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The Effects of Omalizumab on the Late-Phase Response to Nasal and Skin Allergen Challenge
AB50 Abstracts
SATURDAY
189
Relationship Between Leptin, Bronchial Hyperresponsiveness To Mannitol And Urinary Leukotriene E4/exhaled Nitric Oxide Ratio In Asthmatic Children H. Baek1, J. Oh2, H. Lee2; 1Hallym University Gangdong Sacred Heart Hospital, Seoul, REPUBLIC OF KOREA, 2Hanyang University College of Medicine, Seoul, REPUBLIC OF KOREA. RATIONALE: Effects of leptin on airway inflammation and bronchial hyperresponsiveness (BHR) have not yet been demonstrated in the human airway. We speculated that leptin might be more closely related with cysteinyl leukotriene inflammation [as measured by urinary leukotriene E4 (LTE4)] than with eosinophilic inflammation [as measured by fractional exhaled nitric oxide (FENO)]. We also speculated that leptin might be related with BHR to indirect stimuli (mannitol). The aim of this study was to address the relationship between leptin, BHR to mannitol and LTE4/ FENO ratio in asthmatic children. METHODS: Sixty-one prepubertal children between the ages of 6 and 10 years were included and comprised asthmatic (n540) and healthy (n521). We measured FENO and serum leptin levels. We performed mannitol provocation challenges. The urinary concentrations of LTE4 and the 9a-11bPGF2 were measured at baseline and 30 min after mannitol challenge. The response to mannitol was expressed as a provocative dose causing a 15% fall in FEV1 (PD15) and the response-dose ratio (RDR) (% fall in FEV1/cumulative dose). RESULTS: The urinary excretion of 11b-PGF2 (79.8617.8 vs. 33616.6 ng.mmol creatinine-1, peak versus baseline) and LTE4 (48.3616.5 vs. 36.2612.7) increased significantly 30 min after mannitol challenge. There was a significant correlation between serum leptin levels and RDR mannitol (r50.468, P50.021). The serum leptin levels were positively correlated with LTE4/FENO ratios (r50.347, P50.038). CONCLUSIONS: Levels of the leptin are correlated with BHR to mannitol and LTE4/FENO ratios. This suggests that an increased role of mast cells or leukotrienes may exist in the relationship between leptin and BHR to mannitol.
190
Silymarin Reduces OVA-induced Allergic Airway Inflammation D. C. Newcomb1, M. G. Boswell1, M. M. Huckabee1, J. S. Markowitz2, T. V. Hartert1, R. S. Peebles, Jr1; 1Vanderbilt University Medical Center, Nashville, TN, 2University of Florida, Gainesville, FL. RATIONALE: Inexpensive, readily available drugs are needed for prevention and treatment of asthma. Oxidative stress, or an imbalance of reactive oxygen species (ROS) and antioxidants, occurs in asthma with infiltration of inflammatory cells, such as eosinophils, into the airways resulting in inflammation and tissue damage. Silymarin, a flavonoid complex from Silybum marianum (milk thistle plant), reduces ROS by increasing antioxidant enzymes, such as catalase, in human hepatotoxicity and cancer. However, the effect of silymarin on allergic airway inflammation and asthma is unknown. We hypothesized silymarin decreases ovalbumin (OVA)-induced airway inflammation in BALB/c mice by increasing catalase levels. METHODS: BALB/c female mice were sensitized to OVA conjugated with aluminum hydroxide on day -14. Two weeks later, mice were challenged with 1% OVA aerosol daily on days 0 to 3. One hour prior to each OVA challenge mice were orally given silymarin (50-200mg/kg body weight) or vehicle (0.4% methylcellulose). On day 4, blood, bronchoalveolar lavage (BAL) fluid and lungs were harvested. Serum IgE levels and IL-13, a Th2 cytokine upregulated with allergic airway inflammation, were determined by ELISA. Infiltration of inflammatory cells was examined in BAL fluid. Catalase mRNA expression was examined by real-time PCR. RESULTS: Silymarin significantly decreased lymphocytes and eosinophils in the BAL fluid (n511-12, p<0.05) and decreased BAL fluid levels of IL-13. IgE serum levels were not altered with silymarin (p50.013). Silymarin increased mRNA expression levels of catalase (n511-12, p<0.05). CONCLUSIONS: Silymarin attenuated OVA-induced allergic airway inflammation, but had no effect on IgE levels. Therefore, silymarin may be a potential therapeutic for asthma.
J ALLERGY CLIN IMMUNOL FEBRUARY 2012
191
Does the Immunological Status Influence in Behavior of Albini Mice with Experimental Asthma Model? J. C. Muino1, J. C. Cosiansi Bai2, M. Glocker2, S. Cossy Isasi2; 1Universidad Nacional de Cordoba, Cordoba, ARGENTINA, 2Universidad Nacional de Crdoba, Cordoba, ARGENTINA. RATIONALE: Depression is prevalent in asthma and implicated in acute asthma exacerbations. Objective was to examine under controlled laboratory conditions, by which we performed experimental asthma model in mice after C tala immunization and developed experiments to determine whether the immune system response may alter the behavior of mice in a classical depression test. METHODS: We studied 30 Albino Swiss mice, one day old, divided in: (a) asthma induced by C tala injection, 1 ug of glycoprotein intra-peritoneal weekly for 3 weeks (n: 20), and control group injected with PBS (n: 10). All animals were controlled in behavior weekly, from immunization to 21 day later by a method of forced swimming, and finally challenged with aerosolized tala 3 days. All mice were euthanized and lung harvested. Histopathology examination of the lungs was performed. Blood and sera samples were collected and studied to specific IgE to C tala by ELISA RESULTS: The asthmatic presented IgE positive to tala in 20/20, the control group was IgE (-) to C tala, p <0.0001. The tala immunized animals presented asthmatic responses to challenge with tala. The histopathology presented classical asthmatic responses. The behavior was different in the 2 groups. The group (a) presented in first control climbing trends 20/20, at 14 day (swimming) 16/20 and day 21 (floating) 13/20. The (c) group presented only climbing trends in all weekly determinations.(p50.0085). CONCLUSIONS: The results suggest that immunological status induced depression in animals with asthmatic responses and these findings probably explain the depression observed in this type of patients.
192
The Effects of Omalizumab on the Late-Phase Response to Nasal and Skin Allergen Challenge M. O. Paterniti, L. M. Breslin, J. Courneya, P. M. Sterba, M. E. Brummet, Y. Park, D. W. MacGlashan, Jr, B. S. Bochner, S. S. Saini; Johns Hopkins University School of Medicine, Baltimore, MD. RATIONALE: Using omalizumab as a mechanistic tool, we examined the contribution of basophil versus mast cell activation in allergic airway challenge, skin tests and nasal eosinophil recruitment during the late-phase response. METHODS: Cat-allergic adults underwent a randomized, double-blind, placebo-controlled trial of omalizumab. At baseline, anti-IgE and cat allergen-induced BHR (basophil histamine release), cat IST (intradermal skin test) at 15 min (early-phase) and at 24 hours (late-phase), NAC (nasal allergen challenge) with sneezes measured within 45 min (early-phase) and 4-24 hours (late-phase) (recorded based on recollection), pre-NAC nasal lavage eosinophils and 24-hour post-NAC nasal brush for eosinophils were performed. BHR studies were repeated biweekly. Baseline procedures were repeated when cat allergen-induced BHR <80% or on day 56 (NAC-2). RESULTS: Subjects were divided into presumptive treatment (TRE, n57) and placebo groups (PLA, n57) based on the shift of anti-IgE BHR relative to baseline. Average day of NAC-2 was 46 for TRE and 59 for PLA. Early and 24-hour late-phase IST size decreased more in TRE than in PLA (37% vs. 7% and 76% vs. 5%). Nasal lavage eosinophil presence pre NAC-2 decreased more in the TRE compared to PLA (44% vs. -52%) as well as 24hour post-NAC-2 nasal brush eosinophils (57% vs. 25%). Early-phase sneezes decreased more in the TRE than in the PLA (51% vs. -11%), but not in the late-phase (83% vs. 71%). CONCLUSION: Basophil hyporesponsiveness secondary to omalizumab is associated with a reduction in acute and late-phase skin test size, basal and NAC induced nasal eosinophil recruitment, and acute nasal challenge sneezes.
SATURDAY
189
Relationship Between Leptin, Bronchial Hyperresponsiveness To Mannitol And Urinary Leukotriene E4/exhaled Nitric Oxide Ratio In Asthmatic Children H. Baek1, J. Oh2, H. Lee2; 1Hallym University Gangdong Sacred Heart Hospital, Seoul, REPUBLIC OF KOREA, 2Hanyang University College of Medicine, Seoul, REPUBLIC OF KOREA. RATIONALE: Effects of leptin on airway inflammation and bronchial hyperresponsiveness (BHR) have not yet been demonstrated in the human airway. We speculated that leptin might be more closely related with cysteinyl leukotriene inflammation [as measured by urinary leukotriene E4 (LTE4)] than with eosinophilic inflammation [as measured by fractional exhaled nitric oxide (FENO)]. We also speculated that leptin might be related with BHR to indirect stimuli (mannitol). The aim of this study was to address the relationship between leptin, BHR to mannitol and LTE4/ FENO ratio in asthmatic children. METHODS: Sixty-one prepubertal children between the ages of 6 and 10 years were included and comprised asthmatic (n540) and healthy (n521). We measured FENO and serum leptin levels. We performed mannitol provocation challenges. The urinary concentrations of LTE4 and the 9a-11bPGF2 were measured at baseline and 30 min after mannitol challenge. The response to mannitol was expressed as a provocative dose causing a 15% fall in FEV1 (PD15) and the response-dose ratio (RDR) (% fall in FEV1/cumulative dose). RESULTS: The urinary excretion of 11b-PGF2 (79.8617.8 vs. 33616.6 ng.mmol creatinine-1, peak versus baseline) and LTE4 (48.3616.5 vs. 36.2612.7) increased significantly 30 min after mannitol challenge. There was a significant correlation between serum leptin levels and RDR mannitol (r50.468, P50.021). The serum leptin levels were positively correlated with LTE4/FENO ratios (r50.347, P50.038). CONCLUSIONS: Levels of the leptin are correlated with BHR to mannitol and LTE4/FENO ratios. This suggests that an increased role of mast cells or leukotrienes may exist in the relationship between leptin and BHR to mannitol.
190
Silymarin Reduces OVA-induced Allergic Airway Inflammation D. C. Newcomb1, M. G. Boswell1, M. M. Huckabee1, J. S. Markowitz2, T. V. Hartert1, R. S. Peebles, Jr1; 1Vanderbilt University Medical Center, Nashville, TN, 2University of Florida, Gainesville, FL. RATIONALE: Inexpensive, readily available drugs are needed for prevention and treatment of asthma. Oxidative stress, or an imbalance of reactive oxygen species (ROS) and antioxidants, occurs in asthma with infiltration of inflammatory cells, such as eosinophils, into the airways resulting in inflammation and tissue damage. Silymarin, a flavonoid complex from Silybum marianum (milk thistle plant), reduces ROS by increasing antioxidant enzymes, such as catalase, in human hepatotoxicity and cancer. However, the effect of silymarin on allergic airway inflammation and asthma is unknown. We hypothesized silymarin decreases ovalbumin (OVA)-induced airway inflammation in BALB/c mice by increasing catalase levels. METHODS: BALB/c female mice were sensitized to OVA conjugated with aluminum hydroxide on day -14. Two weeks later, mice were challenged with 1% OVA aerosol daily on days 0 to 3. One hour prior to each OVA challenge mice were orally given silymarin (50-200mg/kg body weight) or vehicle (0.4% methylcellulose). On day 4, blood, bronchoalveolar lavage (BAL) fluid and lungs were harvested. Serum IgE levels and IL-13, a Th2 cytokine upregulated with allergic airway inflammation, were determined by ELISA. Infiltration of inflammatory cells was examined in BAL fluid. Catalase mRNA expression was examined by real-time PCR. RESULTS: Silymarin significantly decreased lymphocytes and eosinophils in the BAL fluid (n511-12, p<0.05) and decreased BAL fluid levels of IL-13. IgE serum levels were not altered with silymarin (p50.013). Silymarin increased mRNA expression levels of catalase (n511-12, p<0.05). CONCLUSIONS: Silymarin attenuated OVA-induced allergic airway inflammation, but had no effect on IgE levels. Therefore, silymarin may be a potential therapeutic for asthma.
J ALLERGY CLIN IMMUNOL FEBRUARY 2012
191
Does the Immunological Status Influence in Behavior of Albini Mice with Experimental Asthma Model? J. C. Muino1, J. C. Cosiansi Bai2, M. Glocker2, S. Cossy Isasi2; 1Universidad Nacional de Cordoba, Cordoba, ARGENTINA, 2Universidad Nacional de Crdoba, Cordoba, ARGENTINA. RATIONALE: Depression is prevalent in asthma and implicated in acute asthma exacerbations. Objective was to examine under controlled laboratory conditions, by which we performed experimental asthma model in mice after C tala immunization and developed experiments to determine whether the immune system response may alter the behavior of mice in a classical depression test. METHODS: We studied 30 Albino Swiss mice, one day old, divided in: (a) asthma induced by C tala injection, 1 ug of glycoprotein intra-peritoneal weekly for 3 weeks (n: 20), and control group injected with PBS (n: 10). All animals were controlled in behavior weekly, from immunization to 21 day later by a method of forced swimming, and finally challenged with aerosolized tala 3 days. All mice were euthanized and lung harvested. Histopathology examination of the lungs was performed. Blood and sera samples were collected and studied to specific IgE to C tala by ELISA RESULTS: The asthmatic presented IgE positive to tala in 20/20, the control group was IgE (-) to C tala, p <0.0001. The tala immunized animals presented asthmatic responses to challenge with tala. The histopathology presented classical asthmatic responses. The behavior was different in the 2 groups. The group (a) presented in first control climbing trends 20/20, at 14 day (swimming) 16/20 and day 21 (floating) 13/20. The (c) group presented only climbing trends in all weekly determinations.(p50.0085). CONCLUSIONS: The results suggest that immunological status induced depression in animals with asthmatic responses and these findings probably explain the depression observed in this type of patients.
192
The Effects of Omalizumab on the Late-Phase Response to Nasal and Skin Allergen Challenge M. O. Paterniti, L. M. Breslin, J. Courneya, P. M. Sterba, M. E. Brummet, Y. Park, D. W. MacGlashan, Jr, B. S. Bochner, S. S. Saini; Johns Hopkins University School of Medicine, Baltimore, MD. RATIONALE: Using omalizumab as a mechanistic tool, we examined the contribution of basophil versus mast cell activation in allergic airway challenge, skin tests and nasal eosinophil recruitment during the late-phase response. METHODS: Cat-allergic adults underwent a randomized, double-blind, placebo-controlled trial of omalizumab. At baseline, anti-IgE and cat allergen-induced BHR (basophil histamine release), cat IST (intradermal skin test) at 15 min (early-phase) and at 24 hours (late-phase), NAC (nasal allergen challenge) with sneezes measured within 45 min (early-phase) and 4-24 hours (late-phase) (recorded based on recollection), pre-NAC nasal lavage eosinophils and 24-hour post-NAC nasal brush for eosinophils were performed. BHR studies were repeated biweekly. Baseline procedures were repeated when cat allergen-induced BHR <80% or on day 56 (NAC-2). RESULTS: Subjects were divided into presumptive treatment (TRE, n57) and placebo groups (PLA, n57) based on the shift of anti-IgE BHR relative to baseline. Average day of NAC-2 was 46 for TRE and 59 for PLA. Early and 24-hour late-phase IST size decreased more in TRE than in PLA (37% vs. 7% and 76% vs. 5%). Nasal lavage eosinophil presence pre NAC-2 decreased more in the TRE compared to PLA (44% vs. -52%) as well as 24hour post-NAC-2 nasal brush eosinophils (57% vs. 25%). Early-phase sneezes decreased more in the TRE than in the PLA (51% vs. -11%), but not in the late-phase (83% vs. 71%). CONCLUSION: Basophil hyporesponsiveness secondary to omalizumab is associated with a reduction in acute and late-phase skin test size, basal and NAC induced nasal eosinophil recruitment, and acute nasal challenge sneezes.