Roy Patterson, Ph.D. - US grants

The program has the following goals and objectives. 1. To maintain a colony of 3 groups of rhesus monkeys including normal animals, animals with IgE mediated cutaneous and airway reactivity to ascaris antigen or animals with IgE positive skin reactivity but negative airway reactivity. Because the antigen airway reactors have hyperreative airways this group of allergic rhesus monkeys may closely simulate human IgE mediated asthma. 2. To establish quantitative dose-response reactions to antigen and carbocholine in antigen reactive monkeys and carbocholine reactivity in normal monkeys. The carbocholine reactivity will be an index of the degree of hyperreactivity of the airway. 3. To determine qualitative and quantitative responses to potentially important agonists of airway reactions in selected asthmatics and controls monkeys. These agonists will include leukotriene D4 (LTD4), platelet activating factor (PAF) and histamine releasing agent (HRA) in selected asthmatic and control monkeys for evaluation of qualitative and quantitative individual animal responses. 4. To study receptor antagonists against LTD4 and PAF as inhibiting agents for these agonists and for antigen induced asthma. A lipoxygenase inhibitor will be studied to determine if antigen induced asthma is diminished by pretreating with this agent. The airway response to HRA will be evaluated by using antagonists against H, LTD4 and PAF. 5. To define the pattern of bioactive mediators released into bronchoalveolar lavage (BAL) fluid after antigen challenge and challenge with these mediators. 6. To develop a monkey model of toluene diisocyanate (TDI) asthma based on our human clinical experience in man and our experience with a canine model of TDI asthma.

Project I: This proposal extends the initial evaluation of polymerized antigens to all applicable pollen allergens and initiates studies on dust and mold allergens. Our preliminary studies of polymerized antigen E have provided evidence of greater safety using the same antigenic dose as monomer which will result in fewer injections of allergen and a considerable improvement in cost-benefit ratio for patients. Project II: Studies in this laboratory have demonstrated that we can measure in vitro production of IgE using peripheral blood lymphocytes of patients with hyperimmunoglobulinemia E. The sensitivity of the radioimmunoassay for IgE has been increased. We now propose further studies of IgE production of cells of both allergic and normal individuals and of regulatory mechanisms involved in the production of this immunoglobulin important in allergic disease. Project III: We have found an interesting model of a human disease in an industrial setting induced by inhalation of trimellitic anhydride which combines rapidly with human proteins to form a hapten-protein complex. We have initially characterized IgE mediated reactivity to this hapten. We plan to study IgE, IgG and lymphocyte reactivity directed against this hapten and to correlate the results with the kind and extent of symptoms produced under controlled conditions. Project IV: This project continues studies of the mechanisms of histamine release from allergic basophils. The ability to characterize the biochemical events in the intracellular or cell membrane activated processes provides a potential for pharmacologic inhibition of these processes. Investigators in our laboratory have recently developed the methodology to measure IgE antibodies against ragweed antigen E on the cell membranes of basophils. This permits us to follow seasonal variations of this parameter in the ragweed allergic subject and to study the effect of specific immunotherapy on this determinant of basophil reactivity.

The AADC at Northwestern University is an expanding program which now is composed of the Sections of Allergy-immunology' Occupational Medicine and Pulmonary Medicine of the Department of Medicine and the Division of Allergy of the Department of Pediatrics. Projects focus on immunologic disease particularly of the immediate-type and with a major emphasis on airway diseases. Occupational and environmental diseases due to chemicals acting as antigens (Project I) and allergic aspergillosis (Project II) are model systems of immunologic airway diseases. Allergy to laboratory animals (Project VII) is the study of epidemiology and immunology of these occupational problems. Studies of an improved form of allergen immunotherapy are extended in Project IV. Mechanisms of IgE mediated airway reactions are studied in 3 projects. These include investigations using animal models relevant to occupational immunologic lung disease (Project III), studies of important mediators including leukotrienes and platelet activating factor (Project VI) and studies of the cells which release or produce the mediators which may be involved in eliciting immediate-type allergic responses (Project V). Thus these studies focus on major basic and clinical aspects of important allergic diseases including asthma.