Late-phase reaction in ocular allergy
`Soo Hyun Choi and Leonard Bielory
`
`UMDNJ, New Jersey Medical School, Newark, New
`Jersey, USA
`
`Correspondence to Dr Leonard Bielory, MD, Professor
`of Medicine, Pediatrics, Ophthalmology and Visual
`Sciences, Director, Clinical Research and
`Development, Director, Division of Allergy, Immunology
`and Rheumatology, 90 Bergen Street, Suite 4700,
`PO Box 1709, Newark, NJ 07101, USA
`Tel: +1 973 972 2768; e-mail: bielory@umdnj.edu
`
`Current Opinion in Allergy and Clinical
`Immunology 2008, 8:438–444
`
`Purpose of review
`To determine if the late-phase reaction, which commonly occurs in allergic rhinitis and
`asthma, is also found in ocular allergy.
`Recent findings
`Using PubMed, 542 articles were found; 18 articles in the allergy and ophthalmology
`literature were specifically related to late-phase reaction. Ocular late-phase reaction
`is clinically seen in 50–100% of allergic rhinoconjunctivitis patients, is associated
`with progression to systemic atopic disorders that is allergic rhinoconjunctivitis and
`occurs in several forms including biphasic, multiphasic and a prolonged response.
`Summary
`The existing literature demonstrates that an ocular late-phase reaction also exists and
`has implications in the development severity of disease, change of reactivity and
`progression of the atopic disease state from a localized target organ, such as the nose
`or eye, to a more systemic atopic disorder. The existence of the clinically relevant
`allergic late-phase response is not only limited to the nose, skin and lungs but also
`includes the eyes. The appreciation that the late-phase response may be clinically very
`important as there is a continuum of ocular mast-cell activation during the waking
`hours of the day, a better understanding of its clinical impact may be a more appropriate
`focus in the development of future treatments.
`
`Keywords
`allergic conjunctivitis, conjunctival provocation test, eye allergy symptoms, late-phase
`response, ocular allergy
`
`Curr Opin Allergy Clin Immunol 8:438–444
`ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
`1528-4050
`
`Introduction
`Although late-phase reaction (LPR) is frequently seen in
`allergic nasal, respiratory and skin disease [1,2], the
`clinical impact of LPR in ocular allergy has been ques-
`tioned. Allergic responses in tissues may vary, partially
`because of the heterogeneity of mast cells from different
`tissues [3,4]. Among the different tissues, the eye’s
`anterior surface is easily observed with highly magnifying
`instrumentation (i.e. slit-lamp microscope or other digital
`equipment). In addition, mediator release and cellular
`infiltration can be measured in the immunological fluid
`that bathes the eye’s surface (i.e. tears) and through direct
`examination of the biopsied conjunctiva, which is easily
`accessible [5].
`
`While using the conjunctival provocation test (CPT),
`which was initially employed to study the early-phase
`response (EPR), researchers discovered that the conjunc-
`tiva also exhibited a dose-dependent LPR [6]. As LPR is
`garnering more attention due to its influence on morbid-
`ity and its association with the development of more
`chronic and systemic forms of atopic disorders, it is
`
`becoming important to research the role of LPR in ocular
`allergy. The CPT is an excellent tool that mimics ocular
`allergic responses, allowing for the measurement of
`symptoms, inflammatory mediators, cells and pharmaco-
`logic modulation with the use of the contralateral eye for
`control purposes. The CPT is extremely allergen specific
`and sensitive [7–10] and has proven to be safe and
`effective in confirming a diagnosis of allergy, even in
`cases in which the patient’s history and skin testing were
`doubtful [11] as demonstrated in cases of serologic nega-
`tivity [negative radioallergosorbent test (RAST)], but
`with the presence of a positive ocular provocation
`(positive CPT) [12].
`
`Material and methods/techniques
`All
`journals and review articles were collected using
`PubMed and by manually searching the major allergy
`and ophthalmology journals that are listed below. Key-
`words searched: ocular allergy, eye allergy, LPR, CPT,
`conjunctival
`allergen challenge, eosinophil
`cationic
`protein (ECP), eosinophil, hyper-reactivity and time
`course. The search resulted in 542 articles, with 47 articles
`
`1528-4050 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
`
`DOI:10.1097/ACI.0b013e32830e6b3a
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized r
`
`ibited.
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`APOTEX EX1051
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`reviewed for this analysis that specifically included LPR
`data that included 15 review articles and 32 clinical trials
`with 18 being published since January 2000. In addition to
`the use of allergens, studies using compound 48/80,
`platelet-activating factor (PAF) and histamine were also
`evaluated.
`
`Background
`A sensitized individual who comes into contact with a
`particular allergen at the target site may experience an
`immediate reaction caused by mast cells, known as the
`EPR. The mediators that are stored in the mast-cell
`granules or generated de novo by this EPR also lead to
`a second LPR after 6–24 h [13,14]. LPR is IgE mediated
`and is dependent on an initial activation of the mast cells
`by an antigen [1,2]. LPR has been associated with the
`severity of disease, change of reactivity and progression of
`the atopic disease state from a localized target organ to a
`more systemic atopic disorder
`[15–17].
`In many
`instances, it has been identified that the severity of the
`disease is determined by eosinophils recruited during
`LPR [18–22,23]. Therefore, the study of LPR is essen-
`tial to understand the mechanism of allergic disease and
`the therapeutic approaches that are required.
`
`Allergic responses in tissues may vary, partially because
`of the demonstrable heterogeneity of mast cells from
`different tissues [3,4]. The CPT is an excellent tool that
`mimics ocular allergic responses, which allows for the
`measuring of symptoms, inflammatory mediators, cells
`and pharmacologic modulation. In addition to the use of
`CPT, we reviewed studies conducted using compound
`48/80 (nonimmunologic mast-cell degranulator), PAF,
`histamine and nitric oxide [10,24–31].
`
`Results
`Eighteen studies that involved animal model and human
`studies supported the concept that LPR is clinically
`relevant as measured by signs and symptoms, as well
`as cytological and immunohistochemical changes.
`
`Conjunctival provocation test: signs and symptoms
`The use of CPT in the evaluation of LPR was seen in
`eight of the 18 studies. A study conducted by Bonini et al.
`[32] showed that only with a high allergen dose
`(320 000 BU/ml) challenge, symptoms were noted after
`6 h in seven out of 11 (64%) patients along with EPR at
`20 min. Interestingly, cytologic changes occurred at all
`doses even in the absence of clinical symptoms in the
`EPR and LPR. In the study by Bacon et al. [15], allergic
`sign and symptoms were graded by a scoring system. All
`18 (100%) CPT challenged atopic patients had a median
`allergic sign and symptom score of 12 (range, 7–16) at
`20 min, 13 out of 18 (72%) patients had a score of 9 (range,
`
`Late-phase reaction in ocular allergy Choi and Bielory 439
`
`4–13) at 40 min and 18 of 18 (100%) patients had clinical
`score of 8 (range, 4–14) at 6 h. In the study by Montan
`et al. [13], all 15 patients had allergic symptoms in the
`challenged eye after 10 min; five out of 15 (33%) patients
`had a second increase in symptoms and signs, at 8 and
`24 h, and 12 out of 15 (80%) patients reported itching at
`12 h. In the study conducted by Bonini et al. [33], an
`incremental dose of allergen induced increasingly greater
`clinical reactions at 20 min in the early phase; however,
`only the highest dose (320 000 BU/ml) produced clinical
`reactions at 6 h after the CPT.
`
`In animal studies, Calonge et al. [34] observed the clinical
`signs in actively sensitized guinea pigs for up to 48 h. Lid
`swelling, lid redness and conjunctival redness peaked at
`30 min and decreased until 4 h after the challenge. How-
`ever, there was a second rise from 5 to 8 h after the
`challenge, which was less intense. All of the animals
`exhibited an early rise of their clinical scores, but 75%
`presented with a second peak of clinical observed signs
`and symptoms of LPR. No animals exhibited an isolated
`late rise of their clinical scores. Of the animals that
`experienced a second response, 47% were biphasic, 6%
`were prolonged and 47% were multiphasic. Leonardi et al.
`[35] observed immunized guinea pigs after hapten dini-
`trophenylated (DNP)-lysine allergen challenge. The
`total mean clinical score was measured up to 24 h. The
`LPR was noticed from 4 to 8 h after the challenge and in
`one-third of the experimental eyes, clinical signs waxed
`and waned, another one-third showed biphasic response
`and the remaining demonstrated progressively decreas-
`ing reaction patterns that lasted for 9–12 h.
`
`Conjunctival provocation test: cytological review
`Bonini et al. [32] measured cells from conjunctival scrap-
`ings and tears at different concentrations of CPT. The
`study showed elevated neutrophils in 20 min, eosinophils
`in 6 h and neutrophils, eosinophils and lymphocytes in
`12–24 h. When the CPT concentrations were increased,
`there was an increase in the cell count in the tears. Bacon
`et al. [15] showed an increase in mast cells, neutrophils,
`macrophages, eosinophils, basophils, CD4þ and CD8þ
`cells in a bulbar tissue biopsy of the substantia propria at 6 h
`compared to the control eye that was not challenged in all
`(nine of nine) atopic patients. In the study by Bonini et al.
`[33], it was noted that there was no significant increase in
`eosinophils and lymphocytes when challenged with lower
`doses (i.e. 32 000 and 100 000 BU/ml) at 6 h. However, with
`the high-dose allergen (320 000 BU/ml), there was an
`increase in eosinophils and lymphocytes compared to
`the controls in 10 out of 11 patients.
`
`In animal studies, Magone et al. [36] investigated the role
`of IL-4, IFN-g and IL-12 in the LPR using cytokine
`knockout mice. The study showed that IL-12 knockout
`mice had low cellular levels in the conjunctiva, whereas
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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`440 Eye allergy
`
`IFN-g knockout mice had a prolonged infiltration into
`the conjunctiva during 30 min to 120 h. This study
`suggested that IL-12 plays a role in development of
`the late-phase pathological features of ocular allergy.
`IFN-g suppresses the development of LPR and may
`be used to control the chronic phase of allergic disease.
`The study by Leonardi et al. [35] on the conjunctival
`substantia propria after challenge showed a maximal
`increment of inflammatory cells observed at 3 h for
`macrophages and neutrophils, and at 24 h for eosinophils
`and lymphocytes. A study by Ozaki et al. [23] discussed
`the role of Th2 cells in LPR. Transfer of allergen-specific
`IgE into normal rats induced the clinical signs of the
`EPR, but not eosinophil infiltration in the eye. It was
`noted, however, that the transfer of allergen-primed Th2
`cells induced eosinophil
`infiltrate as well as clinical
`symptoms of LPR.
`
`Conjunctival provocation test: immunohistochemistry
`review
`Bacon et al. [15] conducted a study in which inflammatory
`mediators and tissue adhesion proteins were measured in
`tear samples and tissue biopsies. Twenty minutes after
`the CPT, there was an increase in histamine and tryptase
`levels in the tears. At 6 h, a second increase in histamine
`and ECP, but not tryptase, were measured. There was
`also an increase in E-selectin and intercellular adhesion
`molecule-1 (ICAM-1), but not vascular cellular adhesion
`molecule-1 (VCAM-1), in the tissue biopsy after 6 h in
`eight atopic patients. In the study by Montan et al. [13],
`the ECP in tears was increased in the challenged eye
`when compared to the unchallenged eye at 6, 8 and 24 h.
`The increasing symptoms of the challenged eye corre-
`lated with the increased levels of tear ECP. During the
`study by Ozaki et al. [23], 15 min after ragweed chal-
`lenge to sensitized mice showed clinical signs of allergic
`
`conjunctivitis. Additionally, 24 h after challenge there
`was massive infiltration of eosinophil in the eye on biopsy
`and an increased level of IL-4, IL-5 and IL-13 in regional
`lymph nodes.
`
`Conjunctival provocation test with compound 48/80 and
`platelet-activating factor: signs and symptoms
`Zinchuk et al. [28] conducted a study in which following
`PAF instillation in the eye, severe edema of the lids,
`conjunctival redness and chemosis occurred after 30 min,
`reaching its peak at 2 h. By 6 h, the signs began to
`decrease and by 24 h, the signs were minimal.
`
`Conjunctival provocation test with compound 48/80 and
`platelet-activating factor: immunohistochemistry review
`According to Zinchuk et al. [28] after the instillation of
`PAF in the rat eye, they measured anti-PAF receptor
`(PAF-R) and anti-major basic protein (MBP) antibodies
`to visualize the cells expressing PAF-R and eosinophils.
`PAF-R-positive cells continued to increase until the 24 h
`time period when the study stopped. MBP-positive cells
`(eosinophils) continued to increase until 6 h and at 24 h
`the number started to decrease (Fig. 1). Okumura et al.
`[29] found that C16:0-PAF, C16:0-lyso-PAF and C18:0-
`lyso-PAF in guinea pigs (actively sensitized to oval-
`bumin) showed an increase until 6 h postchallenge.
`There was no related increase in the unsensitized guinea
`pigs. This indicates that PAF may be involved in not only
`EPR but also LPR.
`Papathanassiou et al. [37] studied the effect of topical
`cysLT-receptor antagonist, zafirlukast on the compound
`48/80-induced nitric oxide release in the rat conjunctiva.
`After compound 48/80 challenge, the nitrite level in the
`conjunctival
`lavage fluid increased to 220 and 230%
`(n¼ 4, P < 0.01) compared to the control at 6 h. However,
`
`Figure 1 Major basic protein positive and platelet-activating factor receptor positive cells in platelet-activating factor induced rat
`conjunctivitis
`
`MBP-positive cells
`
`PAF-receptor-positive cells
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`Control 30 min
`
`2 h
`
`6 h
`
`24 h
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`300
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`250
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`200
`
`150
`
`100
`
`50
`
`0
`
`Control 30 min
`
`2 h
`
`6 h
`
`24 h
`
`After PAF 1% solution instillation into rat conjunctiva, intact conjunctiva was obtained from the rat eye. The number of MBP (a marker of eosinophils)-
`positive cells and PAF-receptor-positive cells were measured with immunostaining. Values at each time were compared to values at all other time points
`(P < 0.01). PAF, a major mediator in allergic conjunctivitis caused recruitment of eosinophils during LPR. MBP, major basic protein; PAF, platelet-
`activating factor. Reproduced with permission [28].
`
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`treatment with disodium cromoglycate before the chal-
`lenge and with zafirlukast or levocabastine after the
`challenge attenuated nitrite levels at 6 h after the com-
`pound 48/80 challenge to 150, 121 and 54%, respectively.
`There was no decrease in the nitrite levels with the
`unchallenged conjunctiva. In addition, zafirlukast had
`no significant effect on the histamine content measured
`at 45 min in either the unchallenged or challenged con-
`junctiva (compound 48/80).
`
`Conjunctival provocation test treatment models: signs
`and symptoms
`In clinical studies evaluating the impact of treatment in a
`CPT model, the study by Leonardi et al. [38] demon-
`strated that at 6 h after challenge, the signs and symptoms
`score was lower than at 15 and 30 min, but they were
`present. Both the single dose and the 48 h pretreatment
`with desonide reduced the severity of the immediate
`allergic reaction and the occurrence of the clinical late
`phase, but the 48 h pretreatment with desonide was more
`effective than the single dose before CPT. This study
`suggests that the treatment with a low-dose steroid can
`inhibit or attenuate the allergic reaction phase that
`initiates the transition from early acute to the chronic
`inflammatory response. Desonide provided rapid relief of
`the symptoms during seasonal allergic conjunctivitis
`(SAC) with significant improvement observed in the first
`week of treatment.
`Leonardi and Abelson [39] measured the symptoms
`and signs after 15 min and 5 h after CPT with and without
`olopatadine. Olopatadine reduced the itching and red-
`ness score compared to the placebo group throughout the
`time course. Ahluwalia et al. [40] measured the signs and
`symptoms after CPT with rye grass. In the placebo
`group, the symptom score increased from 0 to 6/15 in
`
`Late-phase reaction in ocular allergy Choi and Bielory 441
`
`10 min, peaked at 7/15 at 20–30 min and stayed at 5/15 at
`180–360 min. Both nedocromil and levocabastine low-
`ered the symptom scores significantly during first 60 min
`(Fig. 2).
`
`Conjunctival provocation test treatment models:
`cytological review
`The study by Miyazaki et al. [41], using short ragweed
`(SRW)-sensitized mice, pollen challenge and evaluating
`the effect of administering the immune-stimulatory
`sequence oligodeoxynucleotides (ISS-ODN) as a single
`dose 3 days before the challenge intraperitoneally,
`demonstrated that the total clinical score after conjunc-
`tival SRW challenge increased to 10/16 (63%) compared
`to 3/16 (19%) with placebo at 20 min, whereas the injec-
`tion of ISS-ODN before the challenge decreased the
`clinical score to 4/16 (25%) at the same time point, that
`is 20 min. The study also showed that 24 h after SRW
`challenge, the eosinophil count increased from 20 to 95%,
`whereas after intraperitoneal ISS-ODN treatment before
`the challenge, the eosinophil count decreased from 95 to
`20%. Similarly, the neutrophil count increased from 15 to
`60% 24 h after challenge with SRW and decreased from
`60 to 10% after ISS-ODN injection. In another animal
`model, Murata et al. [14] conducted an experiment on
`ovalbumin-sensitized guinea pigs and observed the effect
`of secretory leukocyte protease inhibitors (SLPI) on
`eosinophils during the LPR. The antigen conjunctival
`challenge induced an increase in eosinophils starting at
`30 min, eventually reaching its peak at 6–12 h and
`decreasing slowly by 24 h. SLPI
`instillation given
`10 min before the challenge effectually decreased eosi-
`nophil infiltration at 6–12 h. However, there was no effect
`seen at 24 h. In addition, the percentage of degranulated
`eosinophil increased from 0 to 60% at 6 h after challenge
`and it stayed at 60% until 24 h. After treatment with SLPI
`
`Figure 2 Clinical scores and mediators measured after conjunctival provocation test compared with nedocromil-treated and
`levocabastine-treated group
`
`PGD2
`
`0
`
`10
`
`20
`
`30
`
`60
`
`180 360
`
`(c)
`
`16
`14
`12
`10
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`86420
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`Histamine
`
`0
`
`10
`
`20
`
`30
`
`60
`
`180
`
`360
`
`(b)
`
`7
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`65 4 3 21 0
`
`(a)
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0
`
`Total clinical score
`
`0
`
`10
`
`20
`
`30
`
`60
`
`180 360
`
`Ocular challenge was performed with 10 ml of ryegrass extract, followed up until 360 min. Individuals were divided into three groups: placebo, n¼ 12;
`nedocromil sodium (2%) received group, n¼ 14; levocabastine (0.05%) received group, n¼ 22. (a) Total symptom: total symptom score divided by
`maximum total symptom score of 15 (itchingþ hyperemiaþ lacrimationþ chemosis). Data are median scores. Statistically significant (P < 0.05) from
`placebo, nedocromil sodium. (b) Histamine level in tears after challenge: statistically significant (P < 0.05) from placebo. (c) PGD2 level in tears after
`) After placebo; (
`) after nedocromil; (
`) after
`ocular challenge: statistically significant (P < 0.05) from placebo. PGD2, prostaglandin D2. (
`levocabastine. Reproduced with permission [40].
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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`442 Eye allergy
`
`inhibitors, there was also a decrease in the percentage of
`the degranulated eosinophil from 6 to 24 h. It should also
`be noted that there was no effect on the clinical signs of
`EPR by SLPI.
`Sengoku et al. [42] used FK506 (tacrolimus hydrate) to
`show its effect on LPR in ocular allergy. Twenty-four
`hours after an egg albumin challenge, histological analysis
`was performed on egg-albumin-sensitized rats. Com-
`pared to the normal rats, the clinical inflammation score,
`T-cell infiltrate and eosinophil count were significantly
`increased. FK506 decreased all three levels in a dose-
`dependent manner. Betamethasone and fluorometholone
`eye drops also decreased the level of T-cell infiltrate and
`eosinophil count but did not decrease the clinical inflam-
`mation score in comparison to tacrolimus.
`Interestingly, the study by Leonardi and Abelson [39]
`showed a reduced count of neutrophils and total cells at
`30 min and decreased the number of eosinophils, neu-
`
`trophils, lymphocytes and the total cells at 5 h with a
`formulation of a multiple action agent, olopatadine.
`
`Conjunctival provocation test treatment models:
`immunohistochemistry review
`A study completed by Leonardi et al. [43] measured the
`level of histamine at 20 min (EPR) and at 6 h (LPR). One
`tear sample was treated with perchloric acid to inhibit all
`enzymatic activity including histaminase. At 20 min
`(EPR), histamine in both the untreated and treated group
`increased in correlation with the sign and symptom after
`CPT. Post-treatment with lodoxamide showed that the
`tear histamine level during EPR was lower than before
`the CPT. At 6 h (LPR), only the histamine in the treated
`sample increased. With post-treatment with lodoxamide,
`histamine levels were low, but not significantly in the
`treated and untreated group. The low histamine level
`during LPR can be attributed to the dominant cells in
`LPR, which are neutrophils, eosinophils rich in histami-
`nase activity. The dominant cells in EPR, which are the
`
`Figure 3 Ocular allergic diseases are characterized by specific activation of conjunctival mast cells with subsequent release of
`preformed and newly formed mediators
`
`Median values
`
`120
`
`100
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`80
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`60
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`40
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`20
`
`0
`
`0
`
`--20
`
`0.25
`
`0.5
`
`1
`
`6
`
`24
`
`Time (h)
`
`Mast-cell numbers on the ocular surface are increased in all forms of allergic conjunctivitis. Mast-cell activation plays a central role in the development of
`the ocular allergic reaction, which can be divided into an early and a late inflammatory phase. Mast-cell mediators have been measured in tears of
`patients suffering from various forms of allergic conjunctivitis, and in sensitized patients after specific ocular allergen challenge. Histamine, tryptase,
`prostaglandins, leukotrienes, ECP, as well as cellular infiltrates including neutrophils, eosinophils, basophils and macrophages are some of the most
`studied mediators in tears of allergic patients. Recent studies have expanded the evaluations to include cytokines, such as IL-4, TNF-a, fibroblast
`growth factor, as well as various adhesion molecules are also produced and released by various conjunctival cells (including mast cells) and most
`probably play a role in the immunoregulation on the ocular surface allergic and other immune disorders affecting the conjunctival surface. ECP,
`) Histamine; (
`) leukotrienes; (
`)
`eosinophil cationic protein; ICAMP, intercellular adhesion molecule; TNF-a, tumor necrosis factor alpha. (
`) tryptase; (
`) neutrophils; (
`) eosinophils; (
`) basophils; (
`) macrophages; (
`) ICAM; (
`) ECP.
`prostaglandins; (
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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`
`mast cells, lack histaminase activity, which explains the
`higher histamine levels during EPR.
`The study by Leonardi and Abelson [39] showed
`decreased levels of tear histamine levels with olopatadine
`compared to the placebo group. Olopatadine also de-
`creased the level of ICAM-1 at 30 min and 5 h after CPT.
`
`Ahluwalia et al. [40] measured the level of histamine and
`prostaglandin D2 (PGD2) in tear fluid until 360 min after
`CPT. ICAM-1, VCAM-1 and E-selectin was measured in
`conjunctival specimen at 6 and 24 h after CPT. Hista-
`mine levels peaked at 30 and 360 min, whereas PGD2
`had only one peak at 30 min. Nedocromil reduced the
`30 min increase in histamine by 77% but not the 360 min
`increase in histamine. In addition, nedocromil decreased
`the 30 min increase in PGD2 by 70%. Levocabastine did
`not have any effect on either histamine or PGD2 level.
`ECP levels started to increase at 60–360 min and was not
`affected by nedocromil or levocabastine. ICAM-1 was
`decreased with levocabastine by 52% at 6 h and 45% at
`24 h compared to placebo, but it did not have any effect
`on E-selectin or VCAM-1. Nedocromil did not have any
`effect on ICAM-1, E-selectin and VCAM-1, but nedo-
`cromil decreased the 3H4-positive (activated) mast cells
`by 49% at 6 h and by 59% at 24 h (Fig. 2).
`
`Conclusion
`These studies reflect the existence of LPR in ocular
`allergy occurred around 4–24 h in 33–100% of patients.
`This review showed the cytologic evidence of LPR,
`suggested by an increase in eosinophils, lymphocytes,
`basophils, neutrophils, mast cells, various mediators and
`adhesion molecules (Fig. 3). Eosinophils in particular
`have been shown to damage tissue and lead to chronic
`forms of ocular allergic diseases [44–47]. In addition,
`immunologic mediators play a role in LPR and are
`suggested by ECP from eosinophils and histamine.
`The histamine in LPR is possibly from basophils because
`of the noted absence of tryptase and PGD2 in LPR. In
`the animal model studies of allergic conjunctivitis, PAF,
`eosinophils and nitric oxide were observed to increase at
`6 h after the challenge. The studies demonstrate that the
`target for therapy may be more appropriately focused on
`reducing the clinical symptoms of LPR, in addition to the
`EPR. Currently, various histamine blockers, mast-cell
`stabilizers, agents with multiple effects (i.e. on early
`and late phases) and steroids (the best treatment of
`the late phase) are in use. Newer agents that have a
`stronger therapeutic profile on the LPR approaching the
`effect of steroids, but due without their potential side
`effects, are warranted.
`
`There is much to be explored to explain the mechanism
`of LPR in the eyes, including the cause and effect with
`
`Late-phase reaction in ocular allergy Choi and Bielory 443
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`multiple time measurements and longer time period
`follow-ups, in order to effectively evaluate the course
`of the LPR. In addition, as stated above, although CPT is
`very useful in many ways and has not changed over the
`past 30 years, advances in a more objective clinical
`grading system and reproducibility are required.
`
`References and recommended reading
`Papers of particular interest, published within the annual period of review, have
`been highlighted as:
`
`of special interest
` of outstanding interest
`Additional references related to this topic can also be found in the Current
`World Literature section in this issue (p. 495).
`
`1 Charlesworth EN. Late-phase inflammation: influence on morbidity. J Allergy
`Clin Immunol 1996; 98:S291–S297.
`
`2 Hansen I, Klimek L, Mosges R, Hormann K. Mediators of inflammation in the
`early and the late phase of allergic rhinitis. Curr Opin Allergy Clin Immunol
`2004; 4:159–163.
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`Lawrence ID, Warner JA, Cohan VL, et al. Purification and characterization of
`human skin mast cells. Evidence for human mast cell heterogeneity. J Immunol
`1987; 139:3062–3069.
`
`Lowman MA, Rees PH, Benyon RC, Church MK. Human mast cell hetero-
`geneity: histamine release from mast cells dispersed from skin, lung, ade-
`noids, tonsils, and colon in response to IgE-dependent and nonimmunologic
`stimuli. J Allergy Clin Immunol 1988; 81:590–597.
`
`Anderson DF. The conjunctival late-phase reaction and allergen provocation
`in the eye. Clin Exp Allergy 1996; 26:1105–1107.
`
`Proud D, Sweet J, Stein P, et al. Inflammatory mediator release on conjunctival
`provocation of allergic subjects with allergen. J Allergy Clin Immunol 1990;
`85:896–905.
`
`Tuft L, Torsney PJ Jr, Ettelson LN, Heck VM. Ophthalmic and nasal mucosal
`tests as an aid in the determination of house dust allergy. A comparative study.
`J Allergy 1962; 33:448–457.
`
`Tuft L. The value of eye tests with inhalant allergens: a clinical study. Ann
`Allergy 1967; 25:183–191.
`
`9 Moller C, Bjorksten B, Nilsson G, Dreborg S. The precision of the conjunctival
`provocation test. Allergy 1984; 39:37–41.
`
`10 Abelson M, Howes J, George M. The conjunctival provocation test model of
`ocular allergy: utility for assessment of an ocular corticosteroid, loteprednol
`etabonate. J Ocul Pharmacol Ther 1998; 14:533–542.
`
`11 Friedlaender MH. Conjunctival provocation testing: overview of
`recent
`clinical trials in ocular allergy. Curr Opin Allergy Clin Immunol 2002; 2:
`413–417.
`
`12 Leonardi A, Fregona IA, Gismondi M, et al. Correlation between conjunctival
`provocation test (CPT) and systemic allergometric tests in allergic conjuncti-
`vitis. Eye 1990; 4 (Pt 5):760–764.
`
`13 Montan PG, van Hage-Hamsten M, Zetterstrom O. Sustained eosinophil
`cationic protein release into tears after a single high-dose conjunctival
`allergen challenge. Clin Exp Allergy 1996; 26:1125–1130.
`
`14 Murata E, Sharmin S, Shiota H, et al. The effect of topically applied secretory
`leukocyte protease inhibitor on the eosinophil response in the late phase of
`allergic conjunctivitis. Curr Eye Res 2003; 26:271–276.
`
`15 Bacon AS, Ahluwalia P, Irani AM, et al. Tear and conjunctival changes during
`the allergen-induced early- and late-phase responses. J Allergy Clin Immunol
`2000; 106:948–954.
`
`16 Bodtger U, Poulsen LK, Malling HJ. Asymptomatic skin sensitization to birch
`predicts later development of birch pollen allergy in adults: a 3-year follow-up
`study. J Allergy Clin Immunol 2003; 111:149–154.
`
`17 Bodtger U. Prognostic value of asymptomatic skin sensitization to aeroaller-
`gens. Curr Opin Allergy Clin Immunol 2004; 4:5–10.
`
`18 Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma.
`N Engl J Med 1990; 323:1033–1039.
`
`19 Walker C, Kaegi MK, Braun P, Blaser K. Activated T cells and eosinophilia in
`bronchoalveolar lavages from subjects with asthma correlated with disease
`severity. J Allergy Clin Immunol 1991; 88:935–942.
`
`20 Broide DH. Molecular and cellular mechanisms of allergic disease. J Allergy
`Clin Immunol 2001; 108:S65–S71.
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
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`
`444 Eye allergy
`
`21 Leonardi A. The central role of conjunctival mast cells in the pathogenesis of
`ocular allergy. Curr Allergy Asthma Rep 2002; 2:325–331.
`
`35 Leonardi A, Secchi AG, Briggs R, Allansmith MR. Conjunctival mast cells and
`the allergic late phase reaction. Ophthalmic Res 1992; 24:234–242.
`
`22 Trocme SD, Aldave AJ. The eye and the eosinophil. Surv Ophthalmol 1994;
`39:241–252.
`
`23 Ozaki A, Seki Y, Fukushima A, Kubo M. The control of allergic conjunctivitis by
`
`suppressor of cytokine signaling (SOCS)3 and SOCS5 in a murine model.
`J Immunol 2005; 175:5489–5497.
`This highly relevant clinical trial showed Th2-cell regulation of eosinophils in LPR
`using suppressor of cytokine signaling (SOCS)3 and SOCS5 in a murine model.
`
`24 Weimer LK, Gamache DA, Yanni JM. Histamine-stimulated cytokine secretion
`from human conjunctival epithelial cells:
`inhibition by the histamine H1
`antagonist emedastine. Int Arch Allergy Immunol 1998; 115:288–293.
`
`25 Udell IJ, Abelson MB. Animal and human ocular surface response to a topical
`nonimmune mast-cell degranulating agent (compound 48/80). Am J Ophthal-
`mol 1981; 91:226–230.
`
`26 Allansmith MR, Baird RS, Ross RN, et al. Ocular anaphylaxis induced in the rat
`by topical application of compound 48/80. Dose response and time course
`study. Acta Ophthalmol Suppl 1989; 192:145–153.
`
`27 Udell
`IJ, Kenyon KR, Hanninen LA, Abelson MB. Time course of human
`conjunctival mast cell degranulation in response to compound 48/80. Acta
`Ophthalmol Suppl 1989; 192:154–161.
`
`28
`
` Zinchuk O, Fukushima A, Zinchuk V, et al. Direct action of platelet activating
`
`factor (PAF) induces eosinophil accumulation and enhances expression of
`PAF receptors in conjunctivitis. Mol Vis 2005; 11:114–123.
`This valuable clinical trial used PAF-induced allergic conjunctivitis in a murine
`model, which showed clinical signs and symptoms with increased eosinophils
`during LPR.
`29
`
` Okumura N, Fukushima A,
`
`Igarashi A, et al. Pharmacokinetic analysis of
`platelet-activating factor in the tears of guinea pigs with allergic conjunctivitis.
`J Ocul Pharmacol Ther 2006; 22:347–352.
`This important clinical trial showed the relationship between PAF and ocular LPR in
`ovalbumin-induced guinea-pig conjunctivitis.
`30 Abelson MB, Schaefer K. Conjunctivitis of allergic origin:
`immunologic
`mechanisms and current approaches to therapy. Surv Ophthalmol 1993;
`38 (Suppl):115–132.
`31 Meijer F, Tak C, van Haeringen NJ, Kijlstra A. Interaction between nitric oxide
`and prostaglandin synthesis in the acute phase of allergic conjunctivitis.
`Prostag