Invoking the scientific principle that a hypothesis is put forward so we can prove it wrong, it is already past time to reassess one of the more widely accepted tenets of asthma pathogenesis-the" Th2 hypothesis." In its simplest form, the Th2 hypothesis for asthma argues that an augmented T helper type 2 (Th2) cell response, perhaps in concert with a downregulated T helper type 1 (Thl) response, orchestrates the airway hyperresponsiveness and chronic inflammation of asthma. Support for this possibility comes both from general evidence ofCD4+ T cell activation in asthma as well as specific evidence of increased production of Th2-type cytokines, especially interleukin-4 (IL-4) and IL-5, and decreased production of Thl-type cytokines, especially interferon-y (IFN-I'), in samples taken from atopic asthmatic subjects (1). Additional observations linking IL-4 to IgE synthesis, mast cell differentiation, and eosinophil recruitment, and IL-5 to eosinophil differentiation, recruitment, and activation further incriminated the Th2 system in asthma (and other allergic diseases). Similarly, evidence that IFN-I'can inhibit IgE-dependent responses further supported the possibility that downregulation ofT cell-derived IFN-I'could lead to disinhibition and consequent exacerbation of IgE-dependent disease (2, 3).

So what then are the problems with this apparently logical extension of neotraditional immunology to asthmatology? Perhaps the first slip of the foundation can be found in its origin: the dichotomy for CD4+ T helper cell responses is based primarily on behavior in murine, not human, research subjects. It is in mice that IL-2-producing T helper precursor (Thp) cells appear to pass through an intermediate ThO-like stage (with IL-2, IL-4, and perhaps IFN-I'production) and then into" polarized" Thl or Th2 cells: Thl cells selec-