ICI 2016_Abstract Book

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International Congress of Immunology 2016 Abstract Book
3224
Small airway-on-a-chip: a novel microphysiological system
to study human lung inflammation in vitro
Hajipouran Benam, K.1, Villenave, R.1, Lucchesi, C.1, Hubeau, C. 2,
Varone, A.1, Ferrante, T.C.1, Weaver, J.C.1, Bahinski, A.1, Hamilton,
G.A.1 , Ingber, D.E.1
1Harvard University, Wyss Institute for Biologically Inspired
Engineering, Boston, United States, 2Pfizer Inc, Cambridge, United
States
Development of new therapeutics for lung inflammatory and
infectious diseases, such as chronic obstructive pulmonary
disease (COPD) and respiratory viral infections, which are
associated with significant morbidity and mortality, has been
hindered by challenges to study organ-level complexities of
lung inflammation in vitro.
Here, we applied a microengineering technological approach
known as ‘organ-on-chip’ to create a human lung small
airway-on-a-chip that supports full differentiation of a
pseudostratified mucociliary bronchiolar epithelium composed
of cells isolated from normal or diseased donors underlined by
a functional microvascular endothelium, which experiences
continuous blood-like fluid flow. Airway chips lined with well-
differentiated COPD epithelia recapitulated features of the
disease including selective cytokine hypersecretion, increased
neutrophil recruitment, and clinical exacerbations by exposure
to pathogen-mimetic compounds. Using this robust in vitro
method for modeling human lung inflammatory disorders, it
was possible to detect synergistic effects of lung endothelium
and epithelium on cytokine secretion, identify new biomarkers
of disease exacerbation, and measure responses to anti-
inflammatory compounds that inhibit cytokine-induced
recruitment of circulating neutrophils under physiological
vascular shear. Importantly, the ‘synthetic biology’ nature of
our tissue engineering approach allowed us to independently
control and vary key system parameters that influence organ-
level lung mucosal inflammation.
Thus, the human small airway-on-a-chip offers a powerful
complement to animal models for both analyzing human
pathophysiology and carrying out preclinical drug evaluation.
1127
The GARD assay for potency assessment of skin sensitizing
chemicals
Forreryd, A., Zeller, K., Lindberg, T., Albrekt, A.-S., Chawade, A.,
Lindstedt, M.
Lund University, Department of Immunotechnology, Medicon
Village, Lund, Sweden
Allergic Contact Dermatitis (ACD) is caused by adverse immune
reactions in the skin and develops upon repeated exposure to
chemical haptens. To reduce exposure, efforts are being made
to develop assays for identification of such have
previously developed an assay (GARD) based on a biomarker
signature of 200 mRNAs, identified by transcriptomics of a
myeloid cell-line stimulated with reference chemicals (n=38).
GARD classifies unknown compounds binary, as either skin
sensitizers or non-sensitizers, with an accuracy estimated to
89% (on 39 test chemicals). The aim of the current study is to
broaden applicability domain of GARD to include also potency
assessments.
We utilized the versatility of analyzing complete transcriptomes
of cells, divided reference samples into potency groups, (CLP-
labeling: no cat, weak=1B, strong=1A) and identified an
alternative signature for prediction of sensitizing potency, using
Random Forest (RF). To shed additional light into the molecular
mechanisms, we also performed a pathway analysis.
A signature comprising 30 genes was identified. The
performance of the signature was validated by cross-validation
and estimated to an accuracy of 85% (no cat), 83% (1A) and 79%
(1B). We also found a correlation between metabolic and cell-
cycle associated pathways and sensitizing potency.
Combining the original and new signature, we present a testing
strategy with an ability not only to identify sensitizing chemicals,
but rather to perform a more complete risk assessment.
Ongoing work focuses on expanding reference chemicals with
an additional 50 chemicals to improve predictive performance,
and to elucidate molecular mechanism involved in sensitization
potency.
1711
αHER2/CD3 bifunctional RNA engineered human T cells
specifically eliminate HER2+ gastric cancer
Luo, F., Qian, J., Yang, J., Deng, Y., Zheng, X., Liu, J., Chu, Y.
Fudan University, Shanghai, China
Genetically engineered T cells therapy is a promising strategy
in cancer immunotherapy. One successful strategy is chimeric
antigen receptor (CAR)-T cells therapy, but CARs-restricted on
cell surface and side effects of retrovirus are partial limitations
for CAR-T therapy. An alternative strategy is bispecific T cell
engager (BiTE), but the therapeutic potential of BiTEs is
still limited by the short half-life of antibodies, the lack of
endogenous effector T cells in patients with advanced cancer,
and severe adverse effects. In this study, we developed a novel
secretable human epidermal growth factor receptor 2 (HER2)-
targeting BiTE, αHER2/CD3. These αHER2/CD3 RNA engineered
human T cells persistently secreted αHER2/CD3 fusion proteins,
which were released to help engineered T cell to exhibit HER2-
specific activity, or redirect bystander T cells to HER2+ cancer
cells and even inhibit HER2+ cancer cells proliferation directly.
Additionally, HER2+ tumor-bearing mice treated with the
secretable αHER2/CD3 RNA engineered T cells got a significant
tumor growth inhibition and prolonged survival without
observed adverse effect. Thus, the secretable αHER2/CD3 T
cells have the characteristics of high potency, long term and
low toxicity, which might offer an attractive HER2-targeting
immunotherapy for solid tumors.