Inhalation of Toluene Diisocyanate Vapor Induces Allergic Rhinitis in Mice

Abstract

Diisocyanates are the leading cause of occupational asthma, and epidemiological evidence suggests that occupational rhinitis is a comorbid and preceding condition in patients who develop asthma. The goal of the present studies was to develop and characterize a murine model of toluene diisocyanate (TDI)-induced rhinitis. Female C57BL/6 mice were exposed to workplace-relevant concentrations of TDI vapor via inhalation for 4 h/day for 12 days with or without a 2-wk rest period and TDI challenge. Mice exposed 12 consecutive weekdays to 50 parts per billion TDI vapor showed elevated total serum IgE and increased TDI-specific IgG titers. Breathing rates were decreased corresponding with increased inspiratory time. TDI exposure elevated IL-4, IL-5, IL-13, and IFN-γ mRNA expression in the nasal mucosa, suggesting a mixed Th1/Th2 immune response. Expressions of mRNA for proinflammatory cytokines and adhesion molecules were also up-regulated. These cytokine changes corresponded with a marked influx of inflammatory cells into the nasal mucosa, eosinophils being the predominant cell type. Removal from exposure for 2 wk resulted in reduced Ab production, cytokine mRNA expression, and cellular inflammation. Subsequent challenge with 50 parts per billion TDI vapor resulted in robust up-regulation of Ab production, cytokine gene expression, as well as eosinophilic inflammation in the nasal mucosa. There were no associated changes in the lung. The present model shows that TDI inhalation induces immune-mediated allergic rhinitis, displaying the major features observed in human disease. Future studies will use this model to define disease mechanisms and examine the temporal/dose relationship between TDI-induced rhinitis and asthma.

Kujin Suppresses Histamine Signaling at the Transcriptional Level in Toluene 2,4-Diisocyanate–Sensitized Rats

“…We observed similar eosinophil infiltration after TDI-provocation in TDI-sensitized rats (unpublished observation), so it is expected that eosinophil infiltration should be suppressed in the Kujinpretreated group, although we have no data to support this expectation. In TDI-sensitized mice, it has been reported that TDI treatment increases not only Th2-cytokines including IL-4, IL-5, and IL-13 but also Th1 cytokines such as IFN-γ, so the inflammation induced by TDI is associated with a mixed Th1/Th2 immune response (69). In our model rats, the mRNA levels of both Th2-cytokines such as IL-4, IL-5, and IL-13 ( Fig.…”

Suplatast Tosilate Inhibits Histamine Signaling by Direct and Indirect Down-Regulation of Histamine H1 Receptor Gene Expression through Suppression of Histidine Decarboxylase and IL-4 Gene Transcriptions

“…Recently, Johnson et al developed and characterized a murine model of TDI-induced rhinitis (55). They showed that inflammation induced by TDI is associated with a Th1/Th2 mixed immune response and showed that the lower airways showed no evidence of inflammation and that the inflammation and gene expression changes were isolated to the upper airways.…”

Toluene diisocyanate (TDI) induces calcium elevation and interleukine-4 (IL-4) release - Early responses upon TDI stimulation

“…The IgE release from B cells occurs in the presence of interleukine-4 (IL-4) which can be released from T helper cell type 2 (Th2 cells). TDI is well known to stimulate Th2 cells to elevate IL-4 levels (Ban et al, 2006;Johnson et al, 2007;Sun et al, 2007). Not only chronic asthma but also acute reactions induced by TDI…”