Mechanism for maternal transfer of asthma risk

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DESCRIPTION (provided by applicant): Asthma is a significant worldwide health issue. Its etiology is related to the skewing of the Th1/Th2 axis toward Th2. GMCSF and interleukins (IL) 4 and 13 polarize this axis toward Th2. Dendritic cells (DC's) also play a prominent role in asthma. They are potent antigen presenting cells and are uniquely able to prime naive T- cells. Depending on the microenvironment and co-stimulators, DC's can polarize the Th1/Th2 axis in either direction. Some studies also indicate that DC's in asthmatic lungs have aberrant function. Epidemiologic studies have shown that asthma risk in offspring is preferentially transferred maternally. The mechanism is unknown, but may be related to in utero milieu. We postulate that the transplacental passage of GMCSF and IL-4 /13 alters the phenotype of embryonic dendritic cells increasing susceptibility to asthma in offspring. Using a mouse model, this hypothesis will be tested in 3 stages. First, we will determine if GMCSF and IL- 4/13 cross the placenta using cytokine receptor knockout mice. Second, DC characteristics will be compared between the offspring of asthmatic mothers versus non-asthmatic mothers using T-cell proliferation studies. Third, dendritic cell gene expression patterns between these two groups will be compared using gene arrays