activation are related to lipid A of endotoxin. Other relevant substances such as synthetic and water-soluble adjuvants are primarily macrophage activators involved in generating, from macrophages, proinflammatory cytokines such as IL-1, IL-6, and tumor necrosis factor. When administered with protein antigens, these proinflammatory cytokines can have an effect similar to that of standard endotoxin—or of any of the other water-soluble adjuvants and other materials that have adjuvant effects. It is entirely possible that inhaled contaminants, endotoxins, and endotoxin-like proteins, as well as fungal proteins and other irritants such as tobacco smoke, may activate macrophages and generate a proinflammatory milieu. Such a milieu will enhance the basic immunogenicity and allergenicity of inhaled proteins, which act as stimulants of the CD4+ T cell populations in a more standard immunological model.

CONCLUSIONS AND RECOMMENDATIONS

A great deal of knowledge has accumulated in the past 15 years concerning the role of inhaled proteins (including allergens) in airway inflammation. The prospects for the future are bright. Newer techniques of immunological science include the use of sophisticated methods for the detection of proteins. Indeed, such methods as monoclonal antibody-based radioimmunoassays and enzyme-linked immunosorbent assays as well as the potential use and recognition of the actual protein sequences of the allergens involved in inducing allergic responses have led us to consider a whole new approach to detection. Use of these reagents to enhance and better control environmental stimuli is a logical goal, as is the potential use of molecule-based products, including allergen fragments, cytokines, and cytokine inhibitors, to produce immune modulation in the host. Such promising approaches permit considerable optimism regarding the potential interruption of the immune system- and inflammatory-based circuits triggered by inhalation of proteins and allergens and long-term exposure to inhaled indoor allergens.

Evidence suggests that the adjuvant effects associated with macrophage activation are related to endotoxin. Additional research is necessary, however, to clarify this phenomenon.

Research Agenda Item: Determine whether bacterial products (such as endotoxin) or fungal products may act as adjuvants in the immune responses to indoor allergens.

As discussed in earlier chapters of this report, the magnitude of allergen exposure appears to be related to the risk of sensitization. Allergen exposure is also related to the risk of developing asthma and the age at which asthma develops. Genetic and other local host factors are also important in



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