Isocyanates are a leading cause of occupation-related asthma. The pathophysiology of this condition, however, remains poorly understood, in part due to a lack of appropriate animal models. One critical question that is currently unanswered is what role different sites of exposure (i.e. lung versus skin) may play in subsequent development of reactive airway symptoms. In addition, it is unclear what particular antigenic form of an isocyanate is serving as the primary immunogen. Answers to these questions would have enormous impact on development of appropriate measures to protect workers. Our laboratory has established and is studying immune mechanisms to a mouse model of antigen-induced allergic asthma. Recently, we have extended this model to include sensitization through the skin, using a newly developed method of epicutaneous exposure to soluble protein under an occlusive skin patch. The systemic responses induced differ significantly from contact hypersensitivity responses induced by skin painting with haptens in that they involve preferential activation of Th2 cells. Inhaled antigen challenge of epicutaneously immunized mice in our system resulted in lung inflammatory responses with characteristics of human asthma, including airway eosinophilia and increased mucus production. In this study, we propose the development and analysis of a murine model of isocyanate-induced asthma. Specifically, hexamethylene diisocyanate (HDI)-specific immune responses will be established in mice by epicutaneous or inhalational exposure to HDI. The nature of these immune responses will be characterized and compared to responses induced by protein antigens. Underlying the proposal is the hypothesis that unlike what has been observed in a model of ovalbumin induced airway responses, different subsets of T cell (Th1 or CD8) contribute to the pathophysiology observed. This will be tested in 3 specific aims: 1) To determine what type of exposure leads to optimal HDI sensitization; 2) To determine the priming conditions that lead to HDI-induced lung inflammatory responses and airway hyperresponsiveness; and 3) To define the effector cells and molecules mediating lung responses. Establishment of this mouse model will provide a means for future investigation of: 1) the pathophysiology of isocyanate asthma; 2) the relative immunogenicity of different classes or antigenic forms of isocyanates; and 3) the role of different sites of exposure in sensitization. This information will provide valuable insight into the pertinent risk factors for developing isocyanate asthma and will help guide development of appropriate strategies for protection in the workplace.
| Herrick, Christina A; Das, Jyoti; Xu, Lan et al. (2003) Differential roles for CD4 and CD8 T cells after diisocyanate sensitization: genetic control of TH2-induced lung inflammation. J Allergy Clin Immunol 111:1087-94 |
| Herrick, Christina A; Xu, Lan; Wisnewski, Adam V et al. (2002) A novel mouse model of diisocyanate-induced asthma showing allergic-type inflammation in the lung after inhaled antigen challenge. J Allergy Clin Immunol 109:873-8 |
