J ALLERGY CLIN IMMUNOL

VOLUME 129, NUMBER 2

Abstracts AB53

SATURDAY

201 Influence of Maternal Allergen Exposure in the Developmentof Allergic Airway Disease in the Offspring: Effects of Antigenand Timing of Exposure

J. Yang, K. Gabehart, K. A. Correll, A. George, M. L. Collins, E. W. Gel-

fand, A. Dakhama; National Jewish Health, Denver, CO.

RATIONALE: The role of maternal allergen exposure in the development

of allergic airway disease in the offspring is poorly understood. We

examined whether the development of allergic airway disease is deter-

mined during the peri-natal phase and is dependent on the type of allergen

and timing of maternal exposure.

METHODS: Female mice were sensitized or not to ovalbumin (OVA) or

house dust mite (HDM) before mating. At parturition, the offspring were

switched between sensitized mothers and na€ıve mothers. Sensitized

mothers were exposed to allergen during pregnancy or during lactation.

At 6 weeks of age, the offspring were sensitized and challenged with OVA

or HDM, followed by assessment of allergic airway responses.

RESULTS: Compared with mice breastfed by unexposed na€ıve mothers,

mice breastfed by mothers exposed to OVA during lactation, but not during

pregnancy, were protected against the development of allergic airway

disease. OVA-specific Th2 cytokine (IL-4, IL-5, IL-13, IL-10) production

was inhibited; serum levels of total IgE and OVA-specific IgG1 were

attenuated; airway inflammation was reduced; Treg numbers were in-

creased. By contrast, mice breastfed by mothers exposed to HDM during

pregnancy or lactation were not protected against the development of

allergic airway disease. No significant changes were detected in HDM-

specific Th2 cytokine production, specific IgG1 and total IgE levels, lung

inflammation and Treg numbers.

CONCLUSIONS: The susceptibility to develop allergic airway disease

may be determined by breastfeeding and is dependent on the type of

allergen and timing of maternal exposure.

202 Effect of Prenatal Cigarette Smoke Exposure on theDevelopment of Allergic Airway Disease in Mice

K. A. Correll, K. Gabehart, J. Yang, A. George, M. L. Collins, A. Da-

khama; National Jewish Health, Denver, CO.

RATIONALE: Parental cigarette smoke exposure (CS) is associated with

adverse respiratory health in children. However, the effects of prenatal

smoke exposure on allergic sensitization are not well defined. This study

was carried out in a mouse model to define the effects of passive prenatal

smoke exposure on the development of allergic airway disease.

METHODS: Pregnant female micewere exposed during pregnancy to CS

or filtered air and house dust mite (HDM) extract or saline. The offspring

were sensitized twice and intranasally challenged three times with HDM.

Airway inflammation and antibody responses were assessed in the

offspring after the last intranasal allergen challenge. The results were

compared between the different groups and related to maternal allergy and

prenatal CS exposure.

RESULTS: Compared to the offspring of non-allergic mothers, the

offspring of HDM-exposed allergic mothers developed increased airway

responses to HDM following prenatal CS exposure. By contrast, in absence

of maternal allergy, prenatal CS exposure was associated with reduced

allergic airway responses to HDM in the offspring. However, although

prenatal CS exposure was also associated with attenuated allergic airway

responses in the offspring of HDM-allergic mothers, the latter developed

enhanced allergic airway responses to HDM compared to the offspring of

non-allergic mothers in absence CS exposure.

CONCLUSIONS: These findings suggest that prenatal CS exposure may

increase the risk of allergic airway disease in the offspring of allergic

mothers. On the other hand, prenatal CS exposure may also attenuate the

development of allergic airway responses when the mothers are not

allergic.

203 The Single Nucleotide Polymorphism, CRTh2-6373G>A, isAssociated with Allergic Asthma and Increased Expressionof CRTh2

L. Cameron1, E. Campos Alberto1, E. MacLean1, C. Davidson1, D. Bren-

ner2, A. El-Sohemy2, H. Vliagoftis1; 1University of Alberta, Edmonton,

AB, CANADA, 2University of Toronto, Toronto, ON, CANADA.

RATIONALE: CRTh2 (chemoattractant-receptor homologous molecule

expressed on Th2 cells) is expressed by Th2 cells and other cells involved

in allergic inflammation. Single nucleotide polymorphisms in CRTh2(rs11571288, 545659, 634681) have been associated with phenotypes of

allergic disease in ethnically distinct populations, but association of other

CRTh2 SNPs with allergic disorders has not been observed.

METHODS: CRTh2-6373G>A (rs533116) was genotyped in a large eth-

nically diverse population (n51282). The proportion of circulating periph-

eral blood cells expressing CRTh2was determined in subjects with allergic

airways disease and controls as well as in vitro differentiated Th2 cells.

Receptor function was assessed by responsiveness of Th2 cells to the

CRTh2-specific agonist 13,14-dihydro-15-keto-PGD2 (DK-PGD2) and in-

tracellular staining for IL-4 and IL-13.

RESULTS: CRTh2-6373G>A was associated with allergic asthma in

Caucasians (OR 2.67 [1.09 - 6.55]) and expression of CRTh2 was higher

in subjects with allergic airways disease compared to controls. Amongst

allergic individuals, -6373G>A was associated with significantly more

eosinophils and higher expression of CRTh2 by both CD4+ T cells and eo-

sinophils. In vitro, the A allele coincided with a higher percentage of CD4+

T cells expressing CRTh2 under Th2 differentiating conditions and the per-

centage of IL-4 and IL-13 positive cells following DK-PGD2 stimulation.

CONCLUSIONS: These findings show an association between CRTh2-

6373G>A and allergic asthma and suggest this may be mediated by higher

numbers of circulating eosinophils and elevated expression of CRTh2,

leading to heightened responsiveness to PGD2 and production of Th2

cytokines.

204 Transglutaminase 2 Knock-out Protects Against AirwayInflammation And Tissue Remodeling In Ova-specificAllergic Asthma In Mice

G. Hong1, B. Park1, J. Park2, S. Kim3, J. Ro1; 1sungkyunkwan university

of medicine, suwon, REPUBLIC OF KOREA, 2bDepartment of Internal

Medicine, Yonsei University College of Medicine, Division of Allergy

and Immunology, seoul, REPUBLIC OF KOREA, 3bCancer Cell and Mo-

lecular Biology Branch, Division of Cancer Biology, Research Institute,

National Cancer Center, Goyang, REPUBLIC OF KOREA.

Transglutaminase 2 (TGase 2) is over-expressed in a variety of inflamma-

tory diseases including allergic asthma. TGase 2 inhibitors block TGase 2

over-expression. This study aimed to investigate whether TGase 2-/- pro-

tects against airway inflammation and tissue remodeling associated with

OVA-induced allergic asthma in mice. C57BL/6 or TGase 2-/- mice were

sensitized and challengedwith OVA to induce asthma. OVA-specific serum

IgE and leukotrienes (LTs) levels were measured by ELISA, and the re-

cruitment of inflammatory cells into BAL fluid or lung tissues was stained

with Diff-Quik and H&E, goblet cell hyperplasia by PAS. AHRwas deter-

mined in awhole body plethysmographic chamber. Expression of TGase 2,

eosinophil major basic protein (EMBP), VCAM-1, Muc5ac, PLA2 protein

was measured by Western blotting while mRNA levels of Muc5ac, cyto-

kines, MMPs, and TIMPs were quantified by RT-PCR. NF-B levels were

evaluated by EMSA. TGase 2-/- protected against OVA-specific IgE pro-

duction, the recruitment of total inflammatory cells, macrophages, neutro-

phils, lymphocytes and eosinophils in BAL fluid. TGase 2-/- reduced the

number of goblet cells, AHR; expression of EMBP, Muc5ac, VCAM-1,

CD40/CD40L; mRNA levels of several cytokines and chemokines, NF-B

activity, PLA2 expression, and LTs levels in BAL cells and lung tissues.

Expression of TIMP1/2 was recovered with TGase 2-/-.

Our data suggest that TGase 2-/- protects against the expression of numer-

ous molecules associated with airway inflammation and remodeling by

suppressing NF-B activation, and that TGase 2 may be a potential thera-

peutic target for treating allergic asthma.