Perinatal Antigen Exposure and Allergic Asthma

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The overall goal of this project is to determine the impact of perinatal antigen exposure on the development of allergic airway inflammation in a murine model of asthma. It is evident from epidemiological studies that the risk for childhood asthma is increased by having a positive family history of asthma. In particular, allergic sensitization of the newborn is closely linked to maternal but not to paternal allergies. Therefore, we propose that the timing and route of antigen exposure in perinatal life (e.g. transplacental, postnatal oral via breastmilk, or postnatal inhaled) have life-long influences on immune responsiveness that may include heightened sensitivity or tolerance. However, the cells responsible and the mechanisms by which they dictate the functional commitment of the neonate to airway sensitization or tolerance remain to be identified. We will explore how perinatal exposure to the model protein antigen, ovalbumin (OVA), affects development of T- and B cell immune responsiveness. In particular, since it is known that there are ordered waves of T cell development during gestation, with those bearing T cell receptors for antigen (TCR) containing gamma and delta chains (TCRgammadelta cells) appearing first, we will determine how the presence or absence of these cells affects the quantity and quality of the subsequent anti-OVA response. The consequences of perinatal exposure to OVA will be assessed in mice that have reached 6-8 wk of age by comparing the numbers and functional properties of antigen-specific CD4+ TCRalphabeta cells and B cells during immunization (systemic immunity) and aerosol challenge (airway inflammatory response). Thus, we specifically propose to: AIM 1. Determine the impact of perinatal exposure to OVA of parental versus environmental origin on the development of immune responsiveness in offspring. AIM 2. Determine the ability of maternal (or paternal) immune responsiveness to OVA (sensitized vs. tolerant) to modulate immunity to homologous or heterologous antigen in their offspring. AIM 3. Identify populations of leukocytes educated during perinatal life that transfer sensitization or protection to nave mice.