Much attention centers on the contributions of Th1 vs Th2 biased cytokine production in respiratory hypersensitivity. Chemokines are a subfamily of cytokines with pivotal roles in leukocyte trafficking and ontogeny. We recently discovered important roles for CXCR-3 binding chemokines in modulating ongoing allergen specific immunity, reinforcing the proclivity of healthy, non-atopic humans towards protective (rather than Th2 dominated) immune responses to allergen. Here, we propose to focus on the chemokine responses which are disregulated in allergic respiratory tract disease and identify those associated with protective immunity that is thought to underlie clinical tolerance in non-atopic controls. The regulatory mechanisms that control differential expression of Th1 vs. Th2 biased chemokine production in individuals with ongoing immediate hypersensitivity vs. those with clinical tolerance to the same seasonal environmental allergens will be determined as will the role played by differential chemokine reception expression and in vivo modulation in response to seasonal environmental Ag exposure.

Global hypothesis: Altered allergen-specific chemokine production, and chemokine receptor expression, are hallmarks of human allergic respiratory tract disease that are tightly integrated with the Th1/Th2 balance seen upon allergen re-exposure in those exhibiting clinical tolerance vs. hypersensitivity.

Allergic and healthy individuals exhibit differential allergen-specific chemokine production and responsiveness among immune cells.

Utilizing the following,

• 40 healthy participants (control)
• 40 allergic participants with mild allergic rhinitis during the grass pollen season but no evidence of asthma
• 40 allergic participants with mild intermittent asthma AND mild allergic rhinitis during the grass pollen season, we will:

1. Determine cross sectionally and longitudinally, the extent to which differential chemokine production in the CXCR3 and CCR4 families is a hallmark of atopic vs. healthy controls restricted to the allergen-specific component of the immune response. Using short term primary culture systems, immunocytochemistry, and sensitive ELISAs for allergen-driven chemokine protein expression that we developed, we will investigate the in vivo regulation of CXCR3 and CCR4 chemokine families. We will identify differences in chemokine expression and the mechanisms controlling their regulation, the impact of natural in vivo allergen re-exposure, determine the extent to which these are restricted to the allergen-specific component of the response and investigate the relationship between Ag-driven cytokine synthesis and chemokine production in populations with well established hypersensitivity vs. clinical tolerance.
   
   
2. Determine the functional significance of differential CD4T cell chemokine and receptor expression or function in recall responses and identify the mechanisms underlying this difference. Pursuing the striking capacity that we discovered of CXCR3 ligands to selectively enhance protective recall responses of healthy individuals to environmental allergens and our very recent finding of the hypo-responsiveness of allergics to this pathway, we will investigate the mechanisms through which protective vs. Th2 biased immune responses to allergens impact on maintenance of ongoing clinical tolerance vs. hypersensitivity.

• HayGlass publications on PubMed