- Email: [email protected]
Effect of Anti-IgE (Omalizumab) in Chronic Idiopathic Urticaria (CIU) Patients
Abstracts S147
J ALLERGY CLIN IMMUNOL VOLUME 121, NUMBER 2
566
Effect of Anti-IgE (Omalizumab) in Chronic Idiopathic Urticaria (CIU) Patients L. M. Gober, P. M. Sterba, J. A. Eckman, S. S. Saini; Johns Hopkins University, Baltimore, MD. RATIONALE: Omalizumab has shown benefits in allergic asthma and a few cases of CIU. Omalizumab decreases circulating IgE, surface-bound IgE, FceRI receptors on mast cells and basophils, and FceRI-mediated cellular responses. Given the altered mast cell and basophil FceRI function in CIU and the action of omalizumab on these cells, we investigated the effect of omalizumab treatment in subjects with CIU. METHODS: Twenty CIU subjects with active disease despite standard anti-histamine therapy were enrolled in a 6-month, double-blind, placebocontrolled trial of omalizumab using current FDA-approved dosing guidelines for allergic asthma. Subjects completed daily symptom diaries, biweekly urticaria disease assessments, and interval quality of life measures using Skindex-29. Physicians completed biweekly urticaria disease assessments. Subjects underwent blood sampling for basophil functional studies at baseline, 4-weeks and 16-weeks on treatment, and 8 weeks posttreatment. RESULTS: Subjects on omalizumab (n 5 10) demonstrated significantly decreased urticaria severity scores beginning at 2 weeks (patient-assessed, p 5 0.002; physician-assessed, p 5 0.003) that continued throughout treatment (patient-assessed, p 5 0.007; physician-assessed, p 5 0.003 at 16 weeks), improved quality of life at 16 weeks (Skindex-29: symptoms p 5 0.005, functioning p 5 0.006, emotions p 5 0.02), and significantly increased symptom-free days (p 5 0.02 by 2 weeks, p 5 0.0004 by 16 weeks) when compared to placebo controls (n 5 10). Compared to baseline, blood basophil FceRI-mediated degranulation with polyclonal anti-IgE stimulation (0.1 mg/mL) was significantly enhanced (p 5 0.005) after 4 weeks of omalizumab therapy despite evidence of reduced basophil surface-bound IgE (p < 0.00001) and FceRI (p 5 0.00005). CONCLUSIONS: Omalizumab is an effective therapy for the management of CIU although further mechanistic and dosing studies need to be explored. Funding: Genentech
567
The Natural History of Peanut Allergy-Extending Our Knowledge Beyond Childhood J. H. Savage1, S. L. Limb2, N. H. Brereton1, R. A. Wood1; 1Johns Hopkins Hospital, Baltimore, MD, 2US Food and Drug Administration, Rockville, MD. RATIONALE: To characterize adolescents and adults with peanut allergy. METHODS: We studied peanut-allergic teens and adults by obtaining allergy history, skin prick testing (SPT), peanut-specific IgE (pn-IgE), and when indicated, performing double-blind, placebo-controlled, food challenges (DBPCFC). Subjects were divided into early- and late-onset peanut allergy groups based on clinical history. Early-onset subjects reacted to peanut with their first few exposures to peanut products. Late-onset subjects had their first reaction at least 5 years after their first peanut exposure, after tolerating peanut products regularly. RESULTS: Twenty-five early- and 10 late-onset peanut allergy subjects were identified. The median age at peanut allergy diagnosis was 3 years in the early-onset group and 25 years in the late-onset group. The early-onset subjects had significantly larger peanut SPT wheal size (median 5.3 vs 2.9 mm, p 5 0.03), higher pn-IgE levels (median 2.5 vs 0.4 kU/L, p 5 0.05), and were more likely to report a history of a severe reaction (92% vs 50%, p < 0.01). Seventeen met criteria for and 12 underwent a DBPCFC. Eight subjects passed, including 5 early-onset with a history of severe reactions.
The median pn-IgE in subjects who passed a challenge ranged from <0.353.97 kU/L and from <0.35-0.88 kU/L in those who failed a challenge. CONCLUSIONS: Early-onset subjects had significantly more severe symptoms on peanut ingestion, larger SPT wheal size, and higher pn-IgE levels compared to late-onset subjects. However, early-onset subjects can outgrow their allergy even beyond their teenage years. Thus, food challenges in adults should be considered in the appropriate clinical setting. Funding: Johns Hopkins University School of Medicine General Clinical Research Center Grant #M01RR00052
568
Induction of GITR-Ligand Expression in Keratinocytes by TH2 cytokines: Implications for Atopic Dermatitis (AD) A. Byrne1, D. Y. M. Leung1, I. D. Cardona1, Q. A. Hamid2, E. Goleva1; 1 National Jewish Medical and Research Center, Denver, CO, 2University of Montre´al, Meakins-Christie Laboratory, Montre´al, PQ, CANADA. RATIONALE: Mechanisms of crosstalk between keratinocytes and skin infiltrating T cells are poorly defined, but may be central to the pathophysiology of AD. Ligation of the glucocorticoid-induced TNF receptor related protein (GITR) on the surface of CD41CD251 T regulatory (Treg) cells is known to inhibit their suppressive effects. We tested the hypothesis that the ligand for GITR, GITR-L, is expressed by skin keratinocytes in the setting of acute AD and upregulated on keratinocytes exposed to TH2 cytokines. METHODS: Skin biopsies from normal individuals and AD patients were analyzed for GITR-L expression by real-time PCR and immunohistochemical staining. Primary keratinocytes from C57BL/6 mice, human embryonic keratinocytes and murine keratinocyte cell line Pam 212 were exposed to 50 ng/ml of IL4, IL13 or media for 24 hrs. Expression of GITRL mRNA was analyzed by real-time PCR. Protein expression was determined by Western blot. RESULTS: In contrast to normal individuals, keratinocytes from AD patients stained strongly positive for GITR-L (epidermal staining score 1.00 6 0.37 vs. 2.89 6 0.48, p < 0.0007, respectively). GITR-L mRNA expression in AD skin explants (0.344 6 0.110 ngGITR-L/ngGAPDH, n 5 12), was significantly greater than normal controls (0.071 6 0.031, n 5 9) (p 5 0.05). Stimulation of primary and cell line keratinocyte cultures with IL4 and IL13 resulted in significant induction of the GITR-L mRNA expression as compared to media treated cells (p < 0.05). Increased GITRL protein expression was observed in Pam 212 keratinocytes under comparable experimental conditions. CONCLUSIONS: These studies show that keratinocytes have the capability to express GITR-L, thus, demonstrating the surprising potential for a crosstalk mechanism between keratinocytes and Tregs in AD. Funding: NIH
SUNDAY
did vehicle- or UV-inactivated virus-inoculated mice (p < 0.05), providing validation for the microarray analysis. CONCLUSIONS: Because of similarities between mengovirus- and rhinovirus-induced airway inflammation, this model should be useful for studying altered gene expression in response to lower airway picornavirus infection. Funding: NIH grant AI070503
J ALLERGY CLIN IMMUNOL VOLUME 121, NUMBER 2
566
Effect of Anti-IgE (Omalizumab) in Chronic Idiopathic Urticaria (CIU) Patients L. M. Gober, P. M. Sterba, J. A. Eckman, S. S. Saini; Johns Hopkins University, Baltimore, MD. RATIONALE: Omalizumab has shown benefits in allergic asthma and a few cases of CIU. Omalizumab decreases circulating IgE, surface-bound IgE, FceRI receptors on mast cells and basophils, and FceRI-mediated cellular responses. Given the altered mast cell and basophil FceRI function in CIU and the action of omalizumab on these cells, we investigated the effect of omalizumab treatment in subjects with CIU. METHODS: Twenty CIU subjects with active disease despite standard anti-histamine therapy were enrolled in a 6-month, double-blind, placebocontrolled trial of omalizumab using current FDA-approved dosing guidelines for allergic asthma. Subjects completed daily symptom diaries, biweekly urticaria disease assessments, and interval quality of life measures using Skindex-29. Physicians completed biweekly urticaria disease assessments. Subjects underwent blood sampling for basophil functional studies at baseline, 4-weeks and 16-weeks on treatment, and 8 weeks posttreatment. RESULTS: Subjects on omalizumab (n 5 10) demonstrated significantly decreased urticaria severity scores beginning at 2 weeks (patient-assessed, p 5 0.002; physician-assessed, p 5 0.003) that continued throughout treatment (patient-assessed, p 5 0.007; physician-assessed, p 5 0.003 at 16 weeks), improved quality of life at 16 weeks (Skindex-29: symptoms p 5 0.005, functioning p 5 0.006, emotions p 5 0.02), and significantly increased symptom-free days (p 5 0.02 by 2 weeks, p 5 0.0004 by 16 weeks) when compared to placebo controls (n 5 10). Compared to baseline, blood basophil FceRI-mediated degranulation with polyclonal anti-IgE stimulation (0.1 mg/mL) was significantly enhanced (p 5 0.005) after 4 weeks of omalizumab therapy despite evidence of reduced basophil surface-bound IgE (p < 0.00001) and FceRI (p 5 0.00005). CONCLUSIONS: Omalizumab is an effective therapy for the management of CIU although further mechanistic and dosing studies need to be explored. Funding: Genentech
567
The Natural History of Peanut Allergy-Extending Our Knowledge Beyond Childhood J. H. Savage1, S. L. Limb2, N. H. Brereton1, R. A. Wood1; 1Johns Hopkins Hospital, Baltimore, MD, 2US Food and Drug Administration, Rockville, MD. RATIONALE: To characterize adolescents and adults with peanut allergy. METHODS: We studied peanut-allergic teens and adults by obtaining allergy history, skin prick testing (SPT), peanut-specific IgE (pn-IgE), and when indicated, performing double-blind, placebo-controlled, food challenges (DBPCFC). Subjects were divided into early- and late-onset peanut allergy groups based on clinical history. Early-onset subjects reacted to peanut with their first few exposures to peanut products. Late-onset subjects had their first reaction at least 5 years after their first peanut exposure, after tolerating peanut products regularly. RESULTS: Twenty-five early- and 10 late-onset peanut allergy subjects were identified. The median age at peanut allergy diagnosis was 3 years in the early-onset group and 25 years in the late-onset group. The early-onset subjects had significantly larger peanut SPT wheal size (median 5.3 vs 2.9 mm, p 5 0.03), higher pn-IgE levels (median 2.5 vs 0.4 kU/L, p 5 0.05), and were more likely to report a history of a severe reaction (92% vs 50%, p < 0.01). Seventeen met criteria for and 12 underwent a DBPCFC. Eight subjects passed, including 5 early-onset with a history of severe reactions.
The median pn-IgE in subjects who passed a challenge ranged from <0.353.97 kU/L and from <0.35-0.88 kU/L in those who failed a challenge. CONCLUSIONS: Early-onset subjects had significantly more severe symptoms on peanut ingestion, larger SPT wheal size, and higher pn-IgE levels compared to late-onset subjects. However, early-onset subjects can outgrow their allergy even beyond their teenage years. Thus, food challenges in adults should be considered in the appropriate clinical setting. Funding: Johns Hopkins University School of Medicine General Clinical Research Center Grant #M01RR00052
568
Induction of GITR-Ligand Expression in Keratinocytes by TH2 cytokines: Implications for Atopic Dermatitis (AD) A. Byrne1, D. Y. M. Leung1, I. D. Cardona1, Q. A. Hamid2, E. Goleva1; 1 National Jewish Medical and Research Center, Denver, CO, 2University of Montre´al, Meakins-Christie Laboratory, Montre´al, PQ, CANADA. RATIONALE: Mechanisms of crosstalk between keratinocytes and skin infiltrating T cells are poorly defined, but may be central to the pathophysiology of AD. Ligation of the glucocorticoid-induced TNF receptor related protein (GITR) on the surface of CD41CD251 T regulatory (Treg) cells is known to inhibit their suppressive effects. We tested the hypothesis that the ligand for GITR, GITR-L, is expressed by skin keratinocytes in the setting of acute AD and upregulated on keratinocytes exposed to TH2 cytokines. METHODS: Skin biopsies from normal individuals and AD patients were analyzed for GITR-L expression by real-time PCR and immunohistochemical staining. Primary keratinocytes from C57BL/6 mice, human embryonic keratinocytes and murine keratinocyte cell line Pam 212 were exposed to 50 ng/ml of IL4, IL13 or media for 24 hrs. Expression of GITRL mRNA was analyzed by real-time PCR. Protein expression was determined by Western blot. RESULTS: In contrast to normal individuals, keratinocytes from AD patients stained strongly positive for GITR-L (epidermal staining score 1.00 6 0.37 vs. 2.89 6 0.48, p < 0.0007, respectively). GITR-L mRNA expression in AD skin explants (0.344 6 0.110 ngGITR-L/ngGAPDH, n 5 12), was significantly greater than normal controls (0.071 6 0.031, n 5 9) (p 5 0.05). Stimulation of primary and cell line keratinocyte cultures with IL4 and IL13 resulted in significant induction of the GITR-L mRNA expression as compared to media treated cells (p < 0.05). Increased GITRL protein expression was observed in Pam 212 keratinocytes under comparable experimental conditions. CONCLUSIONS: These studies show that keratinocytes have the capability to express GITR-L, thus, demonstrating the surprising potential for a crosstalk mechanism between keratinocytes and Tregs in AD. Funding: NIH
SUNDAY
did vehicle- or UV-inactivated virus-inoculated mice (p < 0.05), providing validation for the microarray analysis. CONCLUSIONS: Because of similarities between mengovirus- and rhinovirus-induced airway inflammation, this model should be useful for studying altered gene expression in response to lower airway picornavirus infection. Funding: NIH grant AI070503