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International Congress of Immunology 2016
Abstract Book
of IL-6 and CCL2, which are further modulated by food matrix
components and may play a role in allergic reactions to fish via
inhalation. Supported by the Austrian Science Fund doctoral
programW1248-B1 and grants SFB 4608 and 4613.
716
The ORMDL3-ceramide axis may be a novel therapeutic
target for the control of allergic airway disease
Sturgill, J.
1
, Oyeniran, C.
2
, Conrad, D.
3
, Spiegel, S.
2
1
Virginia Commonwealth University, Family and Community
Health, Richmond, United States,
2
Virginia Commonwealth
University, Biochemistry, Richmond, United States,
3
Virginia
Commonwealth University, Microbiology and Immunology,
Richmond, United States
Asthma, defined as a chronic inflammatory condition
characterized by episodic shortness of breath with expiratory
wheezing and cough, is a serious health concern. The WHO
estimates that asthma affects more than 230 million people
worldwide. There is a strong genetic component to asthma and
numerous genome-wide association studies have identified
ORM (yeast)-like protein isoform 3 (ORMDL3) as an asthma
associated gene. Surprisingly however, the mechanism by
which ORMDL3 contributes to asthma pathogenesis is not
well understood. The yeast ortholog of ORMDL3 is a negative
regulator of serine palmitoyltransferase (SPT), the rate
limiting step in de novo ceramide synthesis, yet elevations of
ceramide rather than its reduction have been linked to lung
inflammation. Thus, we examined the role of ORMDL3 in asthma
immunopathology. Consistent with its role in yeast, we show
that decreasing expression of ORMDL3 in lung epithelial cells
and macrophages increases ceramide and conversely, modest
increases in ORMDL3 decrease ceramide levels. In a house dust
mite (HDM) mouse model of allergic airway disease, allergen
challenge induced expression of ORMDL3 and resulted in a
concomitant increase in lung ceramide. Intriguingly, the use
of specific drugs, which inhibit ceramide synthesis, prevented
HDM-induced airway hyperreactivity (AHR) and suppressed
airway inflammation. Nasal administration of the orally
available FDA approved prodrug FTY720/fingolimod reduced
both ORMDL3 expression and ceramide production while
mitigating airway inflammation, hyperreactivity, and mucus
hypersecretion in HDM challenged mice. Thus the ORMDL3
-ceramide pathway may be a novel therapeutic target for the
control of allergic asthma.
4544
Effect of CTLA4-Ig on steroid resistant asthma model
Kouyama, S.
1
, Yamaguchi, M.
1
, Ohtomo-Abe, A.
1
, Kamide, Y.
1
,
Hayashi, H.
1
, Watai, K.
1
, Mitsui, C.
1
, Sekiya, K.
1
, Tsuburai, T.
1
,
Fukutomi, Y.
1
, Taniguchi, M.
1
, Ohtomo, T.
2
, Kaminuma, O.
3
, Mori, A.
1
1
National Hospital Organization, Sagamihara National Hospital,
Clinical Research Center, Sagamihara, Japan,
2
National Hospital
Organization, Sagamihara National HospitalTokyo University of
Pharmacy and Life Science, Department of Pharmacotherapeutics,
Hachioji, Japan,
3
University of Yamanashi, The Center for Life
Science Research, Chuo, Japan
Rationale: To investigate the role of helper T (Th) cells in steroid
resistant (SR) asthma, steroid sensitive (SS) and SR Th clones
were selected
in vitro
, and adoptively transferred into unprimed
mice. Effect of CTLA4-Ig was analyzed both
in vitro
and
in vivo
.
Methods:
For
in vitro
evaluation, ovalbumin (OVA) reactive Th
clones were cultured with antigen presenting cells and OVA
in the presence of various concentrations of dexamethasone
(DEX). Proliferative responses of Th clones were measured by
3
H-thymidine incorporation. For
in vivo
assessments, unprimed
BALB/c mice were transferred with Th clones, challenged
with OVA, and administered with DEX subcutaneously.
Bronchoalveolar lavage fluid (BALF) was obtained 48 hr after
challenge, and the number of infiltrating cells was differentially
counted. CTLA4-Ig was administered through nasal inhalation
or venous injection.
Results:
SS and SR clones were selected based on the effect
of DEX on the proliferative responses of antigen-stimulated
Th clones. Airway infiltration of eosinophils and lymphocytes
of mice transferred with SS clones were effectively inhibited
by the administration of DEX. In contrast, those of mice
transferred with SR clones were not significantly inhibited by
DEX. Administration of CTLA4-Ig significantly suppressed the
proliferation of DEX-treated SR clones
in vitro
, and eosinophil
infiltration of SR asthma model transferred with SR clones
in
vivo
.
Conclusions:
Steroid sensitivity of Th clones assessed
in vitro
was consistent with that of adoptively transferred asthma model
assessed
in vivo
. Costimulatory signal mediated through CD28 is
crucial for the inductionof steroid resistanceboth
invitro
and
invivo
.
2066
Are house dust mites (HDM) potential carriers of bacteria
responsible for the induction of sensitisation to microbial
“allergens”?
Dzoro, S.
1
, Mittermann, I.
1
, Nehr, M.
2
, Hirschl, A.
2
, Wikberg, G.
3
,
Johansson, C.
4
, Lundeberg, L.
3
, Scheynius, A.
5
, Valenta, R.
1
1
Medical University of Vienna, Department of Pathophysiology
and Allergy Research, Vienna, Austria,
2
Medical University of
Vienna, Division of Clinical Microbiology, Clinical Institute of
Laboratory Medicine, Vienna, Austria,
3
Karolinska University
Hospital, Dermatology and Venereology Unit, Stockholm,
Sweden,
4
Karolinska Institute and Karolinska University Hospital,
Translational Immunology Unit, Department of Medicine, Solna,
Stockholm, Sweden,
5
Karolinska Institute and Karolinska University
Hospital, Translational Immunology Unit, Department of Medicine
Solna, Stockholm, Sweden
Introduction:
IgE reactivity to various
Staphylococcus aureus
and
Escherichia coli
antigens can be found in up to 25% of atopic
dermatitis (AD) patients. A genomic analysis recently described
S. aureus
and
E. coli
species as abundant bacteria within the
house dust mite (HDM) microbiome. We therefore investigated
the role of mites as potential carriers for IgE sensitisation to
microbial elements in AD patients.
Materials and methods:
Sera from 179 AD patients, was
analysed for IgE reactivity to a comprehensive panel of HDM
allergens by chip analysis, and to
S. aureus
and
E. coli
by
immunoblotting. Selected sera were additionally tested on the