title: Characterization in mice of the immunological properties of five allergenic acid anhydrides.
abstract: 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.
authors.affiliation: Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, UK. rebecca.dearman@CTL.zeneca.com
authors.forename: R J
authors.initials: RJ
authors.lastname: Dearman
authors.forename: E V
authors.initials: EV
authors.lastname: Warbrick
authors.forename: I R
authors.initials: IR
authors.lastname: Humphreys
authors.forename: I
authors.initials: I
authors.lastname: Kimber
mesh_terms: D000485:Allergens / Q000276:immunology* / Q000633:toxicity; D000812:Anhydrides / Q000276:immunology* / Q000633:toxicity; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004137:Dinitrochlorobenzene / Q000633:toxicity; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D010796:Phthalic Anhydrides / Q000633:toxicity
chemical_list: D000485:Allergens; D000812:Anhydrides; D016207:Cytokines; D004137:Dinitrochlorobenzene; D010796:Phthalic Anhydrides; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; C015559:trimellitic anhydride; D007371:Interferon-gamma