title: Methods for the identification of chemical respiratory allergens in rodents: comparisons of cytokine profiling with induced changes in serum IgE.
abstract: No validated or widely recognized test methods are currently available for the prospective identification of chemicals with the potential to cause respiratory allergy. The cellular and molecular mechanisms that result in the induction of chemical sensitization of the respiratory tract are unclear, although there is evidence for the selective development of T helper 2 (Th2)-type responses and, in some cases, the production of IgE antibody. We have therefore examined the utility of cytokine profiling using BALB/c mice, together with the measurement of induced increases in the total serum concentration of IgE in the Brown Norway (BN) rat, as markers for the prospective identification of chemical respiratory allergens. Responses provoked by the reference respiratory allergen trimellitic anhydride (TMA) have been compared with those stimulated by the respiratory sensitizing diisocyanates toluene diisocyanate (TDI) and hexamethylene diisocyanate (HDI) and by the acid anhydride hexahydrophthalic anhydride (HHPA). Topical exposure of BN rats to TMA, TDI and HHPA each provoked marked immune activation (increases in lymph node cellularity and proliferation). However, only treatment with TMA stimulated vigorous increases in the total serum concentration of IgE. In contrast, exposure to HHPA, TDI or HDI failed to provoke significant changes in serum IgE concentration or induced only transient and relatively weak increases in serum IgE levels. In parallel experiments using BALB/c strain mice, however, topical application of all four chemical respiratory allergens provoked a marked Th2-type cytokine secretion profile in draining lymph node cells. These data suggest that the measurement of induced changes in serum IgE is not sufficiently sensitive for the robust identification of chemical respiratory allergens. Furthermore, irrespective of the reasons for variations in TMA-induced IgE production among BN rats, doubts remain regarding the utility of these animals for the characterization of immune responses to chemical allergens. Cytokine profiling using the BALB/c strain mouse apparently provides a more robust method for the hazard assessment of chemical respiratory allergens.
authors.affiliation: Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK. rebecca.dearman@syngenta.com
authors.forename: R J
authors.initials: RJ
authors.lastname: Dearman
authors.forename: R A
authors.initials: RA
authors.lastname: Skinner
authors.forename: N E
authors.initials: NE
authors.lastname: Humphreys
authors.forename: I
authors.initials: I
authors.lastname: Kimber
mesh_terms: D000287:Administration, Topical; D000395:Air Pollutants, Occupational / Q000032:analysis; D000485:Allergens / Q000008:administration & dosage / Q000145:classification / Q000633:toxicity*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003485:Cyanates / Q000633:toxicity; D003509:Cyclohexanecarboxylic Acids / Q000633:toxicity; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D007073:Immunoglobulin E / Q000097:blood / Q000187:drug effects*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D017953:Isocyanates; D008198:Lymph Nodes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010796:Phthalic Anhydrides / Q000633:toxicity; D051381:Rats; D012130:Respiratory Hypersensitivity / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D014051:Toluene 2,4-Diisocyanate / Q000633:toxicity; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D000395:Air Pollutants, Occupational; D000485:Allergens; D003485:Cyanates; D003509:Cyclohexanecarboxylic Acids; D016207:Cytokines; D017953:Isocyanates; D010796:Phthalic Anhydrides; C015262:1,6-hexamethylene diisocyanate; D016753:Interleukin-10; C074866:hexahydrophthalic acid; D014051:Toluene 2,4-Diisocyanate; D007073:Immunoglobulin E; C015559:trimellitic anhydride; D007371:Interferon-gamma