The long term goal of this project is to characterize the immune status of infants at birth and to determine directly in human infants the susceptibility factors and antecedent pathway(s) that lead to eczema in the first two years of life. Early life eczema is a major risk factor for asthma. We will focus on clarifying the relative roles and identifying the participants of the innate and the adaptive immune system in the development of eczema. Preliminary data lead us to discard the current concept that infants at birth have a Th2 """"""""default"""""""" status in favor of a more general state of limited cytokine production in cord blood cells. The hypothetical scenario proposed and tested here is that the immune system at birth has a limited capacity for producing many immune cytokines compared to the adult. This limited capacity may be a result of T cell naivete, immune cell immaturity or active suppression possibly via IL-10 (or some combination of these events). Eczema (we hypothesize) develops in children via complex gene by environment interactions, with an important role for a delayed capacity to produce IFN-gamma that provides a window of opportunity for allergen sensitization. We predict that with full maturation of the response, new sensitization will be reduced but sensitization that has occurred during this window will then be facilitated by LPS. The nature of the fully matured response will be influenced by gene variants in CD14, IL-10 and IL-13.
Three specific aims are proposed. 1. Establish the main cellular mechanisms for the limited capacity of cytokine production of the immune cells of human infants at birth and assess the role of IL-10 in inducing and/or maintaining that status. 2. Test the hypothesis that the development of the response to pattern recognition molecules like LPS is delayed in infants who develop eczema and the delay permits enhanced allergen sensitization. 3. Determine the influence of IL-10, IL-13 and CD14 gene polymorphisms on the mechanism of overcoming the decreased capacity to produce IFN-gamma and on allergic sensitization. This project is a cell biology oriented project that focuses on dissecting immune development in early life in both normal infants and infants at risk for asthma and in doing so interfaces with each of the other projects mainly through providing a biologic context for testing in vivo the impact of genetic polymorphisms and the molecular mechanisms identified.
