UBC Theses and Dissertations
Investigations into the development and mechanism of tolerance induced by the chronic antigen challenge of sensitized guinea pigs Andrew, Deborah Karen
Previous studies have shown that guinea pigs which have been sensitized to ovalbumin (OA) become unreactive to OA aerosol challenge after multiple nonlethal exposures. The present studies were undertaken to define the mechanism(s) of this nonreactivity, or "tolerance". Tolerance was induced in previously sensitized guinea pigs by challenging with OA aerosol one hour/day, five days/week for six weeks. Reactivity was assessed visually and by lung mechanics. Maximum bronchoconstrictive responses were observed in the first two weeks of aerosol challenge, with responses dropping off steadily thereafter until virtually inapparent after five weeks of chronic' challenge. Lung mechanics studies provided an objective means of assessing reactivity. Dynamic compliance (Cdyn) and pulmonary resistance (RL) data confirmed initial strong anaphylactic reactions in the early weeks of chronic challenge which steadily declined over the following five weeks. To investigate the stability of tolerance in the absence of regular aerosol challenge, groups of guinea pigs were withheld from challenge for 4, 6, 8, 10, and 24 day periods. No progressive loss of tolerance occurred when aerosol challenges were withheld for 4 to 24 day periods. In vitro contractile responses of airway smooth muscle from sensitized and tolerant guinea pigs revealed comparable histamine responses in the two groups but a significantly decreased response to OA from tolerant animals. Total lung histamine content was significantly greater in the tolerant animals (5.74 ± 0.76 jug histamine/g wet lung) than in control (3.05 ± 0.33) or sensitized animals (3.30 ± 0.38). Serum from tolerant animals showed a reduced area of blueing compared with serum from sensitized animals by a six hour passive cutaneous anaphylaxis sensitization. Lymphocytes transferred from tolerant guinea pigs to subsequently sensitized animals did not visibly reduce an initial response to OA aerosol challenge. Antigen-induced histamine release from chopped lung preparations was significantly less in tolerant animals (0.34 ± 0.27 μg histamine released/g tissue, 1.0 ± 0.7 % histamine released) than sensitized animals (1.2 ± 0.3 μg histamine released/g tissue, 5.1 ± 1.4 % histamine released) at a low (1.1 x 10⁻⁹ M) OA concentration. It is concluded that antigen-induced mediator release or antibody synthesis may be inhibited in tolerant animals.