PubMed · 14237941
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D J BRAIN. 1965-02-13. TOXIC INSECTICIDES.. https://doi.org/10.1136/bmj.1.5432.450-b
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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.
The evaluation of allergenic potential is a key parameter in the safety assessment of novel proteins, including those expressed in genetically modified crops and foodstuffs. The majority of allergic reactions to food proteins are immediate type hypersensitivity reactions in which the principal biological effector is IgE antibody; the accurate measurement of specific IgE antibody is therefore a critical factor in experimental systems designed to characterize protein allergenic potential. Due to the presence of much higher concentrations of other immunoglobulin isotypes, the assessment of specific serum IgE antibody poses substantial technical challenges. We have examined the utility of the rat basophilic leukemia (RBL) cell line for the measurement of murine IgE responses. RBL cells were sensitized with mouse monoclonal anti-dinitrophenyl (DNP) IgE antibody and challenged with DNP-albumin conjugates with various hapten substitution ratios (SR). Polyclonal anti-OVA IgE antisera were also assessed for activity in the RBL assay. Results were compared with titers measured in homologous passive cutaneous anaphylaxis (PCA) assay. Marked degranulation of RBL cells was induced by conjugates with SRs of between 16 and 32, whereas conjugates with lower SRs (of 10 or 3) failed to elicit significant serotonin release. All conjugates were able to induce mast cell degranulation in vivo in a PCA assay. Anti-OVA antisera with PCA titers of 1/32 to 1/64 failed to stimulate RBL cell degranulation, whereas high titer antibody (1/2048 to 1/4096 by PCA) induced a positive RBL cell response. Successful stimulation of RBL cell degranulation requires not only appropriate epitope densities but also high affinity antibody. These data indicate that this assay is inappropriate for the routine analysis of specific polyclonal IgE antibody responses such as those that are induced by exposure to complex protein allergens.
We here investigated wether genes encoding the interleukins IL-1beta, IL-6 and IL-8, and the chemokines CCL2, CCL3, CCL3L1 and CCL4 are useful markers for sensitization testing in CD34+-progenitor derived dendritic cells (CD34-DC). CD34-DC from at least three donors were exposed during 0.5 up to 24h to the chemical sensitizers nickel sulphate, oxazolone, 2,4-dinitrochlorobenzene (DNCB) and eugenol, and to the irritants sodium dodecyl sulphate (SDS) and benzalkonium sulphate (BC). mRNA expression was evaluated using real-time RT-PCR. We observed a large inter-individual variation in mRNA expression in CD34-DC exposed to the chemicals. No or limited effects on expression were observed for the irritant BC and the weak sensitizer eugenol. All other chemicals modulated the transcript levels of most cytokines that were investigated. Most of the time, no clear-cut distinctions could be made between the sensitizers and SDS. After 24 h, consistent upregulatory effects of all sensitizing compounds on transcript expression of CCL2, CCL3 and CCL4 were observed, whereas SDS (and BC) had no effect. Our findings suggest that the CCL2, CCL3 and CCL4 genes may be selective end-point markers in the CD34-DC model to discern chemical sensitizers from irritants.