Project: Research project

Project Details


Over the past two decades, information concerning the role of eosinophils
in human disease has dramatically increased. The evidence now available
suggests that elaboration of inflammatory mediators, in particular toxic
cationic proteins, by eosinophils plays a critical role in the
pathophysiology of diseases. We wish to investigate the mechanisms of
eosinophil degranulation in human diseases by studying the mechanism of
allergic inflammation, which is one of the most common and established
manifestations of eosinophil degranulation in vivo. We will establish two
in vitro models and one in vivo model, and determine factor(s) and cell(s)
which play a major role in the induction of eosinophil degranulation.
First, a model of lgE-dependent eosinophil degranulation in vitro will be
established by co-incubation of eosinophils with anti-lgE antibody
stimulated peripheral blood mononuclear cells (PBMC). Preliminary results
indicate that lgE-mediated eosinophil degranulation requires accessory
cells (namely PBMC), suggesting the necessity of soluble factor(s) and/or
cellular adhesion for eosinophil activation. Therefore, the production of
cytokines and lipid mediators and the requirement for specific cell types,
cellular contact, and cytokines will be analyzed. Second, a model of
allergen-dependent eosinophil degranulation in vitro will be established
and analyzed by co-incubation of eosinophils with ragweed antigen, sera
from patients with ragweed-sensitive asthma, and PBMC. Although this model
is similar to IgE-dependent eosinophil degranulation as described above,
it is different in that this model does not require cell-bound lgE and
that not only lgE but also IgG and/or lgA may participate. Third, the
modulators of eosinophil activation in vitro will be identified and their
interaction will be investigated by studying the effects of cytokines,
extracellular matrix proteins, adhesion molecules, and immobilized
immunoglobulins. Here, we wish to utilized the insights of goal l and 2
and to reconstitute the system using purified molecules. Fourth, a model
of murine allergic eosinophilic peritonitis will be established and
investigated to determine and characterize critical factor(s) for
eosinophil degranulation in vivo. This project will integrate the above 4
goals to investigate the mechanism of eosinophil degranulation in human
diseases. Goal l and 2 are designed to understand and mimic the in vivo
environment using anti-IgE-induced eosinophil degranulation (goal l) and
allergen-induced eosinophil degranulation (goal 2). The physiologic
factors for initiation and modulation of eosinophil degranulation in vitro
will be identified and reconstituted to mimic anti-lgE- and allergen-
induced eosinophil degranulation using purified molecules (goal 3). The
murine in vivo model of eosinophilic peritonitis will be analyzed as an in
vivo system based on and compared to the in vitro experiments (goal 4).
The achievement of these goals may results in better understanding of the
mechanism of eosinophil degranulation in diseases and provide new
approaches in the treatment of patients with allergic and inflammatory
StatusNot started


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