title: Cytokine mRNA profiles for isocyanates with known and unknown potential to induce respiratory sensitization.
abstract: Isocyanates are low-molecular-weight chemicals implicated in allergic asthmatic-type reactions. Identification of chemicals likely to cause asthma is difficult due to the lack of a validated test method. One hypothesis is that differential cytokine induction (Th1 versus Th2 profiles) in the draining lymph node following dermal application can be used to identify asthmagens and distinguish them from contact allergens. In this study, we compared the cytokine mRNA profiles of six chemicals: toluene diisocyanate (TDI), diphenylmethane-4,4'-diisocyanate (MDI), dicyclohexylmethane-4,4'-diisocyanate (HMDI), isophorone diisocyanate (IPDI), p-tolyl(mono)isocyanate (TMI), and meta-tetramethylene xylene diisocyanate (TMXDI). Whereas TDI and MDI are well-known respiratory sensitizers, documentation for HMDI, IPDI, TMI, and TMXDI is limited, but suggests that HMDI and IPDI may have respiratory sensitization potential in humans and TMI and TMXDI do not. Following dermal exposure of BALB/c mice, all six isocyanates induced cytokines characteristic of a Th2 response. Although LLNAs suggested that the doses chosen for the RPA were immunologically equivalent, the isocyanates tested differentiated into two groups, high responders and low responders. However, two of the low responders (TMI and TMXDI) were further tested and induced higher levels of Th2 cytokine message than dinitrochlorobenzene (not an asthmagen). Further study of these chemicals is needed to determine whether the Th2 cytokine responses observed for these low responders is predictive of asthmagenic potential or represents an insufficient signal.
authors.affiliation: University of North Carolina, Curriculum in Toxicology, Chapel Hill, NC 27599, USA. lisa_plitnick@merck.com
authors.forename: L M
authors.initials: LM
authors.lastname: Plitnick
authors.forename: S E
authors.initials: SE
authors.lastname: Loveless
authors.forename: G S
authors.initials: GS
authors.lastname: Ladics
authors.forename: M P
authors.initials: MP
authors.lastname: Holsapple
authors.forename: R J
authors.initials: RJ
authors.lastname: Smialowicz
authors.forename: M R
authors.initials: MR
authors.lastname: Woolhiser
authors.forename: P K
authors.initials: PK
authors.lastname: Anderson
authors.forename: C
authors.initials: C
authors.lastname: Smith
authors.forename: M J K
authors.initials: MJ
authors.lastname: Selgrade
mesh_terms: D000485:Allergens / Q000145:classification / Q000276:immunology / Q000633:toxicity*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D017953:Isocyanates / Q000145:classification / Q000276:immunology / Q000633:toxicity*; D023441:Local Lymph Node Assay; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D012333:RNA, Messenger / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000139:chemically induced* / Q000276:immunology; D012260:Ribonucleases / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000485:Allergens; D016207:Cytokines; D017953:Isocyanates; D012333:RNA, Messenger; D012260:Ribonucleases