H Scheerens, TL Buckley, EM Davidse, J Garssen, FP Nijkamp and H Van Loveren
Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands.

Toluene diisocyantate (TDI) is a low-molecular-weight compound that is known to cause occupational asthma in 5% to 10% of exposed workers. These patients exhibit marked airway hyperresponsiveness and granulocyte accumulation in the airways, and 10% to 20% were also determined to have TDI-specific IgE in their serum. In this study, we developed a murine model for TDI-induced asthma. After several sensitization and challenge regimens were tested, it was decided that optimal sensitization was observed after mice (BALB/c) were skin sensitized with TDI (1%) two times on two consecutive days and challenged intranasally 8 d later with TDI (1%). Sensitized mice exhibited tracheal hyperreactivity to carbachol 24 h after challenge (69% increase in maximal contractile response). In contrast, no differences between the control and TDI-treated groups was observed 2 and 48 h after challenge with 1% TDI. There appeared to be no elevation in TDI-specific IgE antibodies in the serum at all time points measured. In addition, no influx of leukocytes could be detected histologically in the trachea and lung tissue or airway lumen 2, 24, and 48 h after the challenge. Surprisingly, the tracheal hyperreactivity was associated with a marked increase in myeloperoxidase but not eosinophil peroxidase activity in the lung tissue and in the cells of the bronchoalveolar lavage fluid at 24 h after the challenge. To investigate the role of lymphocytes in the induction of tracheal hyperreactivity, mice were passively sensitized by intravenous injection of lymphoid cells from TDI-sensitized donor mice. Similar to active sensitization, adoptive transfer of lymphocytes from sensitized donors resulted in tracheal hyperreactivity 24 h after challenge of the recipients. In conclusion, these data show that TDI is capable of inducing lymphocyte-dependent but IgE-independent tracheal hyperreactivity in the mouse that is not associated with cellular infiltration in the airways. This model can be used to further investigate the possible mechanisms involved in the development of occupational asthma induced by TDl.

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