Cytokine Profiles In Asthma And Allergic Diseases

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Asthma is an inflammatory disease of the airways. After allergen exposure, IgE bearing cells, such as mast cells and basophils, are first activated. Later, T lymphocytes enter the airways, are activated by allergen and play a key role in regulating this inflammatory response through the elaboration of cytokines such as IL-4, IL-5 and IFN-gamma. This project seeks to examine the cytokine and mediator profiles of mast cell, basophil and T cell subpopulations that may be involved in the generation of inflammation in asthmatic airways. Tryptase is a pro-inflammatory protease mediator produced principally by mast cells. We examined peripheral blood to determine if other cell populations might also be capable of tryptase expression. Tryptase expression in peripheral blood leukocytes was limited to the basophil lineage. Surprisingly, basophil tryptase expression varied by more than 100 fold between individuals and in the high tryptase expressing individuals was comparable to that of tissue mast cells. Basophil tryptase expression did not correlate with asthma or asthma severity. These results suggest that tryptase represents an additional mediator through which basophils may contribute to allergic inflammation. When activated by allergen cross-linking of IgE, basophils play an effector role by their secretion of mediators such as histamine and IL-4. To examine a potential role for basophils as a non-IgE dependent source of such mediators, we examined the effect of diesel exhaust particles (DEP) on basophils. DEP is a component of air pollution that acts as a Th2-polarizing adjuvant in vivo. After DEP exposure in vitro, basophils produced IL-4 and released histamine in a non-IgE dependent manner. DEP showed no synergy with allergen activation. Basophils decrease expression of FceRI upon treatment with the investigational allergy drug anti-IgE/omalizulab. We examined the kinetics and pharmacodynamics of this decrease by following FceRI expression during a clinical trial. Omalizumab caused a 70% decrease in FceRI expression that was maximal by 14 days after the study drug and was sustained 28 days after a single dose.