Based on the knowledge that secretory IgA forms the first line of immune defense at the interface between body tissues and the outside environment and on emerging insight into the interrelatedness of various anatomically separate compartments of the secretory immune system, this proposal seeks to demonstrate the efficacy and potential of eliciting protective immunity in the respiratory tract via primary immunization in the gut, a route that offers both theoretical and practical advantages compared to direct immunization of the respiratory tract itself. The project will employ in a model system a natural respiratory pathogen of mice, Sendai virus, a member of the parainfluenza group. Initial efforts will focus on developing a method of immunization of the gut associated lymphoid tissue that gives rise to a brisk IgA immune response in both intestinal and respiratory secretions as evaluated principally by enzyme linked immunosorbent assay. Immunization schemes for eliciting anti- viral immunity will employ live or inactivated virus along with cholera toxin and muramyl dipeptide as adjuvants, and also liposomes containing purified viral protein plus the above adjuvants as well as antibody to class II major histocompatibility antigens in order to target the liposomes to the immune system. Following development of a means for stimulating an effective, gut based secretory IgA response in the respiratory tract, the protective properties of such antibodies will be investigated in several ways, including challenge of tracheal organ cultures from immunized mice with live virus, measurement of virus titers in mouse lungs after challenge in vivo, and determination of virus LD50 in immunized vs. control mice. The mechanism of respiratory immunity after immunization of the gut will be further studied by adoptive transfer of serum and lymphocytes from the mesenteric nodes of immunized donor mice as well as by experiments employing virus-specific monoclonal antibodies, including especially those of the IgA class. Overall, the proposed studies should illuminate the potential of the secretory immune system and in particular secretory IgA, for induction of immunoprophylaxis against common infections of the respiratory tract, and should help the development of effective new strategies for immunization against some important common human infections.
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