A guinea pig model of pulmonary hypersensitivity to industrial/environmental chemicals has been developed in which animals exposed to the chemicals via inhalation develop pulmonary or dermal hypersensitivity dependent upon the particular chemical. By employing dose (or concentration)-response methodology, and omitting the use of adjuvants, the potencies of the chemicals for causing sensitization as well as the target organ have been determined. Sensitization responses may occur within minutes upon provocation exposure (immediate-onset responses, IAR), or hours later (LAR). Dual responses (IAR and LAR) may also occur. The mechanism(s) underlying these responses are not known. This proposal will test the hypothesis that certain classes of antibody (i.e. IgG1, and IgE) mediate IAR and LAR. In addition, the hypothesis that quantities of IgG2, IgA and IgM block responses to IgG1 and IgE will be tested using passive transfer methodology. Monoclonal antibodies will be produced to each of the immunoglobulin classes. Sensitization may progress to asthma. The presence of airway hyperactivity (AHR) to bronchoconstrictive agents (i.e., histamine) is a hallmark of asthma. Conditions conducive to development of chronic airway disease are not known. This proposal will also test the hypothesis that repeated IAR and LAR within a set span of time, result in AHR and asthma. Initially, the hypothesis will be tested using ovalbumin (OA), a potent protein allergen and pathogen-free Hartley guinea pigs. Later, inbred animals will be used to assess genetic contribution. Guinea pigs will be sensitized via inhalation of OA, then challenged to elicit either IAR or IAR and LAR. The development of AHR will be monitored by bronchial response to increasing concentrations of aerosolized histamine. Asthma will be assessed by AHR and detection of reversible airways obstruction. The mechanism underlying development of asthma will be examined using pulmonary immunohistochemistry assessing antigen and antibody in the lung. Lung sections will additionally be evaluated for: eosinophilia, eosinophil basic protein, inflammation, and epithelium integrity.
