- Email: [email protected]
Therapeutic Administration of Allergen-specific CD4+CD25+ Regulatory T Cells Suppresses Chronic Allergen-induced Airway Inflammation and Remodelling in a Murine Model
S84 Abstracts
SATURDAY
Therapeutic Administration of Allergen-specific CD4+CD25+ Regulatory T Cells Suppresses Chronic Allergen-induced Airway Inflammation and Remodelling in a Murine Model J. Kearley, D. S. Robinson, C. M. Lloyd; Leukocyte Biology Section, NHLI, Faculty of Medicine, Imperial College, London, UNITED KINGDOM. RATIONALE: CD4+CD25+ regulatory T cells can inhibit excessive immune responses in vivo. We have previously demonstrated that prophylactic administration of allergen-specific CD4+CD25+ regulatory cells suppressed acute allergen-induced airway inflammation in a murine model. In the present study, we sought to determine the effect of therapeutic administration of regulatory T cells in a model of chronic allergeninduced airway disease METHODS: Mice were sensitised to ovalbumin and challenged with this allergen through the airways for 5 consecutive days. After this acute challenge phase, allergen-specific CD4+CD25+ cells were administered, and airway challenges were continued to induce chronic inflammation and airway remodelling. RESULTS: Administration of CD4+CD25+ cells decreased lung eosinophilia, (from 5.1±0.7 to 2.6±0.5 X103 cells/mg) and reduced expression of IL-5, IL-13 and TGF-. Mucus production was also decreased but airway hyperreactivity was unaffected. Suppression of inflammation was associated with a significant increase in lung IL-10 expression (from 802±83 to 1024±55 pg/ml;p<0.05). We also examined airway remodelling and found that peribronchiolar collagen deposition was reduced by 25% in mice that received CD4+CD25+ cells, potentially due to decreased lung TGF- levels as this cytokine has been implicated in remodelling. CONCLUSIONS: For the first time we have demonstrated a therapeutic role for CD4+CD25+ regulatory T cells in chronic allergen-induced airway disease. Therefore, enhancing the activity of these regulatory cells could be of potential benefit in the treatment of human asthma. Funding: Wellcome Trust
328
Occurrence of Wheezing and Being Overweight in the First Five Years of Life in a Birth Cohort at High Risk for the Development of Asthma/Allergy Z. Zhang1, H. Lai1, M. Evans2, R. Gangnon2, E. Anderson3, J. Gern3, R. Lemanske4; 1Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, 2Biostatistics and medical informatics, University of Wisconsin-Madison, Madison, WI, 3Pediatrics, University of Wisconsin-Madison, Madison, WI, 4Pediatrics, Medicine, University of Wisconsin-Madison, Madison, WI. RATIONALE: The association between asthma and obesity is unclear in young children. Therefore, in a birth cohort genetically at increased risk for the development of asthma/allergy, we prospectively evaluated the temporal associations between the occurrences of wheezing and being overweight in the first five years of life. METHODS: Data from 224 children in the COAST (Childhood Origins of Asthma) project who had complete data on wheezing and overweight status between birth and age 5 years were analyzed. RESULTS: Proportionately more children who ever wheezed in the first three years of life were overweight at age 5 years compared to those who never wheezed (30.1% vs. 18.2%, OR=2.1, p=0.03). Birth weight > 85th percentile (OR=3.2, p=0.006) and rapid weight-gain at 0-6 months (O.R.=4.4, p=0.003) were also associated with higher risk of being overweight at age 5 years. Exclusive breastfeeding > 2 months was not protective for being overweight at age 5 years (O.R.=0.97, p=0.93). Significant risk factors for wheezing during the 5th year of life included wheezing in the first three years (O.R.=9.4, p<0.0001) and exclusive breastfeeding > 2 months (O.R.=2.8, p=0.03). Children whose mothers had current asthma were more likely to wheeze during the 5th year of life (O.R.=2.0, p=0.07).
329
J ALLERGY CLIN IMMUNOL FEBRUARY 2006
CONCLUSIONS: In the COAST cohort of children, wheezing during the first three years of life was associated with a greater risk of being overweight at age 5 years. Exclusive breastfeeding increased the risk of wheezing during the 5th year of life. Funding: NIH, USDA, American lung association The Relationship of Breastfeeding, Overweight and Asthma in School Children X. Mai1, A. L. Kozyrskyj1,2, E. A. C. Sellers2, J. J. Liem2, A. B. Becker2; 1Faculty of Pharmacy, University of Manitoba, Winnipeg, MB, CANADA, 2Pediatrics & Child Health, University of Manitoba, Winnipeg, MB, CANADA. RATIONALE: Breastfeeding may be a protective factor for childhood overweight and asthma. However, few studies have investigated the interactive relationship between breastfeeding and overweight in the development of asthma. METHODS: A nested case-control study of a 1995 Manitoba birth cohort comprised 252 children with pediatric allergist-diagnosed asthma and 469 controls at 8 - 10 years of age (mean age of 9 years). Information on exclusive breastfeeding was obtained by questionnaire. Overweight was defined as body mass index 85th percentile for age and gender. RESULTS: 26.8% of the children exclusively breastfed 12 weeks were overweight at age 9 years compared with 40.1% of the children exclusively breastfed < 12 weeks (p < 0.001). Exclusive breastfeeding 12 weeks was inversely associated with asthma (crude OR 0.73, 95% CI 0.53-1.00). A similar association was obtained after controlling for overweight (adjusted OR 0.76, 95%CI 0.55-1.05). Children who were exclusively breastfed < 12 weeks and were overweight at age 9 years had the highest rate of asthma, while, children who were exclusively breastfed 12 weeks and were not overweight had the lowest rate (43.8% vs. 31.3%, p = 0.02). Children who were breastfed < 12 weeks but were not overweight, and children who were breastfed 12 weeks but were overweight had the intermediate rate of asthma (36.5% and 35.3%). CONCLUSIONS: Breastfeeding is inversely associated with asthma, and the protective effect is modified by overweight. Breastfeeding for at least 12 weeks and the absence of being overweight appear to play synergistic role in asthma protection. Funding: Canadian Institute of Health Research
330
Elevated BMI at Age 3 Years Predicts Wheeze at Age 5, Independent of Wheeze Earlier in Life M. S. Perzanowski, I. F. Goldstein, R. G. Barr, B. Sheares, G. L. Chew, R. S. Garfinkel, C. P. Pulgarin, R. M. Whyatt, F. P. Perera, R. L. Miller; Columbia Children’s Center for Environmental Health (CCCEH), Columbia University, New York, NY. RATIONALE: Recent cross-sectional studies have shown an association between obesity and pediatric asthma, but few birth cohorts have assessed this relationship prospectively. METHODS: As part of an ongoing birth cohort study in New York City, children of Dominican and African-American mothers underwent height and weight measurement at age 24 (n= 288) and 36 (n=253) months, plus detailed questionnaires from birth to 60 months. Body mass index (BMI) percentile for age was calculated using the CDC growth charts for age. Wheeze was defined as report of wheeze in the last 12 months. Logistic regression models included gender, maternal asthma, ethnicity and environmental tobacco smoke exposure. RESULTS: At ages 24 and 36 months, 39% and 43% of the children had a BMI >85 percentile for age. At ages 24, 36 and 60 months, wheeze in the last 12 months was reported for 25%, 16% and 28% of children, respectively. For the 121 children in the cohort who had reached age 5 years, BMI >85% at age 36 months predicted wheeze at 60 months (adjusted OR 2.6 [1.03-6.6]) overall and after adjustment for wheeze from
331
SATURDAY
Therapeutic Administration of Allergen-specific CD4+CD25+ Regulatory T Cells Suppresses Chronic Allergen-induced Airway Inflammation and Remodelling in a Murine Model J. Kearley, D. S. Robinson, C. M. Lloyd; Leukocyte Biology Section, NHLI, Faculty of Medicine, Imperial College, London, UNITED KINGDOM. RATIONALE: CD4+CD25+ regulatory T cells can inhibit excessive immune responses in vivo. We have previously demonstrated that prophylactic administration of allergen-specific CD4+CD25+ regulatory cells suppressed acute allergen-induced airway inflammation in a murine model. In the present study, we sought to determine the effect of therapeutic administration of regulatory T cells in a model of chronic allergeninduced airway disease METHODS: Mice were sensitised to ovalbumin and challenged with this allergen through the airways for 5 consecutive days. After this acute challenge phase, allergen-specific CD4+CD25+ cells were administered, and airway challenges were continued to induce chronic inflammation and airway remodelling. RESULTS: Administration of CD4+CD25+ cells decreased lung eosinophilia, (from 5.1±0.7 to 2.6±0.5 X103 cells/mg) and reduced expression of IL-5, IL-13 and TGF-. Mucus production was also decreased but airway hyperreactivity was unaffected. Suppression of inflammation was associated with a significant increase in lung IL-10 expression (from 802±83 to 1024±55 pg/ml;p<0.05). We also examined airway remodelling and found that peribronchiolar collagen deposition was reduced by 25% in mice that received CD4+CD25+ cells, potentially due to decreased lung TGF- levels as this cytokine has been implicated in remodelling. CONCLUSIONS: For the first time we have demonstrated a therapeutic role for CD4+CD25+ regulatory T cells in chronic allergen-induced airway disease. Therefore, enhancing the activity of these regulatory cells could be of potential benefit in the treatment of human asthma. Funding: Wellcome Trust
328
Occurrence of Wheezing and Being Overweight in the First Five Years of Life in a Birth Cohort at High Risk for the Development of Asthma/Allergy Z. Zhang1, H. Lai1, M. Evans2, R. Gangnon2, E. Anderson3, J. Gern3, R. Lemanske4; 1Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, 2Biostatistics and medical informatics, University of Wisconsin-Madison, Madison, WI, 3Pediatrics, University of Wisconsin-Madison, Madison, WI, 4Pediatrics, Medicine, University of Wisconsin-Madison, Madison, WI. RATIONALE: The association between asthma and obesity is unclear in young children. Therefore, in a birth cohort genetically at increased risk for the development of asthma/allergy, we prospectively evaluated the temporal associations between the occurrences of wheezing and being overweight in the first five years of life. METHODS: Data from 224 children in the COAST (Childhood Origins of Asthma) project who had complete data on wheezing and overweight status between birth and age 5 years were analyzed. RESULTS: Proportionately more children who ever wheezed in the first three years of life were overweight at age 5 years compared to those who never wheezed (30.1% vs. 18.2%, OR=2.1, p=0.03). Birth weight > 85th percentile (OR=3.2, p=0.006) and rapid weight-gain at 0-6 months (O.R.=4.4, p=0.003) were also associated with higher risk of being overweight at age 5 years. Exclusive breastfeeding > 2 months was not protective for being overweight at age 5 years (O.R.=0.97, p=0.93). Significant risk factors for wheezing during the 5th year of life included wheezing in the first three years (O.R.=9.4, p<0.0001) and exclusive breastfeeding > 2 months (O.R.=2.8, p=0.03). Children whose mothers had current asthma were more likely to wheeze during the 5th year of life (O.R.=2.0, p=0.07).
329
J ALLERGY CLIN IMMUNOL FEBRUARY 2006
CONCLUSIONS: In the COAST cohort of children, wheezing during the first three years of life was associated with a greater risk of being overweight at age 5 years. Exclusive breastfeeding increased the risk of wheezing during the 5th year of life. Funding: NIH, USDA, American lung association The Relationship of Breastfeeding, Overweight and Asthma in School Children X. Mai1, A. L. Kozyrskyj1,2, E. A. C. Sellers2, J. J. Liem2, A. B. Becker2; 1Faculty of Pharmacy, University of Manitoba, Winnipeg, MB, CANADA, 2Pediatrics & Child Health, University of Manitoba, Winnipeg, MB, CANADA. RATIONALE: Breastfeeding may be a protective factor for childhood overweight and asthma. However, few studies have investigated the interactive relationship between breastfeeding and overweight in the development of asthma. METHODS: A nested case-control study of a 1995 Manitoba birth cohort comprised 252 children with pediatric allergist-diagnosed asthma and 469 controls at 8 - 10 years of age (mean age of 9 years). Information on exclusive breastfeeding was obtained by questionnaire. Overweight was defined as body mass index 85th percentile for age and gender. RESULTS: 26.8% of the children exclusively breastfed 12 weeks were overweight at age 9 years compared with 40.1% of the children exclusively breastfed < 12 weeks (p < 0.001). Exclusive breastfeeding 12 weeks was inversely associated with asthma (crude OR 0.73, 95% CI 0.53-1.00). A similar association was obtained after controlling for overweight (adjusted OR 0.76, 95%CI 0.55-1.05). Children who were exclusively breastfed < 12 weeks and were overweight at age 9 years had the highest rate of asthma, while, children who were exclusively breastfed 12 weeks and were not overweight had the lowest rate (43.8% vs. 31.3%, p = 0.02). Children who were breastfed < 12 weeks but were not overweight, and children who were breastfed 12 weeks but were overweight had the intermediate rate of asthma (36.5% and 35.3%). CONCLUSIONS: Breastfeeding is inversely associated with asthma, and the protective effect is modified by overweight. Breastfeeding for at least 12 weeks and the absence of being overweight appear to play synergistic role in asthma protection. Funding: Canadian Institute of Health Research
330
Elevated BMI at Age 3 Years Predicts Wheeze at Age 5, Independent of Wheeze Earlier in Life M. S. Perzanowski, I. F. Goldstein, R. G. Barr, B. Sheares, G. L. Chew, R. S. Garfinkel, C. P. Pulgarin, R. M. Whyatt, F. P. Perera, R. L. Miller; Columbia Children’s Center for Environmental Health (CCCEH), Columbia University, New York, NY. RATIONALE: Recent cross-sectional studies have shown an association between obesity and pediatric asthma, but few birth cohorts have assessed this relationship prospectively. METHODS: As part of an ongoing birth cohort study in New York City, children of Dominican and African-American mothers underwent height and weight measurement at age 24 (n= 288) and 36 (n=253) months, plus detailed questionnaires from birth to 60 months. Body mass index (BMI) percentile for age was calculated using the CDC growth charts for age. Wheeze was defined as report of wheeze in the last 12 months. Logistic regression models included gender, maternal asthma, ethnicity and environmental tobacco smoke exposure. RESULTS: At ages 24 and 36 months, 39% and 43% of the children had a BMI >85 percentile for age. At ages 24, 36 and 60 months, wheeze in the last 12 months was reported for 25%, 16% and 28% of children, respectively. For the 121 children in the cohort who had reached age 5 years, BMI >85% at age 36 months predicted wheeze at 60 months (adjusted OR 2.6 [1.03-6.6]) overall and after adjustment for wheeze from
331