educational grant from Schering/Key Pharma-
`ceuticals, Schering Corporation.
`Reprint requests: Harold S. Nelson, MD, National Jewish Medical and
`Research Center, 1400 Jackson St, Denver, CO 80206.
`Copyright © 1999 by Mosby, Inc.
`0091-6749/99 $8.00 + 0 1/0/101679
`
`S138
`
`Abbreviations used
`ECP: Eosinophil cationic protein
`ICAM-1:
`Intercellular adhesion molecule-1
`mRNA: Messenger RNA
`SCF: Stem cell factor
`VCAM-1: Vascular cell adhesion molecule-1
`
`EFFECTOR MECHANISMS
`Eosinophils
`
`The most prominent effector cell in allergic rhinitis
`and in the late-phase reaction of the nose to allergen chal-
`lenge is the eosinophil.5 The number of eosinophils, par-
`ticularly activated eosinophils (EG2+), increases substan-
`tially in the epithelium and lamina propria during the
`allergic response.6 Intranasal steroids reduce eosinophil
`numbers by inhibiting eosinophil recruitment and migra-
`tion into the nasal airways and promoting eosinophil
`apoptosis.7,8
`Clinical studies have confirmed the ability of intranasal
`steroids to reduce total1 and activated9 eosinophil num-
`bers and eosinophil cationic protein (ECP)1 in nasal
`lavage fluid in the late phase of the reaction to allergen
`challenge and in both seasonal10 and perennial7 rhinitis. A
`study by Klementsson et al10 compared placebo and
`budesonide (200 mg given once daily) in 22 patients with
`allergic rhinitis caused by natural birch pollen exposure.
`During the birch pollen season patients in the placebo
`group had increases in the proportion of total and activat-
`ed eosinophils, increased levels of ECP in nasal lavage
`fluid, and increased nasal responsiveness to methacholine
`(Fig 1). Intranasal budesonide significantly reduced the
`proportion of total and activated eosinophils and blocked
`the increased nasal responsiveness.
`Corticosteroids have no direct effect on eosinophil
`chemotaxis or degranulation. Therefore reduction in
`eosinophil numbers probably represents a combination
`of an inhibition of eosinophil influx as a result of corti-
`costeroid-induced inhibition of cytokine and chemokine
`production7,9 and increased apoptosis, reflecting a direct
`effect on the eosinophil itself.8
`The cytokines and chemokines involved in migration
`and activation of eosinophils include (1) IL-4 and IL-13,
`which up-regulate vascular cell adhesion molecule-1
`(VCAM-1) on the vascular endothelium (VCAM-1 inter-
`acts with the adhesion molecule very-late antigen-4 on
`the surface of the eosinophil promoting margination), (2)
`IL-1 and TNF-α, which induce intercellular adhesion
`
`

`

`J ALLERGY CLIN IMMUNOL
`VOLUME 104, NUMBER 4, PART 1
`
`Nelson S139
`
`FIG 1. Intranasal steroid treatment during birch pollen season significantly reduced
`eosinophil influx (A) and activation (B) and reduced nasal hyperresponsiveness (C) com-
`pared with placebo. A, Proportion of eosinophils harvested from nasal mucosa before and
`during pollen season. Open boxes,Mean values ± SEM for placebo group; solid boxes,val-
`ues obtained during glucocorticoid treatment. Asterisk, P< .005; dagger, P< .001 for com-
`parisons of active treatment versus placebo. B, Levels of ECP in nasal lavage fluid before
`and during pollen season. Open boxes,Mean values ± SEM for placebo group; solid boxes,
`values obtained during glucocorticoid treatment. Arrow,Start of treatment. Asterisk, P< .05
`for comparisons of active treatment versus placebo. C, Methacholine-induced secretion
`before and during pollen season. Open boxes,Mean values ± SEM for placebo group; solid
`boxes,values obtained during glucocorticoid treatment. Asterisk, P< .05 for comparisons of
`active treatment versus placebo. (Adapted with permission from Klementsson H, Svensson
`C, Anderson M, Venge P, Pipkorn U, Persson CGA. Eosinophils, secretory responsiveness
`and glucocorticoid-induced effects on the nasal mucosa during a weak pollen season. Clin
`Exp Allergy 1991;21:705-10.)
`
`molecule-1 (ICAM-1) on the vascular endothelium (a
`contributor to eosinophil migration), (3) the chemokines
`RANTES and macrophage inflammatory protein-1α,
`which are chemotactic for eosinophils, and (4) IL-3, IL-
`5, and GM-CSF, which promote eosinophil activation
`and survival.
`
`Basophils and mast cells
`
`An influx of basophils characterizes the late-phase
`reaction to nasal allergen challenge,1 whereas the less
`intense and more prolonged allergen exposure with sea-
`sonal and perennial rhinitis results in an increase in
`
`

`

`S140 Nelson
`
`J ALLERGY CLIN IMMUNOL
`OCTOBER 1999
`
`TABLE I. Cytokine/chemokine expression in nasal inflammation and effect of intranasal corticosteroids
`
`Cytokine
`IL-1b
`
`IL-4
`
`IL-5
`
`IL-6
`
`IL-13
`
`IL-16
`
`TNF-α
`
`Action
`Activates B and T lymphocytes
`Up-regulates ICAM-1
`Up-regulates VCAM-1
`IgE isotype switch in B cells
`Activates TH2 lymphocytes
`Up-regulates IgE receptors
`Eosinophil activation and survival
`
`Promotes IgE synthesis
`Converts B cells to plasma cells
`Enhances T-cell activation
`Promotes VCAM-1
`IgE isotype switch
`Chemoattractant for CD4+ T lymphocytes
`
`Up-regulates ICAM-1 and VCAM-1
`
`GM-CSF
`
`Eosinophil attraction, activation, and survival
`
`SCF
`Chemokine
`RANTES
`
`IL-8
`MP-1a
`
`Mast cell growth and survival
`
`Eosinophil chemotaxis
`Histamine-releasing factor
`Chemotaxis for mast cells
`Chemotaxis
`Histamine-releasing factor
`
`Respiratory cell source
`Epithelial cells13
`Macrophages
`CD4+ T lymphocyte26
`> Mast cells5,18
`
`↑ in AR
`16
`
`5, 23
`17-19
`
`References
`↓ by CS
`16
`
`17-19
`
`T lymphocytes26
`Mast cells5,20
`Eosinophils5
`Mast cells20
`
`T lymphocytes
`> Mast cells17
`Epithelial cells23
`Subepithelial cells23
`Mast cells5
`T lymphocytes
`Epithelial cells13
`Mast cells
`T lymphocytes5
`Epithelial cells16
`Epithelial cells24
`
`Epithelial cells5
`
`5, 23
`17, 18
`
`18 (No 9)
`20 (No 9)
`
`20
`
`20 (No 9)
`
`17, 23
`
`23
`
`5
`
`5, 18
`16
`
`24
`
`16
`
`16
`16
`
`17
`
`23
`
`16, 25
`
`24
`
`16
`
`16
`16
`
`AR, Allergic rhinitis; CS, corticosteroid; MIP-a, macrophage inflammatory protein 1a.
`
`mucosal (tryptase only) mast cells5 and perhaps
`basophils1 in the nasal mucosa. Corticosteroids have no
`effect on mast cell mediator release, but they do inhibit
`mediator release from basophils. Topical corticosteroids
`markedly reduce the influx of basophils during the late-
`phase response to nasal allergen challenge1 and prevent
`the increase in mucosal mast cells with chronic allergic
`stimulation, both seasonal7 and perennial.7,11 Topical
`corticosteroids do not reduce baseline numbers of
`mucosal mast cells but do decrease levels of histamine in
`the mucosa.12
`
`Plasma exudation
`
`Entry of plasma into the nasal lumen has been demon-
`strated after histamine and allergen challenge and in sea-
`sonal allergic rhinitis.13 In patients with seasonal allergic
`rhinitis intranasal steroids have been shown to reduce
`exudation as measured by nasal lavage fluid levels of
`bradykinin and fibrinogen.14 This could result from a
`direct effect on the vascular endothelial cells, be the result
`of decreased release of permeability factors, or both.14
`
`Adhesion molecule expression
`Expression of the endothelial adhesion molecules
`ICAM-1 (induced by IL-1 and TNF-α) and VCAM-1
`
`(induced by IL-4 and IL-13) has been reported to be
`increased in patients with both seasonal and perennial aller-
`gic rhinitis.15 Reduction in the expression of these adhesion
`molecules by corticosteroids would be anticipated because
`levels of the inducing cytokines are reduced.16-20
`
`Nasal hyperresponsiveness to allergen, hista-
`mine, and methacholine
`
`Nonspecific reactivity of the nose to histamine3 and
`methacholine4 is typically increased in perennial allergic
`rhinitis. Intranasal steroids reduce this hyperresponsiveness
`and also block the increase in sensitivity to allergen that
`follows allergen challenge, the so-called priming effect.2
`
`Specific IgE response
`
`Circulating levels of allergen-specific IgE increase dur-
`ing seasonal pollen exposure. This increase has been
`shown to be blocked by treatment with intranasal steroids
`in seasonal allergic rhinitis caused by birch21 and rag-
`weed22 pollen. The mechanism for this reduction in spe-
`cific IgE antibody could be decreased allergen penetration
`to T cells, reduction in antigen-presenting Langerhans’
`cells, or a decrease in the release of IL-4, although the last
`mechanism is less likely because IL-4 has no effect on
`committed B cells.
`
`

`

`J ALLERGY CLIN IMMUNOL
`VOLUME 104, NUMBER 4, PART 1
`
`Nelson S141
`
`FIG 2. Intranasal steroid treatment during allergen challenge significantly reduced levels of IL-1β during early and
`late phases of allergic response compared with placebo. Figure shows hourly levels of IL-1β detected by ELISA
`in nasal secretions of allergic subjects after antigen challenge. Open boxes,Mean values ± SEM for the placebo
`group; solid boxes,values obtained for beclomethasone dipropionate treatment group. B,Baseline; Dil,diluent
`(saline solution); AF,Afrin7 nasal spray solution; AG, antigen. Asterisk, P< 0.05; dagger, P< .01. (Adapted with
`permission from Sim TC, Reece LM, Hilsmeirer KA, Grant A, Alam R. Secretion of chemokines and other cytokines
`in allergen-induced nasal responses: inhibition by topical steroid treatment. Am J Respir Crit Care Med
`1995;152:927-33. Official journal of the American Thoracic Society. © 1995 American Lung Association.)
`
`FIG 3. Intranasal steroid treatment significantly inhibited increases in IL-13 mRNA-positive cells (A) and IL-13
`immunoreactive cells (B) in patients with allergic rhinitis challenged with allergen. Nasal biopsy specimens were
`taken at baseline (before) and 24 hours after allergen challenge (after). Results are expressed as number of pos-
`itive cells per field. Statistical analyses were done with paired t test. P < .001. (Adapted with permission from
`Ghaffar O, Laberge S, Jacobson MR, et al. mRNA and immunoreactivity in allergen-induced rhinitis: comparison
`with IL-4 expression and modulation by topical glucocorticoid therapy. Am J Respir Cell Mol Biol 1997;17:17-24.
`Official journal of The American Thoracic Society. © 1997 American Lung Association.)
`
`

`

`S142 Nelson
`
`DIRECTOR MECHANISMS
`
`The director mechanisms are the forces behind the
`effector mechanisms. Important components of the direc-
`tor mechanisms include epithelial cells, antigen-present-
`ing cells, and T lymphocytes. In addition, 2 major effec-
`tor cells, eosinophils and mast cells, contribute as director
`cells as well through their release of cytokines (Table I).
`
`Epithelial cells
`
`Epithelial cells are active participants in the inflam-
`matory response. These cells release a variety of chemo-
`tactic and proinflammatory cytokines, including IL-1,
`IL-8, GM-CSF, TNF-α,13 IL-16,23 and stem cell factor
`(SCF).24 There is substantial evidence that intranasal
`steroids inhibit the expression or release of many of
`these cytokines (Table I).5,13,16,17-20,23-26 Corticosteroids
`may decrease eosinophil survival by abrogating the pro-
`moting effect on eosinophil survival by epithelial cells,
`in part by corticosteroid modulation of GM-CSF
`release.25
`SCF, a major chemoattractant and growth and differ-
`entiation factor for mast cells, is produced by epithelial
`cells, endothelial cells, and fibroblasts. Significantly
`increased messenger RNA (mRNA) for SCF was found
`in epithelial cells from patients with allergic rhinitis com-
`pared with normal controls.24 Corticosteroid treatment
`reduced the number of cells producing SCF in vivo and
`in vitro. Mast cells are found to be increased in the nasal
`epithelium of patients with allergic rhinitis. Increased
`epithelial cell SCF production may be responsible for
`this increase. Some of the effect of glucocorticosteroids
`in allergic rhinitis may be through inhibition of growth,
`differentiation, or chemotaxis of mast cells.
`
`Antigen-presenting cells
`
`Antigen-presenting Langerhans’ cells, characterized by
`the surface antigens CD1a and HLA-DR, ingest allergens
`in the nasal mucosa and then migrate to the regional
`lymph nodes, where they stimulate T lymphocytes. The
`number of Langerhans’ cells in the nasal mucosa and lam-
`ina propria increases after repeated allergen challenges
`and during the pollen season.13 Treatment with topical
`steroids markedly reduces the number of detectable
`Langerhans’ cells.27 Whether the number of cells or only
`their surface markers (CD1a) are reduced is uncertain.
`
`Lymphocytes
`
`T lymphocytes are thought to be the principal cells
`that orchestrate the immune inflammatory response in
`the nose.5 The number of lymphocytes bearing the CD4+
`and CD25+ (IL-2R) surface antigens has been found to
`be increased after nasal allergen challenge28 and in
`patients with seasonal and perennial allergic rhinitis.29
`Study results are conflicting regarding the effect of
`intranasal steroids on the number of T lymphocytes.
`Intranasal steroids were found not to significantly reduce
`the number of T cells or their activation (IL-2R+) in
`patients with perennial allergic rhinitis.27 However, 6
`
`J ALLERGY CLIN IMMUNOL
`OCTOBER 1999
`
`weeks of treatment with topical corticosteroids, when
`followed by nasal allergen challenge, was reported to
`reduce numbers of T lymphocytes, both CD4+ and CD8+,
`to a greater extent in the surface epithelium than in the
`lamina propria,23 and corticosteroid treatment was
`reported to decrease both CD4+ and CD8+ T lympho-
`cytes in nasal polyps.30 The effect of intranasal steroids
`on lymphocytes may depend on the intensity of the aller-
`gen stimulus and the dose and duration of the therapy.6
`After nasal allergen challenge, an increase was found
`in the number of activated T cells (CD25+) and CD4+ T
`cells expressing mRNA for IL-4 and IL-5.28 IL-4 is
`thought to be important in recruiting eosinophils through
`up-regulation of VCAM-1, in IgE synthesis through
`inducing isotype switching in B cells, in up-regulating
`high- and low-affinity IgE receptors, and in activating
`TH2-type T lymphocytes. Topical corticosteroids have
`been shown to attenuate IL-417,18,20 but not IL-517,20 or
`IL-620 mRNA expression. With seasonal exposure, there
`was an increase in the B lymphocytes targeted for isotype
`switching to IgE production.19 This was blocked by top-
`ical corticosteroids.
`The data suggest that an important role of cortico-
`steroids is to block the production and secretion of
`cytokines by TH2 CD4+ T lymphocytes, which control
`recruitment and activation of eosinophils, mast cells, and
`basophils and IgE production.
`
`Cytokines
`
`Studies after nasal allergen challenge or natural expo-
`sure have shown increased release of or expression of
`mRNA for many cytokines and chemokines, which may
`have relevance in the allergic inflammatory response in
`the nose (Table I). In most of these studies blocking
`expression of these cytokines and chemokines by pread-
`ministration of intranasal steroids has been demonstrat-
`ed (Fig 3).
`
`CONCLUSION
`
`Intranasal steroids reduce the influx of inflammatory
`cells into the nasal mucosa in response to allergic stim-
`uli. This reduces the release of inflammatory mediators
`and the development of nasal hyperresponsiveness. The
`inhibition of allergic inflammation results from the
`action of corticosteroids in blocking the synthesis and
`release of cytokines and chemokines from T lympho-
`cytes, epithelial cells, eosinophils, and mast cells.
`Although attenuation of the allergic inflammatory reac-
`tion can be demonstrated after single doses of topical
`corticosteroids, their full benefit is achieved only after
`regular use over days or weeks.
`
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`J ALLERGY CLIN IMMUNOL
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