Conjunctival Allergen Challenge:
`Models in the investigation of
`Ocular Allergy
`
`Marla B. Abelson, M D, and Oliver Loeffler
`
`Address
`Ophthalmic Research Assocrates. 863 Turnpike Street. North Andover,
`MA 0| 845. USA.
`E-rnatl: mbabelson@otaclinical.com
`Current Allergy and Asthma Reports 2003. 313637368
`Current Science Inc. ISSN 629-7322
`Copyright © 2003 by Current Science lnc.
`
`Recently. the number of agents to treat ocular allergy has
`increased dramatically from three (pheniramine. antazoline.
`cromolyn) to more than a dozen. A general increase in the
`incidence of atopy in recent years and the fact that patients
`are becoming less tolerant of bothersome signs and symp-
`toms have been driving forces in this increase. As visual
`tasking. such as reading and working on a computer. has
`become more prevalent. there is an increased awareness of
`ocular allergy and the impact it has on quality of life and
`productivity at work and school. VWth the need for more
`effective medications. the development of models. such as
`the conjunctival allergen challenge (CAC). has made the
`identification of new agents more efficient. In this article,
`we review the relevant background on the science behind
`allergen challenges in the eye. how models are designed.
`and how models are used in the field today.
`
`Introduction
`
`is estimated that as many as '30 million Amelitans arc
`It
`all’ected by ocular allergy—almost 3 We ol' the popttlation
`
`1]. (time lour types ol‘ allergic coniunctivitis (atopic
`lteratoconiunctivitis, vernal Loratoconiunctivitis, sea-
`sonal/perennial allergic conjunctivitis [SAC/PAR), and
`tll'llgvlntlttt't‘tl allergic conjunctivitis), the most prevalent
`litrms are SM L, triggered by pollens, and l‘;\(? triggered by
`dust or dander ‘lhe bt'ithersomc signs and symptoms
`caused by ocular allergy will cause signilicanl decreases in
`quality of life and ability to function, sleep problems,
`decreased ability to visual task, and ellects on social inter
`actions, all leading to missed time at work, owing to visits
`to the doctor’s office, and decreased productivity. 'l'herc-
`iorc, it
`is important not only that therapeutic modalities
`be developed for ocular allergic sufferers, but also that the
`model or methods by which these treatments are identi
`
`lied and tested be accurate and reliable. In the pursuit oi
`cl‘l’ettive therapies. thc conittnctival allergen challenge
`((1:\(I] model has been developed. 'l‘his model has
`allowed precise control ol coni’ounding lactors that are
`present in the typical environmental study and has
`helped to evaluate and bring to market ellective medica
`[ions for ocular allergy.
`I'he model has also been very
`uscl'ul in elucidating the allergic and inflammatory mech—
`anisms ol the ocular sttrlace,
`in itlentilying the cells and
`mediators that are involved, and in itlcntilying targets tor
`novcl therapies. In this artit lc, we review the (int; model.
`compare it with the emironmental design. and look at
`how it has helped contribute lurther understanding to
`ocular disease and therapy,
`
`Basic Science ol‘thc (Coniunctival
`Challenge Model
`(ll—those who filli-l-t‘l' from ocular allergic conditions, at
`least ()lll’io stiller lrom h.-v\(L/'l’.-\(Z.
`lhesc diseases are trigr
`geretl when an allergen tomes in contact with (‘onitlnclit'al
`mast cells containing lgli molecules bottnd to the cytoplas-
`mit memlnanc.
`llie crosselinlx'ittgol pairs oi lgli molecules
`with allergen initiates a cascade ol intercellular changes
`that result in masrccll degranulalicm. Understanding the
`host ollsubstances released, and how they interact, has
`been driven by use ol' challenge models.
`Various mediators and cytokincs are released from the
`mast cell during degranulation, leading to the clinical signs
`and symptoms oi allergy, and the propagation ot'thc reaction
`('l'ablc I ). The primary inflammatory mediator released
`during this process is histan‘tine, as confirmed by a series ol
`studies [liltiul lnstillation olhistamine into theeye repro—
`duces in a dosedependent fashion the signs and symptoms
`of allergic coniunctivitis: itching, redness, cltemosis, tearing,
`and lid swelling. in tact, histamine is the only mediator that
`cart reproduce the entire clinical allergic condition in the eye
`|2|. l urthermorc, instillation of substances known to induce
`degranulalion of mast cells (secretagogues) and the release of
`histamine also produce the allergic condition in both animal
`and human eyes |3|. lhe collection ofhistaminc in tears is
`dillicult, however, because the enzyme histaminase is also
`released during IDflSI’CGll degranulation and works to break
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`3 64 Ocular Allergy
`
`_—__——————-
`
`Tryptases
`Serine proteases
`Carboxypeptidase A
`
`Table I. Mediators released by the mast: cell
`’____—_——
`Preformed mediators
`Histamine
`Chymases
`Heparin
`Proteoglycans
`Newly formed mediators
`Leukotriene B4
`Leukotriene C4, D4, E4
`Prostaglandin D2
`Platelet-activating factor
`Mastecell-derived cytokines/
`chemokines
`TNF-tr
`|L~ll3. |L-3, IL-4, IL—5.
`lL—lor.
`lL-6, |L-l0
`MCP
`Interferon-y
`Granulocyte-macrophage
`Macrophage-inhibitory
`
`protein colony—stimulating factor
`
`Thromboxanes
`HHT
`HPETE/HETE
`
`Eotaxin
`RANTES
`
`
`
`(Loniunctival challenges have also been used to identify
`other mediators that are present in allergic patients.
`'l‘ryptase is a good marker for mast—cell degranulation as the
`mast cell is the only cell in the body that contains this netr
`ropeptidase,
`l'ryptase levels were found to be increased in
`patients who were symptomatic with SAC and in patients
`after challengingthe conjunctiva with allergens, compound
`48/80, and mechanical rubbing [ l0]. Implications of this
`study were twofold: it showed that tryptase is a goocl
`indicator of mastvcell degranulation, and it showed that
`conjunctival challenges can be used to induce mast-cell
`degranulation. Studies in which the coniunctiva was chal-
`lenged with allergen have shown increases in histamine.
`kinins, prostaglandins, albumin, and ’l‘r\r\‘lll-csterase (tolue
`ene—sulfoetrypsinorginine methyl ester) Ill l; leukotrienes
`H4, (.74, D4, and M [l2|; eosinophil cationic protein (lit’ll’)
`l 13h and histaminase | l4|. An understanding ofthe release
`of histarninase, the enzyme that breaks down the released
`histamine, following a coniunctival challenge is especially
`important in understanding the time course ofsigns and
`symptoms. The challenge models have also been used to
`study effects that occttr on the epithelium in allergic dis
`eases. for example, it has been shown that coniunctival epi-
`thelium expresses intracellular adhesion molecules (lt‘AJ‘yl,
`l} following challenge | l5].
`During the acute allergic reaction, there are many
`chemotactic factors released from the mast cell; the actual
`cellular infiltrate that would he expected to subsequently
`occur in the eye is more ambiguous Some of the mediators
`released from the mast cell, such as PM". interleukin-5,
`lll‘ll4, PUDZ, and tumor necrosis factor {'I‘Nl"), Will help to
`recruit leukocytes, lympl‘rotytes, and more mast cells in the
`coniunctiva. However, usually only high doses of allergen
`in a challenge test will provoke cellular infiltrate ol‘eosino-
`phils. neturophils, basophils, lymphocytes, and mast cells
`in selected patients [161, with ranges of 20 mintrtes to (i to
`24 hours following challenge. furthermore, not all patients
`have cellular infiltrate irr their environment, and SM", gent-i:
`ally occurs in the absence of cellular recruitment | 1700,18],
`A second peak for continuation of the acute phase) in
`symptoms has been demonstrated during this late phase at
`6 h |l9| following a coniunctival challenge with high doses
`of allergen. This reaction at 6 h was accompanied by
`increased histamine and eosinophil calioniC PFOIt‘ill levels
`(liCl’ereleased from eosinophils), and upregulated adhe-
`sion molecules, as compared with pie-challenge baseline
`values [20°l. Although mast~cell numbers were increased in
`this latter study, interestingly prtase levels were not during
`this late time point, indicating a potential role for cells
`other than mast cells {such as basophils) during this late
`phase. However, it is important to mention that infiltrate in
`general is not correlated with an increase in clinical signs
`and symptoms, and although an increase might be seen fol-
`lowing CACs on the cellular level, this does not necessarily
`reach the clinical threshold necessary to induce signs and
`symptoms. Nonetheless, the study of cellular infiltrate is
`
`
`
`HETE-—hydroxyetcosatetraenoic acid: HHTihydroxyheptadeca-
`trienoic acid: HPETE-hydraperoxyeicosatetraenoic acid:
`lLe-interleukin: MCPimonocyte chemoattractant protein;
`RANTESe regulated on activation, normal T-cell expressed and
`secreted: TNFitumOr necrosis factor,
`__—_————
`
`lis—
`down the released histamine, which pealcs at 3 minutes. I
`tami nase levels were found to be lower in patients with vernal
`lteratoconiunctivits resulting in chronically elevated hista-
`mine levels, indicating that this condition is allergic in nature
`[4”. Inactivation of l'ristaminase allows the collection and
`measurement of tear histamine levels lollowing instillation of
`allergen in the human eye.
`l-‘our histamine receptors have
`been identified in the human body, although two, I
`l1 and I ll,
`have been identified in the eye |3|. 'l'he binding of histamine
`to the I
`[1 receptors on nerve endings leads to itch, and bind-
`ing to I I, and II; receptors on endothelial vascular smooth
`muscle leads to dilation (redness) and endothelial gaping
`(swelling). 'l‘he blocking of these receptors with selective
`antagonists results in a decrease in itching and redness. l-‘ure
`thcnnore, more recently it has been shown that by instilling a
`potent mast-cell stabilizer into human eyes prior to allergen
`challenge, histamine levels are reduced, which correlates with
`reduced signs and symptoms [tr-0|.
`The effects of many of the mediators were investigated by
`instilling each ofthem onto the eye and observing cffects clin
`ically and histologically. llor example, platelet activating factor
`(PM) was found to be a potent chenroattradant for eosino
`phils and neutrophils, leading to intravascular margination in
`the conjunctiva [7]; prostaglandin ”2 resulted in redness,
`coniunctival chemosis, mums discharge, and eosinophil infilA
`trate [8|; and in the human eye leukotricne H4 (lil'BL‘l) did not
`produce vasodilation; however, biopsy revealed infiltration of
`pt)lyrnorphonucleat‘ infiltrates (l lnpubiished data), whereas
`
`11!
`.14 and 12104 [9] elicited no observable effect. PAP, leulcot-
`rienes, and prostaglandins are all newly formed mediators
`produced in the arachidonic acid pathway during the break-
`down of phospholipids from the mast-cell membrane.
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`365
`Conillflt‘llVfll Allergen Challenge 0 Abelson rl'ml Luciller
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`
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`very important in the complete understanding of the aller-
`gic mechanisms, for severe chronic conditions, and as a sur-
`rogate end point for the release of chernotactic factors from
`mast cells (ft), mast—cell degranulation).
`'I'he eariier discussion was not intended to give a fill!
`review ofthe allergic mechanisms in the eye; however, the
`compilation of research highlights ways in which conjunc-
`tival challenge models have been ttsed to understand the
`pathophysiology of the octrlar surface. ‘l'he clinical rele-
`vance ofthe corriunctival challenge is validated by the simA
`ilarities seen between the reactions tollowing a challenge
`with the reactions seen irr symptomatic atopic patients
`with allergic conjunctivitis.
`
`[Environmental Model for Studying
`Allergic ('Zonjrrnctivitis
`'l he environmental model for testing the efiectivent-‘ss of
`anti-allergy agents has been used extensively throughout the
`world, and was the original manner in which ocular allergy
`was studied. In fact, the “environmerrtal” concept is trsed
`throughout the medical research field to study almost all dis-
`eases.
`I‘he idea is that a patient can he given the medication
`to Lise at home and either rrraintains a diary. or returns to the
`office for follow up visits. A study rising the environmental
`model might be conducted during the course of several
`weeks to months. In ocular allergy, the patient can be given a
`diary to record severity ofsyrnptoms (itching) and perceived
`signs (redness) on a daily basis. Generally patients are given
`scales to use as a reference in grading At predetermined time
`interyals, the patients return to the office for osaniinations by
`the investigator. 'l'hese ollice visits serve as safety visits—to
`determine efficacy and to review compliance with dosing
`and record keeping in the diary. (Zonipliance can also be
`monitored utilizing telephone contacts tirade by study staff
`between office visits,
`
`factors Affecting Data in the
`Environmental Model
`
`Although this type ofstudy design most accurately reflects
`what would occur in .r t lirrical setting in the individual
`patient, several confounding factors might interfere with
`the analysis and combination of data from patients within
`the same office and those seen at different sites in Inlllllv
`
`center studies. Particularly in studying an acute condition
`such as allergic coniurrctivitis, the Viability and variability ol
`the results and interpretation ofthe data might be difficult.
`These issues relate to five main concepts: 1) enrollment of
`sensitized atopic individuals; 2) exposure to offending
`allergens; .3] reliance on subjective data and compliance;
`and 4) placebo effect.
`'l'he environmental model relies on the fact that the
`
`patients enrolled suffer from the condition that is being
`studied. therefore, patients enrolled in environmental
`ocular allergy studies need to be atopic, and specifically
`
`allergic in the eye. If they are not, there is no way to ensure
`that the individual will be allergic to the particular allere
`gens that are in season, ()ften, skin testing is performed to
`qualify patients, and it
`is assumed they will have ocular
`allergy. However, in our experience, we have found an
`approximately 60% to 70% correlation between positive
`skin tests and positivn reaction to allergen instilled in the
`eye; therefore, ifsldn testing is solely relied on, some
`patients will he enrolled who might not have allergy to the
`pollen in season. Others have also seen a similar correla-
`tion |2l |, Often, entry criteria require a patient to present
`in the office with a positive sltin test .rnd positive clinical
`signs arid sympton'rs ol'octrlar allergy. hi this case,
`it is
`important to ensure that standard diagnostic criteria are
`being followed
`The second, and most obvious, problem associated
`with the environmental model is the inability to regulate
`each participant's exposure to various allergens. liach indi-
`Vidual is exposed to various degrees and types of allergens
`owing to diflerences in work habits; life style; natural varia-
`tion in pollen counts between home and workplace;
`indoor pets or plants, use of air conditioning, fairs, or verr
`tilation ducts that would move airborne allergens through
`otrt the borne/office; density ofplarrts outside; and natural
`variations in pollen counts. Additionally, some behavioral
`modifications, such as avoidance of allergen during the
`allergy season, might further complicate the issue. If the
`patient is not experiencing significant signs and symptoms,
`it is more diflictrlt to identify a drug effect. Alternatively, if
`a patient reports to the office with few signs or symptoms,
`it could be due to a lack ofexposure to offendingallergens.
`'l'lie scheduled office visits that are included in the
`
`study design to ensure a degree of objectivity are prohlern
`atic owing to the unlikelihood of having patients whose
`worst allergic symptoms are tinted synchronously with the
`predetermined scheduled visit. Patient diaries can he used
`to traclt signs and/or symptoms daily, and the patient's
`assessment of exposure to the outdoors and pollen counts
`are recorded within the geographic area ofthe study site by
`a pollen-counting station. But, patients might be allergic to
`indoor allergens or exposed to other irritants. It is titres—
`tionable, therefore, whether a regional pollen count [or
`patienterecorded exposure) is a true measure of personal
`allergen exposure. lnterestingly, clinical signs and symp~
`toms are not always exactly correlated with the absolute
`values of pollen cotrnts [22L l‘ollerr cotrnts can vaty even
`within the same area and will differ based on the exact
`
`location of the counter itself. Perhaps the fact that pollen—
`counting stations are not validated by standard criteria
`between sites might also play a role,
`'1 he third issue is the reliance on patierit's diaries to deter‘
`mine drug efficacy. The diaries t ontaiti a high level ofsubjeo
`tivity owing to dilierences in syrriptorn interpretation among
`people. Although stantlardiyecl scales can be used. environ»
`mental studies rely on data recorded for primary efficacy vari
`ables of itching and redness by the patients themselves.
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`366 Ocular Allergy
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`(.Iornpliance issues affect the quality of results, as one must
`assume that in some cases subiecas will neglect to enter data
`in a timely fashion, and their later "back-till" prior to the next
`office visit.
`Another issue involved with the use ofthe environmental
`model is the high rate ofplacebo effect seen. A placebo drop,
`many times an artificial tear, can effect allergy treatment, 'lhcy
`do this by acting as a barrier to prevent allergen from attack-
`ing the coniunctival surface, helping to dilute allergen and
`mediators in the tear film, and acting as an eyewash. Such
`environmental studies are known to have placebo effect rat-
`ings as high as 50% and (50% [23,24]. Although it is difficult
`to completely eliminate, the placebo effect is a significant fac-
`tor. and it can be expected to play a larger role in environmen-
`tal studies in which it acts as an eyewash, compared with
`single-drop studies in the (NI model.
`
`The (Ioniunctival Allergen Challenge Model for
`Studying Allergic Conjunctivitis
`To evaluate anti-allergic agents in a more controlled manner,
`(j,r\(,‘,s lrave been developed. l listamine produces a dose—
`dependent response when instilled in the eye, and thus has
`been used as a model for screening antiiallergic drugs.
`Although such an agent can help evaluate drugs with antihis-
`taminic properties [25], and dnrgs that actively reduce red—
`tress, such as vasoconstrictors |2ti|, this challenge is not
`directly stimulating mast-cell degranulation, as happens with
`allergen. Substances such as compound 48/801 which is a
`secretagogue that induces rnasticell cit-granulation, have also
`been used in human challenge tests [ lO|. i lowever, because
`the secretagogues do not induce an immunologic reaction
`via an lgii—mediated pathway, they might not be appropriate
`for et-ralirating agents with mast-cell stabilizing activities. the
`(EM) |27| was developed as the most accurate replication of"
`the true allergic reaction, because it is 1in mediated, and
`results in mastcell degr'anulation.
`The standard controlled (SAC study design includes two
`baseline visits.
`the first is a titration visit, and a selected
`
`allergen is instilled into both eyes ofthe patient. Signs and
`symptoms are then graded on standardized scales. Allergen
`is instilled into the eyes at increasingconcentrations until a
`prespecified threshold of clinical response is achieved. the
`threshold scores, however, need to he set considering the
`reaction that resembles a natural allergic reaction—in
`other words, one that provides sufficient improvement of
`drug over placebo, but does not stimulate such a large reac—
`tion that it cannot be modulated by the dnrg. The intent of
`the study also needs to be considered when evaluating this
`threshold and allergen used. for example, a high dose of
`allergen is generally required to stimulate a significant celi
`ltrlar infiltrate and to correlate this infiltrate with clinical
`
`signs and symptoms. However, this reaction might be
`higher than that usually seen in the enviromnent. When
`critically evaluating data from a study, the methodology
`and allergen dose used should be considered in determin—
`ing clinical relevance.
`
`Once the threshold allergen dose is determined in the
`patient, the patient returns for a confirmation visit. At this
`visit, the dose that elicited a sufficient reaction at the first
`visit is instilled in both eyes. This second visit confirms the
`consistency and reproducibility ofthe reaction in the
`patient. Patients who demonstrate a sufficient and reproduc-
`ible response proceed to a third visit.
`Both onset and duration of action ofthe agent can be
`evaluated using the CAL) tnodel. The patient can be closed
`with the study treatment (placebo in one eye and drug in
`the other; dr'trg in both; or drug A in one and drug Ii in the
`contralatcral eye) and then challenged with the appropri-
`ate dose ofallergen in both eyes, The eyes are then evalrr
`ated for signs and syrnptorrrs, and the appropriate analysis
`is performed. To evaluate duration of action, the challenge
`can be perlor'rned at a specific time following instillation of
`treatment. for example, ifthe patient is challenged ti hours
`following instillation of the drug, then it is clear that the
`drug effects last at least 6 hours. ()nset and duration of
`action are evaluated at separate office visits.
`Safety during allergen challenge cannot be emphasized
`enough, because coniunctival instillation can prodrrce signifi-
`cant nasal, throat, and respiratory reactions. l laving trained
`medical personnel and appropriate emergenQ' equipment
`on-site is critical.
`
`Advantages ofthe Coniunctival Allergen
`Challenge Model
`'lite (.IAtJ model mimics the signs and symptoms ofan ocular
`allergic response accurately in a controlled setting [2%--].
`The instillation of the threshold dose in the subject's eyes
`consistently results in itching and redness.
`liy enrolling patients based on their response to a (MC,
`orily those patients who actually have ocular allergy are
`being enrolled. 'i‘lre titration ofallet'gen during the first visit
`provides a rrrethod for obtainingthe threshold dose needed
`for adequate reactivity. the coupling of the titration with
`the second visit for confirmation ensures r'eiirodtrcibility.
`“the (2M) model contains a level ofinternal control that is
`not seen in the environmental model because the bilateral
`instillation of drtrg and placebo serves as a highly reproduc-
`ible internal control
`
`'lhe paticnt's exposure to offending allergens and
`certainty that the drug is being tested in an allergic eye is
`controlled by precisely instilling allergen in the office, in
`patients who are asymptomatic at baseline when they enter
`the office. 'i‘herelore. variable exposure patterns to allergens
`typically seen between patients in ern‘ironmental designs is
`controlled. By completing the study in the ”otfseason" (re,
`not during the pollen season] with allergens that the
`patients are allergic to,
`it can be further ensured that any
`environmental exposure will not confound the results.
`By inducing the allergic reaction in the office, a trained.
`masked examiner can be used to evaluate the primary signs
`
`{redness and chenrosis). The primary symptoms can also
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`367
`tionjunctival Allergen Challenge - Abelson and laieffler
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`be evalttated by the patients using standardized scales in
`the office while being observed by stttdy staff, ensuring
`grading is done properly and that the patients correctly
`trnderstand the scales. ‘l'he CM". allows a titnely and cone
`cise evaluation for the effects ofthe investigational drug.
`Also, with the instillation ofthe study treatments in the
`office, compliance is ensttred.
`
`Use of the Conjunctival Allergen Challenge
`Model for Evaluation of Drugs
`Owing to the (TAG model's high level ofinternal control, seri—
`sitivity, and reproducibility, it can be used in several ways.
`'l‘he (LAC. model is very applicable for studies involving a
`comparison of efficacy between drug and placebo
`[29, {0.3! '| The (3M) model can also be trsed to compare a
`drug with an active control. This has beert done by rnarty
`groups using various agents available for eye allergy
`|32,33,34-,3S".}60|. llsing the CAC, precise comparisons
`ofonset of action and duration of action can be measured,
`which cannot be accurately evaluated in environmental stud-
`ies. It
`is important to note that in the challenge studies, in
`which standardized scales are used, a specilied ttnit change
`between drug and placebo on that scale can be defined as
`being clinically signilicarrt. This is different from showing
`statistical significance, which can occur without clinical sig-
`nificance. for example, typically on the 04 scale, a trnit
`change is considered by the FDA to be clinically signilicant.
`l lowever, even ifa dntg might not produce a clinically signif-
`icant response ofone lull unit. the CAC model is still very
`useful for evaluating efficacy and in helping to select agents
`for fun her testing (cg, dose ranging).
`[Environmental and (1M) models can be combined. in
`
`this design, patients are first exposed to a (1M1. Patients
`who respond sufficiently to an initial (LAC are enrolled
`irtto the study with an environmental design. This model
`helps to ensure that patients who are enrolled are atopic
`and, tnore specifically. are sensitive in the eye to the alter:
`gen currently iii-season, during which the study is con
`ducted.
`l‘liis hybrid model has successfully been used to
`study the mastecell stabilizer pernirolast [35“].
`A unique use ol the (IAC is to study effects of drugs on
`nasal signs and symptoms. Inflammatory mediators,
`released during the allergic reaction in the conjunctiva.
`and/or allergen itself, can drain through the nasolacri trial
`duct into the inferior turbinate of the nose and produce
`clinically significant nasal itching, sneezing, congestion,
`and rhinorrhea. Similar to mediators, topical drugs cart
`also drain from the eye irtto the nose. In fact, we have seen
`an effect of potent allergy eye drops on nasal signs and
`symptoms. in both challenge models and environmental
`studies | 300,370].
`
`Conclusions
`We can see how the (LAC model has been a useful tool for the
`
`development of new agents for ocular allergy, and to help fur—
`ther otrr understanding of the patltophysiology ofocular
`allergy. 'I'he controls afforded by the use ofthis type ofrnodel
`lead to more reliable results and help to mitigate many ofth
`issues we see with standard environmental studies.
`
`Challenge tests have been used for years in the fields of
`asthma and allergic rhinitis. The ophtbalrnic division at the
`HM has been a leader in accepting the (AC model, and has
`helped otrr field tremendously by giving us an efficient study
`design in which to evaluate the condition and to pave the way
`for the development of novel pharmaceuticals. With the rec-
`ognition ofthe significance of using the model for the drug
`development process, as a pathway for drug approval, we are
`actually now seeing agents being developed first specifically
`for the eye, as a proofof concept for other indications. A thorr
`ough understanding of the model is required to ensure that
`at‘ttrrate interpretations are made from the results, .rnd that
`the study is still designed appropriately, matching the plrare
`niacology ofthe agent, clinically relevant mechanisms ofthe
`disease process, and the objectives ofthe study
`
`References and ltecommended Reading
`l‘apers of particular interest, published recently, have been
`highlighted as.
`-
`Of importance
`--
`()l'majorimportance
`
`
`
`I
`m
`
`1
`
`-t
`
`Abelson Mlt. (.lbapirr MI. (Zurrenl and future topical treatments
`for ocular allergy. t
`'mrrp ()plrtlrtrlrrrtrl Update 1000, 1:303 .. ti 7.
`r\l1t‘l5(3lit\lli,
`.'\lltil1'4llllll1l\’1Rl Histamine and the eye. in .lrrmrtr-
`rrtiltrgt' (HUI fillHillllt'f‘tl’lfitlftl‘fll' ”"th Lye l,tlltt‘d by Silverstein \M.
`O'Connor(.‘l. New \ork' Masson; I'JT‘lfltsL in}.
`Abelson Mil, Smith EM. Levocabasline: evaluation in the his
`tamiue and compound 48/80 models ofocular allergy in
`humans. (Jplrtlrrrlrrrrtltrgy l‘Jtfib‘. 95:149-444‘)?
`1, Abelson Hit, leonartli
`\t‘\, Smith fM, er :tl.‘ I-listaminase activ-
`ity in patients with vernal keraloconjttnctivitis. ()pl'rtltrrlrrreltrey
`100‘), I02: l 0387 l ‘)b i
`v\belsonMli,.t\ll.'tnsrt‘ritirl\1ll‘ Histamine and the eye. In lrrrrrttt
`utility and lrrmttrimpatlrtiltrgy or the lz‘ye. lldited by Silt-erstein NM,
`O'Con nor (II. New York: Masson, 1970.30 5464.
`fr." 1 corrardi .\. Abelson M' Mast cell stabilizing effects of
`olopatadine following allergen challenge in humans
`|ahslract|. .-\lt\’t) 200.1, in press.
`Ibis is the first study cor reiating clinical effects and the indices ol'mast
`cell stabilizing properties, including decreased histamine levels. for a
`therapeutic agent with multiple actions in ocuiar allergic subjects.
`7.
`(itjtilgL‘ MA, smith LM, Hertly (II ,
`t't' at. Platelet activating fac-
`tor induced inflammation following topical ocular challenge
`Iabslractf ltll't’al (Jplrrlralrrrnl \r’is hit I990. 3](Suppl):tfl.
`.\be|son Mlt, .Vladiwale NA, Weston ll li'l'he role ofprostaglandin
`D2 in allergic ocular disease. In limit International Syrrrpostirm a}
`the lirtitrtmulvgy tutti lmrrrrrrinparlrttltr-qt' of the Lye. lldited by 0't‘mr-
`nor (Ill, (:lratit'llt‘r IW. [\ew York; Masson, 1085, I (x K7 ] (so.
`\v‘eston ll l, Abelson Nth Leukotriene Cr! in rabbit and human
`eyes [abstract]. lrrt'est ()lf’llfflllflfitll‘ \'i.~‘ Sir l'Jfll. 26(Suppl):l‘ll.
`litrtrtts Sl, OthSnet lx'l, Abelson MH, Schwartz I It: the level of
`tryptase in human tears: an indicator of activation of con—
`junctival mast cells. ()plrrlralrrwlney l‘J‘m, l)7: l 675* t {is}.
`
`h‘.
`
`t).
`
`10.
`
`Ayla Pharma LLC (IPR2020-00295) EX. 1025 p. 005
`
`Ayla Pharma LLC (IPR2020-00295) Ex. 1025 p. 005
`
`

`

`
`
`368 Ocular Allergy
`
`
`
`li.
`
`ll.
`
`[3
`
`l-i.
`
`1'1
`
`ill,
`
`I’toutl l). hwcct i, .\tt‘in l’, H til. Inflammatory tnt‘diator rclcase
`on conittnctival provocation ofalicrgit stthiccts with aller-
`gun, i «‘\llyt};t-(.‘lt‘tt lilllllillltil Wilt), 85:5'H’t—‘lti3
`liisgaarti Ii, lUI'LiriiUlClillifitHl AW. t ltarit-stttt 8, it til; Procinc»
`lion oi luticutriL-nL-s in human sitin and conjunctival tnutosa
`alter spccii‘tc allergen chalicngt‘.
`illct'gt' l”H‘L-“)irll7*'i) l.
`liorak i, huh I, ilitschwchr R.
`('1 air lil‘icct oftotttinttous allcrv-
`gen challenge on clinical symptoms and tnm‘liatot' release in
`dllSi’lltilk‘ullltlrgii patients. .\llt't'fqt‘ NOS, 3 iztu‘iiTl.
`.\i‘tclson Mil,
`l,L‘t)litll‘Lli .\.\. Smith IM. it til: Ilistamiti-asc atliv-
`ity in patients with vernal kcraloconiunctivitis. ()ttlttitttitttttlugt'
`1995, It)" I‘lSH— mm.
`(iipt'antli (I, [lust .ttglia h, l’c‘stt‘(1.01M.Alict‘girstthiects
`csprrss intct'ct‘llular adhesion tnolcctticrl [ICAM-t or (£1354)
`on epithelial cells ol'coniunctitut .tl’tcr allergen cltailcngcJ
`silict‘gt't ittt lillmtilltll 10‘! %, ‘)l:7h"tw"l.‘
`lionttti S, Hottini h. \"crch'tottt- «\ at al.‘ Inflammatory t‘hangrs
`in cottiunctival scrapings al‘tcr allergen provocation in
`humans. l .ilit'tgt't‘ it}: ittttttttttnl
`l'lh‘H. Bl:-l(sJ—-li\‘l
`i7," Antlt-tsutt Ill, .\lacicml ll).\, Elatiticlct- 5M. ('l a! . St-asonai alley
`git coniuntlivitis is accompanied by incrcast-tl tnast Ct‘ll
`tutntlit‘rs in tht‘ ahst-nct- of Icltlmcytc infiltration. (,liil i rt!
`aim-gt 19‘)? 17:1tltttl—Itltvit.
`Rt‘stllts ol this stutly show that ittliitt'.ttt‘ t-I'trosinophiis anti liL‘LllFl)
`plttls was not sum in tttot'c than 30”“ ot stthtcrts with scasottal tilit'i
`gic cottittnttii‘ttis. litis sttggcstctl the ai'tscttcr oi .t t‘lil'iit allv l't‘lt‘Vtilil
`latc pltasc I'L'Jt'litlll. tn thc mus oi tttttsl palicnts.
`its.
`\ln‘ison Mil. Matiiwaic N, \M-stott Ill. (Zonjunctival rosinw
`pltils in allcrgic octtlar ciise‘as‘c. .\rt it ()ttittltaitttui
`i‘ih’i,
`ttttzsrfiiaattf
`i,t‘lllttli't.li A.
`l‘apa \', Mila/ro (.‘, 5n titi ,\t .: l‘llitacy anti salt‘ly
`oi ticsonidc phosphate tor the trcatntcnt ol' allcrgic conjunc-
`tivitis. ( mitt‘tl ltltll. 2iz47tt7-‘it‘ii
`ilacott '\. .'\i1i'ii\.\‘.|lltl
`ll.
`lt'.1]li
`\. rt (ti: luar anti coniunctival
`changes during, the allergcn-induccd early antl latt‘rphasc
`rcsponscs. l .\ilt'tgtt [in llllliluilt'l 2mm.
`it)(v:‘)t1h‘v ‘H-i.
`litts Hlilll_\ shows an cviclcnt ittilttx ol t't-Ils into thc cottiunrtit'a loi
`
`lowing a high tiost‘ oiallctgt‘n.
`lhs' iarls ot a pcalt oi It'yptast' ti
`ting
`lili‘ilrlll'\-ti1iiiltilit)fi ltllitlwingIlialii‘ll‘fit‘iliklitali‘fiilltll tnasttciis
`might not ht: tit'gtatutlalittg tlurtttg this titnc.
`(Iorrciatiott
`ll
`l.t.’Uiltli'tii .\.