Description: This project will determine
the mechanisms by which environmental tobacco smoke (ETS) modifies
defined phases of the human allergic response in children. Epidemiological
data suggests that parental smoking is a major risk factor for
allergic sensitization. We will determine the in vivo
biological effects of ETS on the induction and enhancement of
the specific allergic airway response under clinically relevant
conditions and dissect the cellular and molecular mechanisms
involved. We will use inhalation challenges in adults and children
to define directly how ETS exposure either induces de novo and/or
exacerbates ongoing allergic inflammation in the human airway.
These human studies will be complemented with animal studies
which will answer key genetic and developmental issues that can
not be addressed as rigorously in humans. Aim #1 will determine
the mechanisms by which ETS alters the in vivo IgE antibody response
in the human upper airway. We will determine if ETS directly
alters IgE production from mucosal B cells (by inducing germ
line transcription or isotype switching) or if it acts indirectly
by modifying the airway mucosal environment (by inducing cytokine
production or cell surface receptors). Aim #2 will determine
if exposure to ETS alters IgE-independent inflammatory responses
in the human upper airway by increasing chemokine production
(MCP-1, MCP-3, MIP-1, RANTES and eotaxin) or their ability of
increasing cellular infiltration and activation. Both of these
aims will rely on ETS inhalation challenge studies on groups
of allergic non-asthmatic children and adults. Aim #3 will test
the hypothesis that the in vivo allergic antibody response
due to chronic exposure to ETS is controlled by genetic background
and age by using an established animal model. Our work will provide
new insights into environmental effects of childhood allergic
disease by performing direct experimentation to answer questions
previously studied by solely epidemiological means.
