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Cytokine mRNA profiles for isocyanates with known and unknown potential to induce respiratory sensitization

Cytokine mRNA profiles for isocyanates with known and unknown potential to induce respiratory sensitization,10.1016/j.tox.2004.11.001,Toxicology,L. M.

Cytokine mRNA profiles for isocyanates with known and unknown potential to induce respiratory sensitization   (Citations: 14)
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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.
Journal: Toxicology , vol. 207, no. 3, pp. 487-499, 2005
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    • ...However, evidence of monoisocyanate immune reactivity has recently been reported, showing that repeated dermal exposures to p-tolyl isocyanate induced increased levels of the Th2 characteristic cytokines IL-4, IL-10 and IL-13 in mice, equal to that of known respiratory sensitizers [...

    Linda Svensson-Elfsmarket al. Rats Repeatedly Exposed to Toluene Diisocyanate Exhibit Immune Reactiv...

    • ...Cytokine profiling bases hazard identification on the induction of high levels of Th2 cytokines and low levels of Th1 cytokines in the draining lymph node (Dearman et al., 2003; Plitnick et al., 2005) relative to responses induced by appropriate negative and vehicle controls...
    • ...Using an RNase protection assay, Plitnick et al. (2005) studied cytokine expression for six isocyanate species, including some welldocumented asthmagens based on human and animal studies, but also some chemicals for which there was little or no data to support or refute a role in the induction of asthma...
    • ...The 14-day protocol mimicked those reported by Dearman et al. (2002) and Plitnick et al. (2005)...
    • ...Because studies showing hyperresponsiveness to Mch following dermal exposure to other chemicals employed longer sensitization regimens (Klink and Meade, 2003), the 14-day protocol was extended to include an additional round of sensitizations, the 28-day protocol (Fig. 1). For this preliminary experiment, mice (12 per group) were exposed to 2% HMDI, 2% MDI, or 1% DNCB based upon doses reported by Plitnick et al. (2005)...
    • ...(2) Based on results of the preliminary study, the 28-day protocol was used to expose mice in the following treatment groups (six mice per group): 1% TDI, 2% MDI, 2% HMDI, 2%IPDI, 1%TMI, 1% TMXDI, 1% DNCB, and vehicle (experiment 2). Doses used were the same as those used by Plitnick et al. (2005)...
    • ...Because the dermal sensitization studies noted in the Introduction employed exposure regimens considerably longer than the standard 14day cytokine profile protocol (Dearman et al., 2002; Plitnick et al., 2005), exposure protocols for 28 as well as 14-day protocols were used (Fig. 1). Figure 2 shows that after both the 14- and 28-day protocols, total serum IgE titers for the diisocyanate-treated groups were significantly increased ( p< ...
    • ...Cytokine mRNA expression in lymph nodes removed at 28 days produced an expression pattern similar to that observed by Plitnick et al. (2005) at 14 days in that the diisocyanates could be grouped into high (TDI, MDI, and HMDI) and low (IPDI, TMI, and TMXDI) responders based on cluster analysis (Fig. 4). However, when DNCB was added to the analysis, all of the diisocyanates except TDI clustered with DNCB...
    • ...Several observations can be made from these data: First, the treatment groups cluster in a manner similar to that for message shown in Figure 4 and as reported by in the Plitnick et al. (2005) study...
    • ...These data support the findings of Plitnick et al. (2005), which reported TDI, MDI, HMDI, IPDI, TMI, and TMXDI can be divided into high and low responders based on Th2 cytokine profiles...
    • ...The pattern of responses for IL-4, IL-10, and IL-13 was very similar when message was assessed by RNAse protection assay (Plitnick et al, 2005), or reverse transcription– PCR (RT-PCR), or when cytokine protein was measured ex vivo...
    • ...TDI, MDI, and HMDI enhanced Th2 cytokine responses in the draining lymph node and are known to induce asthma in humans (see Plitnick et al., 2005 for review of human and animal studies for all of the diisocyanates tested here)...

    MaryJane K. Selgradeet al. Inconsistencies between Cytokine Profiles, Antibody Responses, and Res...

    • ...A second method, known as cytokine profiling, bases hazard identification on induction of Th2 cytokines in the draining lymph node (Dearman et al, 2003; Dearman & Kimber, 2001; Plitnick et al, 2005) compared to appropriate negative and vehicle controls...

    MaryJane K. Selgradeet al. Immunotoxicology of Inhaled Compounds—Assessing Risks of Local Immune ...

    • ...assay, Plitnick et al. (2005) studied cytokine expression for 6 isocyanate species,...
    • ...with asthma). The 14 day protocol mimicked those reported by Plitnick et al. (2005) and...
    • ...group) were exposed to 2% HMDI, 2% MDI, or 1% DNCB based upon doses reported by Plitnick et al. (2005)...
    • ...(experiment 2). Doses used were the same as those used by Plitnick et al. (2005)...
    • ...the standard 14 day cytokine profile protocol (Dearman et al. 2002; Plitnick et al. 2005),...
    • ...pattern similar to that observed by Plitnick et al. (2005) at 14 days in that the...
    • ...asthma in humans (see Plitnick et al 2005 for review of human and animal studies for all...

    MaryJane K. Selgradeet al. INCONSISTENCIES BETWEEN CYTOKINE PROFILES, ANTIBODY RESPONSES, AND RES...

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