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CD4+CD25+ Cells and Laboratory Animal Allergy
165
Adverse Effects of Danazol in the Prophylactic Treatment of Hereditary or Acquired C1-Inhibitor Deficiency W. Kreuz, E. Aygo¨ren-Pu¨rsu¨n, I. Martinez-Saguer, E. Rusicke, T. Klingebiel; University Hospital Frankfurt, Frankfurt, GERMANY. RATIONALE: C1-Inhibitor (C1-INH)- deficiency, hereditary (HAE) or acquired (AAE), is characterized by recurrent angioedema. Patients with frequent and/or severe manifestations of HAE/AAE can be considerably impaired in daily life. Prophylactic treatment is therefore important for many patients. The attenuated androgen danazol can be used for longterm prophylaxis in HAE/AAE. However, many adverse effects are recognized. We aimed at assessing the whole range of adverse effects during danazol prophylaxis in our own patient group. METHODS: A retrospective chart analysis was performed. The charts of all patients that received treatment with danazol were analyzed concerning danazol-related adverse effects. RESULTS: 93 patients with danazol treatment were identified (81 - HAE type 1; 4 - HAE type 2; 5 - AAE; 3 - no C1-INH deficiency). The duration of danazol administration ranged from 0,1 to 25.0 years, administered doses ranged from 0.14 mg/d to 1200 mg/d. Main adverse effects encountered were of psychopathological nature, i.e. depression (47%), indisposition (28%) and panic disorder (10%). Moreover headache (40%), considerable weight gain (39%), arterial hypertension (30%) and migraine (10%) were documented. Dose-dependency was seen in affected females who suffered from virilisation (79%). Symptoms were frequently reversible with discontinuation of the drug. Only 10% of patients experienced no adverse affects at all, whereas the majority of patients suffered from multiple adverse effects simultaneously. CONCLUSIONS: The administration of the attenuated androgen danazol is limited by a large array of adverse effects, which is particularly dissatisfying in view of the long-term nature of the treatment.
166
T-Cell Receptor (TCR)-Mediated Upregulation of BLT1 (LTB4 Receptor) Expression and Activation of Human T Cells by LTB4 A. Ahuja, A. Dakhama, H. Ohnishi, J. J. Lucas, E. W. Gelfand; National Jewish Medical and Research Center, Denver, CO. RATIONALE: BLT1, the high affinity receptor for leukotriene B4 (LTB4), has been implicated in the development of airway hyperresponsiveness and allergic airway inflammation in murine models and in asthma (JACI 117:577-582, 2006). This study investigated the induction of BLT1 expression and activation of human peripheral blood T cells via LTB4-BLT interactions. METHODS: T cells were isolated to high purity (>97% CD31) by negative selection from peripheral blood of healthy human subjects. Cells were stimulated in culture with anti-CD3/anti-CD28, followed by analysis of BLT1 expression on CD41 or CD81 T cells. Activation of T cells following ligation of BLT1 by LTB4 was assessed by intracellular Ca21 mobilization and mitogen-activated protein kinase (MAPK) phsophorylation. RESULTS: BLT1 expression was not detected on freshly isolated, resting (non-stimulated) CD4 or CD8 T cells. Following activation of cells with anti-CD3/anti-CD28, BLT1 expression was induced in a time-dependent fashion on both CD4 and CD8 T cells. Addition of LTB4 triggered intracellular Ca21 mobilization and MAPK phosphorylation in activated but not in resting CD4 and CD8 T cells. CONCLUSIONS: Both CD4 and CD8 T cells express BLT1 upon TCR activation. Engagement of BLT1 with LTB4 results in activation of these cells. Together, with observations made in mice, these findings suggest an important role for the LTB4-BLT1. Funding: This work was supported by NIH grants HL-36577 and HL61005, and by EPA grant R825702
167
The Role Of Th1 And Th2 Response In Allergic Rhinitis Children With Or Without Sensitization To Food Allergens A. Nakonechna1, T. Umanetz2, V. Lapshin2, A. R. D. van Bergen3; 1 National Medical University, Kiev, UKRAINE, 2Institute of Pediatry, Obstetrics and Gynaecology, Kiev, UKRAINE, 3Novidec Ltd, Neston, UNITED KINGDOM. RATIONALE: Patients with allergic rhinitis (AR) show allergic symptoms to fruits, vegetables and nuts in 48-72%. Oral allergy syndrome (OAS) is based on cross-reaction of pollen-allergen specific IgE with homologous food proteins. In AR pathogenesis there is a prevalence of Th2 response with an ensuing increase in cytokines production. This study investigated the cytokines production by Th1 and Th2 in AR children with or without sensitization to food allergens. METHODS: Sixty children (8-12 years) with AR were observed. Group I 32 AR patients; group II 28 AR and OAS patients. Sensitivity to pollen allergens was tested by SPT. Food allergy in OAS patients was determined by questionnaire and SPT. IL-5, IL-10, g-IFN levels were measured by ELISA. RESULTS: 26.7% of patients were sensitized to grass’, 20.0% to trees and 53.3% to grass’, trees and weeds pollen. OAS patients more often had positive SPT to birch, alder, mugwort. 71.4% of gr.II had allergic reactions to food: hazelnut, apple, carrot, peanut. Fruits and vegetables sensitivity was confirmed by SPT in 78.6%. Blood eosinophils and total IgE were elevated in all patients. IL-5 production increased to 163.465.1 pg/ml in gr.I and 198.366.2 in gr.II, and IL-10 to 14669 in gr.I and 17768 in gr.II. The g-IFN level decreased to 257.666.2 in gr.I and 232.665.2 in gr.II. CONCLUSIONS: AR children can be sensitized to food allergens that may cause OAS, especially in patients with increased functional activity of Th2. The function of Th2 (identified by cytokines production) was activated in AR patients, especially in combination with OAS. Funding: National Medical University
168
CD41CD251 Cells and Laboratory Animal Allergy H. Jeal, A. Newman Taylor, M. Jones; NHLI @ Imperial College, London, UNITED KINGDOM. RATIONALE: The functionality of T regulatory cells has been shown to be diminished in non-atopic individuals compared with atopics. In this pilot study we investigated whether a difference in the ability of CD41CD251 T cells to suppress proliferation and cytokine production could be seen between individuals with and without laboratory animal allergy, a common occupational health problem. METHODS: CD41CD251 and CD41CD25- T cells were isolated from the peripheral blood of 12 currently exposed rat skin prick test (SPT) positive and 10 rat SPT negative individuals and 2 non-exposed controls using MACs immunomagnetic beads. Inhibition of proliferation and cytokine production was analysed. RESULTS: CD41CD25- cells proliferated to a significantly greater degree than PBMCs (p<0.01) and CD251 cells (p<0.001) in all individuals. Inhibition of proliferation to rat by CD41CD251 T cells did not differ between cases and exposed controls but was much higher in non exposed controls. IL-5 suppression was greater in exposed controls (>50% suppression 5 4/6) compared with cases (>50% suppression 5 1/7). CONCLUSIONS: Differences in the ability of CD41CD251 cells to suppress proliferation could not be seen between cases and exposed controls. However failure of these cells to suppress IL-5 production in cases could contribute to the development of their allergic disease. Funding: Clinical Research Committee at the Royal Brompton Hospital
SATURDAY
Abstracts S43
J ALLERGY CLIN IMMUNOL VOLUME 119, NUMBER 1
Adverse Effects of Danazol in the Prophylactic Treatment of Hereditary or Acquired C1-Inhibitor Deficiency W. Kreuz, E. Aygo¨ren-Pu¨rsu¨n, I. Martinez-Saguer, E. Rusicke, T. Klingebiel; University Hospital Frankfurt, Frankfurt, GERMANY. RATIONALE: C1-Inhibitor (C1-INH)- deficiency, hereditary (HAE) or acquired (AAE), is characterized by recurrent angioedema. Patients with frequent and/or severe manifestations of HAE/AAE can be considerably impaired in daily life. Prophylactic treatment is therefore important for many patients. The attenuated androgen danazol can be used for longterm prophylaxis in HAE/AAE. However, many adverse effects are recognized. We aimed at assessing the whole range of adverse effects during danazol prophylaxis in our own patient group. METHODS: A retrospective chart analysis was performed. The charts of all patients that received treatment with danazol were analyzed concerning danazol-related adverse effects. RESULTS: 93 patients with danazol treatment were identified (81 - HAE type 1; 4 - HAE type 2; 5 - AAE; 3 - no C1-INH deficiency). The duration of danazol administration ranged from 0,1 to 25.0 years, administered doses ranged from 0.14 mg/d to 1200 mg/d. Main adverse effects encountered were of psychopathological nature, i.e. depression (47%), indisposition (28%) and panic disorder (10%). Moreover headache (40%), considerable weight gain (39%), arterial hypertension (30%) and migraine (10%) were documented. Dose-dependency was seen in affected females who suffered from virilisation (79%). Symptoms were frequently reversible with discontinuation of the drug. Only 10% of patients experienced no adverse affects at all, whereas the majority of patients suffered from multiple adverse effects simultaneously. CONCLUSIONS: The administration of the attenuated androgen danazol is limited by a large array of adverse effects, which is particularly dissatisfying in view of the long-term nature of the treatment.
166
T-Cell Receptor (TCR)-Mediated Upregulation of BLT1 (LTB4 Receptor) Expression and Activation of Human T Cells by LTB4 A. Ahuja, A. Dakhama, H. Ohnishi, J. J. Lucas, E. W. Gelfand; National Jewish Medical and Research Center, Denver, CO. RATIONALE: BLT1, the high affinity receptor for leukotriene B4 (LTB4), has been implicated in the development of airway hyperresponsiveness and allergic airway inflammation in murine models and in asthma (JACI 117:577-582, 2006). This study investigated the induction of BLT1 expression and activation of human peripheral blood T cells via LTB4-BLT interactions. METHODS: T cells were isolated to high purity (>97% CD31) by negative selection from peripheral blood of healthy human subjects. Cells were stimulated in culture with anti-CD3/anti-CD28, followed by analysis of BLT1 expression on CD41 or CD81 T cells. Activation of T cells following ligation of BLT1 by LTB4 was assessed by intracellular Ca21 mobilization and mitogen-activated protein kinase (MAPK) phsophorylation. RESULTS: BLT1 expression was not detected on freshly isolated, resting (non-stimulated) CD4 or CD8 T cells. Following activation of cells with anti-CD3/anti-CD28, BLT1 expression was induced in a time-dependent fashion on both CD4 and CD8 T cells. Addition of LTB4 triggered intracellular Ca21 mobilization and MAPK phosphorylation in activated but not in resting CD4 and CD8 T cells. CONCLUSIONS: Both CD4 and CD8 T cells express BLT1 upon TCR activation. Engagement of BLT1 with LTB4 results in activation of these cells. Together, with observations made in mice, these findings suggest an important role for the LTB4-BLT1. Funding: This work was supported by NIH grants HL-36577 and HL61005, and by EPA grant R825702
167
The Role Of Th1 And Th2 Response In Allergic Rhinitis Children With Or Without Sensitization To Food Allergens A. Nakonechna1, T. Umanetz2, V. Lapshin2, A. R. D. van Bergen3; 1 National Medical University, Kiev, UKRAINE, 2Institute of Pediatry, Obstetrics and Gynaecology, Kiev, UKRAINE, 3Novidec Ltd, Neston, UNITED KINGDOM. RATIONALE: Patients with allergic rhinitis (AR) show allergic symptoms to fruits, vegetables and nuts in 48-72%. Oral allergy syndrome (OAS) is based on cross-reaction of pollen-allergen specific IgE with homologous food proteins. In AR pathogenesis there is a prevalence of Th2 response with an ensuing increase in cytokines production. This study investigated the cytokines production by Th1 and Th2 in AR children with or without sensitization to food allergens. METHODS: Sixty children (8-12 years) with AR were observed. Group I 32 AR patients; group II 28 AR and OAS patients. Sensitivity to pollen allergens was tested by SPT. Food allergy in OAS patients was determined by questionnaire and SPT. IL-5, IL-10, g-IFN levels were measured by ELISA. RESULTS: 26.7% of patients were sensitized to grass’, 20.0% to trees and 53.3% to grass’, trees and weeds pollen. OAS patients more often had positive SPT to birch, alder, mugwort. 71.4% of gr.II had allergic reactions to food: hazelnut, apple, carrot, peanut. Fruits and vegetables sensitivity was confirmed by SPT in 78.6%. Blood eosinophils and total IgE were elevated in all patients. IL-5 production increased to 163.465.1 pg/ml in gr.I and 198.366.2 in gr.II, and IL-10 to 14669 in gr.I and 17768 in gr.II. The g-IFN level decreased to 257.666.2 in gr.I and 232.665.2 in gr.II. CONCLUSIONS: AR children can be sensitized to food allergens that may cause OAS, especially in patients with increased functional activity of Th2. The function of Th2 (identified by cytokines production) was activated in AR patients, especially in combination with OAS. Funding: National Medical University
168
CD41CD251 Cells and Laboratory Animal Allergy H. Jeal, A. Newman Taylor, M. Jones; NHLI @ Imperial College, London, UNITED KINGDOM. RATIONALE: The functionality of T regulatory cells has been shown to be diminished in non-atopic individuals compared with atopics. In this pilot study we investigated whether a difference in the ability of CD41CD251 T cells to suppress proliferation and cytokine production could be seen between individuals with and without laboratory animal allergy, a common occupational health problem. METHODS: CD41CD251 and CD41CD25- T cells were isolated from the peripheral blood of 12 currently exposed rat skin prick test (SPT) positive and 10 rat SPT negative individuals and 2 non-exposed controls using MACs immunomagnetic beads. Inhibition of proliferation and cytokine production was analysed. RESULTS: CD41CD25- cells proliferated to a significantly greater degree than PBMCs (p<0.01) and CD251 cells (p<0.001) in all individuals. Inhibition of proliferation to rat by CD41CD251 T cells did not differ between cases and exposed controls but was much higher in non exposed controls. IL-5 suppression was greater in exposed controls (>50% suppression 5 4/6) compared with cases (>50% suppression 5 1/7). CONCLUSIONS: Differences in the ability of CD41CD251 cells to suppress proliferation could not be seen between cases and exposed controls. However failure of these cells to suppress IL-5 production in cases could contribute to the development of their allergic disease. Funding: Clinical Research Committee at the Royal Brompton Hospital
SATURDAY
Abstracts S43
J ALLERGY CLIN IMMUNOL VOLUME 119, NUMBER 1