IMMUNOTOXICITY OF ACID ANHYDRIDES IN THE LUNG

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DESCRIPTION: (Adapted from the Investigator's Abstract) Acid anhydrides, used in a number of industries, cause the immunotoxic response of allergy. The long term goal is to understand the mechanism of immunotoxicity of the acid anhydrides in the lung so rational therapeutic approaches can be designed. A guinea pig model of trimellitic anhydride (TMA)-induced allergy will be used because it mimics many symptoms seen in the allergic human. Animals will be sensitized ID with TMA and 3 wk later challenged intratracheally with antigen (TMA coupled to serum albumin). Components of the immunotoxic response to TMA which will be monitored include: broncho-constriction and an immediate decrease in circulating platelets; increased airway microvascular and pulmonary vascular permeability; lung hemorrhage; and eosinophil, neutrophil and mononuclear cell infiltration into the lung. The hypothesis is that TMA-GPSA combines with cytophilic IgG1 and/or non-cytophilic IgG2 Ab in the airspace and/or the circulation to cause complement activation with a resultant decrease in circulating platelets: both of which are required for the immunotoxic response to TMA. TMA- GPSA-specific IgG1 and IgG2 will be measured by ELISA in the serum and bronchoalveolar lavage (BAL) of actively-sensitized animals and correlated with the immunotoxic response. The ability of purified IgG1/IgG2 Ab to mediate the immunotoxic response will be determined in passively-sensitized animals. To determine which antibody mediates complement participation, animals will be passively sensitized with IgG1 or IgG2, depleted of complement with Cobra Venom Factor, and the response to TMA assessed. To determine if complement activation occurs in the circulation or airspace, complement cleavage product C3a will be assayed in plasma and BAL by a Western blot method. In vitro studies will determine combinations of antigen, Ab, and BAL cells which result in C3a generation or BAL cell activation. An isolated tracheal preparation will be used to determine if antigen movement (with or without Ab and C) is limited by epithelial permeability. The importance of platelets will be assessed by determining if platelets sequester in the lung and whether depleting platelets or preventing their aggregation affects the immunotoxic response. These studies will determine if cytophilic Ab can evoke participation of the complement system and if cytophilic plus non-cytophilic Ab can predict the immunotoxic response.