Background: Atopic disease is associated with skewing of immune responses away from a TH1 toward a TH2 profile. Previous studies have implicated this cytokine imbalance in the development of disease. However, it is not known whether normalization of this imbalance is conversely associated with disease resolution.Objective: To further delineate the role of reduced TH1 and increased TH2 cytokine production in the pathogenesis of atopic disease and to determine whether disease resolution is associated with alteration of cytokine profiles, we investigated cytokine responses in a cohort of adult patients with asthma followed from childhood.Methods: A cohort of wheezy children and control subjects aged 7 to 10 years were recruited from 1964 to 1967. Subjects were reevaluated every 7 years to monitor the outcome of childhood asthma. At the 42-year follow-up, 89 subjects from this cohort were evaluated for mitogen and house dust mite (HDM)-induced TH1 (IFN-γ) and TH2 (IL-4, IL-5, and IL-13) cytokine responses. Cytokine responses were compared in patients with ongoing asthma, patients with resolved asthma, and control subjects.Results: Patients with severe ongoing asthma had significantly reduced HDM-induced IFN-γ production compared with that of control subjects and patients with resolved asthma. In contrast, HDM-induced IFN-γ production in patients with resolved asthma was equivalent to that seen in control subjects. Patients with ongoing and resolved asthma produced significantly higher levels of IL-5 in response to HDM compared with that seen in control subjects, with levels being equivalent in patients with active and resolved asthma. HDM-induced IL-13 production was significantly increased in the patients with resolved asthma when compared with that seen in the control subjects. PHA-induced cytokine responses did not parallel HDM-induced responses.Conclusion: Patients with persistent and severe atopic asthma have a reduced HDM-induced TH1 response, whereas those with resolved asthma do not. This suggests that reduced HDM-induced IFN-γ production might be an important factor contributing to ongoing severe asthma and that normalization of allergen-induced TH1 responses might be important for disease resolution. The finding that all subjects with a history of asthma displayed increased HDM-induced TH2 (IL-5 and IL-13) cytokine responses, irrespective of the presence or absence of asthma, suggests that increased TH2 responses reflect the presence of the atopic state per se rather than being specifically linked to asthma. (J Allergy Clin Immunol 2002;110:450-6.)