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Ex Vivo Characterization of the CD4+ T Cell Response to Ara h 1
Abstracts AB257
J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 2
Bepotastine Besilate Ophthalmic Solution 1.5% Reduces Tearing 16 Hours Following Dosing in the Conjunctival Allergen Challenge (CAC) Model of Allergic Conjunctivitis J. I. Williams1, E. B. McLaurin2, F. K. Kurata3, M. B. Abelson4, J. A. Gow1, T. R. McNamara1; 1ISTA Pharmaceuticals, Inc., Irvine, CA, 2Total Eye Care, PA, Memphis, TN, 3East West Eye Institute, Los Angeles, CA, 4 Ora, Inc., Andover, MA. RATIONALE: To establish the safety and efficacy of bepotastine besilate ophthalmic solution 1.5%, a dual-acting histamine H1 receptor antagonist, compared to placebo in reducing tearing at 16 hours after ophthalmic dosing using the Conjunctival Allergen Challenge (CAC) model of allergic conjunctivitis. METHODS: Two CAC clinical trials were each 7 week, double-masked, randomized, placebo-controlled studies. Eligible subjects were assigned randomly to either bepotastine besilate 1.5% (n578) or placebo (n579). Tearing as a secondary efficacy endpoint was graded as either absent or present. The principal statistical test for pooled data analysis was Fisher’s exact test. RESULTS: In both the Intent-to-Treat population and the Per-Protocol _0.0045) was population, statistically significant reduction in tearing (P< demonstrated for bepotastine besilate ophthalmic solution 1.5% for all observation time points at 16 hours post-dosing. Discontinued subjects included placebo group subjects (n58) for subject decision/noncompliance, and bepotastine besilate ophthalmic solution 1.5% subjects for subject decision/non-compliance (n55) or other reasons (n53). Additional study visits were not needed for any enrolled subjects. CONCULSIONS: Bepotastine besilate ophthalmic solution 1.5% was statistically superior to placebo in reducing tearing based upon the pooled data from 2 CAC clinical trials after ophthalmic dosing. These data support clinical effectiveness for reduction of tearing associated with allergic conjunctivitis in patients dosing with bepotastine besilate ophthalmic solution 1.5%.
CONCLUSIONS: In this study, once-daily treatment with CIC-HFA 80mg demonstrated statistically significant improvements in rTOSS. Numerical improvements in iTOSS and individual reflective and instantaneous ocular symptoms of SAR were observed with both CIC-HFA 80mg and CIC-HFA 160mg.
996
998
An Evaluation of the Effect of Ciclesonide Hydrofluoroalkane Nasal Aerosol on the Ocular Symptoms of Seasonal Allergic Rhinitis B. Martin1, P. Ratner2, W. Howland3, C. Andrews4, H. Huang5, S. Y. Desai5, F. Bode5; 1Southwest Allergy and Asthma Center, San Antonio, TX, 2 Sylvana Research Associates, San Antonio, TX, 3Sirius Clinical Research, Austin, TX, 4Diagnostics Research Group, San Antonio, TX, 5 Sepracor Inc, Marlborough, MA. RATIONALE: Ciclesonide hydrofluoroalkane nasal aerosol (CIC-HFA) is currently in development for the treatment for allergic rhinitis. The ability of CIC-HFA to relieve the ocular symptoms associated with seasonal _12 years of age. allergic rhinitis (SAR) was evaluated in subjects > METHODS: Data for this analysis was collected as part of a placebo-controlled, double-blind, parallel group, multicenter study in subjects with a _2 year history of SAR randomized to CIC-HFA 80mg (N5226), CIC> HFA 160mg (N5225), or placebo (N5220) once-daily in the morning for 2 weeks. Change from baseline in reflective total ocular symptom score (rTOSS) averaged over the 2-week treatment period was a key secondary endpoint. Instantaneous total ocular symptom score (iTOSS) and individual reflective and instantaneous ocular symptom scores of tearing eyes, itchy eyes, and redness of eyes averaged over the 2-week treatment period were also evaluated. The rTOSS and iTOSS were recorded in the intent-totreat subject population and were evaluated in subjects with baseline _5 (CIC-HFA 80mg:N5165, CIC-HFA 160mg:N5159, rTOSS> _5 (CIC-HFA 80mg:N5138, CIC-HFA Placebo:N5161) and iTOSS> 160mg:N5141, Placebo:N5146) respectively. RESULTS: CIC-HFA 80mg demonstrated a statistically significant improvement in rTOSS (P50.0124). CIC-HFA 80mg and CIC-HFA 160mg demonstrated numerical improvements in iTOSS (P<0.05 for both, unadjusted for multiplicity) and individual reflective and instantaneous ocular symptom scores of tearing eyes, itchy eyes, and redness of eyes compared to placebo.
Ex Vivo Characterization of the CD41 T Cell Response to Ara h 1 J. H. DeLong1, K. Hetherington2, E. Wambre1, D. Robinson3, W. W. Kwok1,4; 1Benaroya Research Institute, Seattle, WA, 2Austin Regional Clinic, Austin, TX, 3Virginia Mason Medical Center, Seattle, WA, 4University of Washigton, Seattle, WA. RATIONALE: Peanut allergy is life-threatening and is becoming increasingly common. Oral immunotherapy using peanut proteins is efficacious but has considerable adverse effects. Knowledge of T cell epitopes could facilitate the development of safer vaccines based on recombinant hypoallergens or T cell epitopes. METHODS: Tetramer Guided Epitope Mapping was used to identify CD41 T cell epitopes in the peanut allergen Ara h 1. PE-labeled tetramers of MHC class II molecules were then loaded with these antigenic Ara h 1 peptides and were used to stain PBMC from peanut-allergic human donors directly ex vivo. The ex vivo frequencies and surface marker expression of these cells were examined following anti-PE bead enrichment. RESULTS: We examined cells specific for 12 unique Ara h 1 epitopes among the MHC class II alleles DRB1*0101, *0401, *0404, *1101, *1401 and DRB5. In peanut-allergic subjects, these cells express CD45RO, CD25 and CCR4, but not CRTH2, ex vivo and are present at a range of frequencies with a mean average of 9 per million CD41 T cells. CONCLUSIONS: CD41 T cells in peanut-allergic subjects recognize a variety of epitopes within the Ara h 1 protein. These are memory cells but they do not express CRTH2 ex vivo, distinguishing them from cells specific for other allergens such as grass and tree pollens.
997
Distinct Maturational Stages Lead to Different Fates of Pathologic and Protective Allergen-Specific CD41 memory T Cells during Specific Immunotherapy E. Wambre1, J. H. DeLong1, D. Robinson2, W. W. Kwok1; 1Benaroya Research Institute, Seattle, WA, 2Virginia Mason Medical Center, Seattle, WA. RATIONALE: Monitoring allergen-specific CD41 T cell responses is essential for understanding mechanisms linked either with the pathogenesis or regulation of allergic inflammation and for identifying potential biomarkers predicting the response to allergy vaccine. METHODS: MHC class II tetramer technology was used in an ex vivo approach to assess the alder pollen-specific CD41 T cell response in allergic and non-allergic individuals. Longitudinal analysis of the frequency, surface marker phenotype and cytokine profile of these cells was performed to study the mechanism involved in either allergic inflammation or tolerance induction. RESULTS: Alder pollen allergic and non allergic individuals both have functionally and phenotypically distinct circulating allergen-specific CD41 memory T cells which can be ascribed to a particular subset of differentiated antigen-experienced CD41 T cells. Allergen-specific CD41 Th2 cells represent the most frequent subset in allergic individuals absent in non-allergic individuals. During allergen-SIT, we observed that chronic high-dose allergen stimulation promotes a different response in allergenspecific CD41 T cells according to their differentiation state. These include the total depletion of pathogenic allergen-specific CD41 T cells with no significant changes in frequency of protective allergen-specific CD41 T cells. CONCLUSIONS: Making the link between differentiation stages of the allergen-specific CD41 memory T cells with functional capacity and apoptosis-susceptibility, our data propose both novel mechanism for allergenSIT and reliable biomarkers that may have the potential to predict the clinical response to allergen-SIT.
TUESDAY
995
J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 2
Bepotastine Besilate Ophthalmic Solution 1.5% Reduces Tearing 16 Hours Following Dosing in the Conjunctival Allergen Challenge (CAC) Model of Allergic Conjunctivitis J. I. Williams1, E. B. McLaurin2, F. K. Kurata3, M. B. Abelson4, J. A. Gow1, T. R. McNamara1; 1ISTA Pharmaceuticals, Inc., Irvine, CA, 2Total Eye Care, PA, Memphis, TN, 3East West Eye Institute, Los Angeles, CA, 4 Ora, Inc., Andover, MA. RATIONALE: To establish the safety and efficacy of bepotastine besilate ophthalmic solution 1.5%, a dual-acting histamine H1 receptor antagonist, compared to placebo in reducing tearing at 16 hours after ophthalmic dosing using the Conjunctival Allergen Challenge (CAC) model of allergic conjunctivitis. METHODS: Two CAC clinical trials were each 7 week, double-masked, randomized, placebo-controlled studies. Eligible subjects were assigned randomly to either bepotastine besilate 1.5% (n578) or placebo (n579). Tearing as a secondary efficacy endpoint was graded as either absent or present. The principal statistical test for pooled data analysis was Fisher’s exact test. RESULTS: In both the Intent-to-Treat population and the Per-Protocol _0.0045) was population, statistically significant reduction in tearing (P< demonstrated for bepotastine besilate ophthalmic solution 1.5% for all observation time points at 16 hours post-dosing. Discontinued subjects included placebo group subjects (n58) for subject decision/noncompliance, and bepotastine besilate ophthalmic solution 1.5% subjects for subject decision/non-compliance (n55) or other reasons (n53). Additional study visits were not needed for any enrolled subjects. CONCULSIONS: Bepotastine besilate ophthalmic solution 1.5% was statistically superior to placebo in reducing tearing based upon the pooled data from 2 CAC clinical trials after ophthalmic dosing. These data support clinical effectiveness for reduction of tearing associated with allergic conjunctivitis in patients dosing with bepotastine besilate ophthalmic solution 1.5%.
CONCLUSIONS: In this study, once-daily treatment with CIC-HFA 80mg demonstrated statistically significant improvements in rTOSS. Numerical improvements in iTOSS and individual reflective and instantaneous ocular symptoms of SAR were observed with both CIC-HFA 80mg and CIC-HFA 160mg.
996
998
An Evaluation of the Effect of Ciclesonide Hydrofluoroalkane Nasal Aerosol on the Ocular Symptoms of Seasonal Allergic Rhinitis B. Martin1, P. Ratner2, W. Howland3, C. Andrews4, H. Huang5, S. Y. Desai5, F. Bode5; 1Southwest Allergy and Asthma Center, San Antonio, TX, 2 Sylvana Research Associates, San Antonio, TX, 3Sirius Clinical Research, Austin, TX, 4Diagnostics Research Group, San Antonio, TX, 5 Sepracor Inc, Marlborough, MA. RATIONALE: Ciclesonide hydrofluoroalkane nasal aerosol (CIC-HFA) is currently in development for the treatment for allergic rhinitis. The ability of CIC-HFA to relieve the ocular symptoms associated with seasonal _12 years of age. allergic rhinitis (SAR) was evaluated in subjects > METHODS: Data for this analysis was collected as part of a placebo-controlled, double-blind, parallel group, multicenter study in subjects with a _2 year history of SAR randomized to CIC-HFA 80mg (N5226), CIC> HFA 160mg (N5225), or placebo (N5220) once-daily in the morning for 2 weeks. Change from baseline in reflective total ocular symptom score (rTOSS) averaged over the 2-week treatment period was a key secondary endpoint. Instantaneous total ocular symptom score (iTOSS) and individual reflective and instantaneous ocular symptom scores of tearing eyes, itchy eyes, and redness of eyes averaged over the 2-week treatment period were also evaluated. The rTOSS and iTOSS were recorded in the intent-totreat subject population and were evaluated in subjects with baseline _5 (CIC-HFA 80mg:N5165, CIC-HFA 160mg:N5159, rTOSS> _5 (CIC-HFA 80mg:N5138, CIC-HFA Placebo:N5161) and iTOSS> 160mg:N5141, Placebo:N5146) respectively. RESULTS: CIC-HFA 80mg demonstrated a statistically significant improvement in rTOSS (P50.0124). CIC-HFA 80mg and CIC-HFA 160mg demonstrated numerical improvements in iTOSS (P<0.05 for both, unadjusted for multiplicity) and individual reflective and instantaneous ocular symptom scores of tearing eyes, itchy eyes, and redness of eyes compared to placebo.
Ex Vivo Characterization of the CD41 T Cell Response to Ara h 1 J. H. DeLong1, K. Hetherington2, E. Wambre1, D. Robinson3, W. W. Kwok1,4; 1Benaroya Research Institute, Seattle, WA, 2Austin Regional Clinic, Austin, TX, 3Virginia Mason Medical Center, Seattle, WA, 4University of Washigton, Seattle, WA. RATIONALE: Peanut allergy is life-threatening and is becoming increasingly common. Oral immunotherapy using peanut proteins is efficacious but has considerable adverse effects. Knowledge of T cell epitopes could facilitate the development of safer vaccines based on recombinant hypoallergens or T cell epitopes. METHODS: Tetramer Guided Epitope Mapping was used to identify CD41 T cell epitopes in the peanut allergen Ara h 1. PE-labeled tetramers of MHC class II molecules were then loaded with these antigenic Ara h 1 peptides and were used to stain PBMC from peanut-allergic human donors directly ex vivo. The ex vivo frequencies and surface marker expression of these cells were examined following anti-PE bead enrichment. RESULTS: We examined cells specific for 12 unique Ara h 1 epitopes among the MHC class II alleles DRB1*0101, *0401, *0404, *1101, *1401 and DRB5. In peanut-allergic subjects, these cells express CD45RO, CD25 and CCR4, but not CRTH2, ex vivo and are present at a range of frequencies with a mean average of 9 per million CD41 T cells. CONCLUSIONS: CD41 T cells in peanut-allergic subjects recognize a variety of epitopes within the Ara h 1 protein. These are memory cells but they do not express CRTH2 ex vivo, distinguishing them from cells specific for other allergens such as grass and tree pollens.
997
Distinct Maturational Stages Lead to Different Fates of Pathologic and Protective Allergen-Specific CD41 memory T Cells during Specific Immunotherapy E. Wambre1, J. H. DeLong1, D. Robinson2, W. W. Kwok1; 1Benaroya Research Institute, Seattle, WA, 2Virginia Mason Medical Center, Seattle, WA. RATIONALE: Monitoring allergen-specific CD41 T cell responses is essential for understanding mechanisms linked either with the pathogenesis or regulation of allergic inflammation and for identifying potential biomarkers predicting the response to allergy vaccine. METHODS: MHC class II tetramer technology was used in an ex vivo approach to assess the alder pollen-specific CD41 T cell response in allergic and non-allergic individuals. Longitudinal analysis of the frequency, surface marker phenotype and cytokine profile of these cells was performed to study the mechanism involved in either allergic inflammation or tolerance induction. RESULTS: Alder pollen allergic and non allergic individuals both have functionally and phenotypically distinct circulating allergen-specific CD41 memory T cells which can be ascribed to a particular subset of differentiated antigen-experienced CD41 T cells. Allergen-specific CD41 Th2 cells represent the most frequent subset in allergic individuals absent in non-allergic individuals. During allergen-SIT, we observed that chronic high-dose allergen stimulation promotes a different response in allergenspecific CD41 T cells according to their differentiation state. These include the total depletion of pathogenic allergen-specific CD41 T cells with no significant changes in frequency of protective allergen-specific CD41 T cells. CONCLUSIONS: Making the link between differentiation stages of the allergen-specific CD41 memory T cells with functional capacity and apoptosis-susceptibility, our data propose both novel mechanism for allergenSIT and reliable biomarkers that may have the potential to predict the clinical response to allergen-SIT.
TUESDAY
995