Occupational exposure to certain
acid anhydrides, including
trimellitic anhydride (TMA),
maleic anhydride (MA),
phthalic anhydride (PA),
hexahydrophthalic anhydride (HHPA) and
methyltetrahydrophthalic anhydride (
MTHPA), has been associated with the development of respiratory
allergy or
asthma. There is considerable debate about the mechanisms through which such chemicals may cause respiratory sensitization, particularly concerning a universal requirement for specific
IgE antibody. Despite the controversy regarding an obligatory role for
IgE, there is a growing consensus that chemical
respiratory hypersensitivity is associated with the selective development of T lymphocytes with a type 2 (Th2) phenotype. In the current investigations we have characterized in mice the nature of immune responses provoked by prolonged topical exposure to five
acid anhydrides. Under application conditions where similar overall immunogenicity was achieved, we have compared
cytokine responses induced by PA, MA, HHPA and
MTHPA with those provoked by concurrent exposure to TMA or to the reference contact
allergen 2, 4-dinitrochlorobenzene (
DNCB). Lymph node cells (LNC) draining the site of topical exposure to
DNCB invariably expressed high levels of the type 1
cytokines interferon-gamma (IFN-gamma) and
interleukin-12 (IL-12), but only low levels of the type 2
cytokines interleukin-4 (IL-4) and
interleukin-10 (IL-10). In each experiment, TMA-activated LNC displayed the converse, type 2, phenotype of
cytokine production. The other
acid anhydrides in each case provoked a type 2
cytokine secretion profile, with comparable
IL-10 expression but somewhat less vigorous
IL-4 production compared with that observed following exposure to the reference respiratory
allergen TMA. In every experiment relatively low levels of IFN-gamma and
IL-12 were elaborated by
acid anhydride-activated LNC, with the exception of PA-stimulated LNC that displayed increased amounts of
IL-12 in comparison with other
acid anhydrides. Thus, prolonged topical exposure of mice to five different
acid anhydrides in each case resulted in the development of a predominantly Th2-type
cytokine secretion phenotype, consistent with the ability of these materials to provoke
asthma and respiratory
allergy through a type 2 (possibly
IgE-mediated) mechanism. Taken together with the results of previous investigations with a wider range of chemical
allergens, these data suggest that induced
cytokine secretion patterns or 'fingerprints' allow discrimination between contact and respiratory
allergens and consequently represent a suitable approach to prospective evaluation of respiratory sensitization hazard.