MUCOSAL IMMUNITY - IMPLICATIONS FOR VACCINE DEVELOPMENT

The mucosal surfaces in e.g. the gastrointestinal, respiratory and urogenital tracts represent a very large exposure area to exogenous agents including microorganisms. Not surprising, therefore, these mucosal tissues are defended by a local immune system with properties and functions that in many respects are separate from the systemic immune system. The intestine is the largest immunological organ in the body. It comprises 70-80% of all immunoglobulin-producing cells and produces more secretory IgA (SIgA) (50-100 mg/kg body weight/day) than the total production of IgG in the body (ca. 30 mg/kg/day). The local immune system of the gut has two main functions: to protect against enteric infections, and to protect against uptake of and/or harmful immune response to undergraded food antigens. The best known entity providing specific immune protection for the gut is the SIgA system. The resistance of SIgA against normal intestinal proteases makes antibodies of this isotype uniquely well suited to protect the intestinal mucosal surface. The main protective function of SIgA antibodies is the <<imune exclusion>> of bacterial and viral pathogens, bacterial toxins and other potentially harmful molecules. SIgA has also been described to mediate antibody-dependent T cell-mediated cytotoxicity (ADCC), and to interfere with the utilization of necessary growth factors for bacterial pathogens in the intestinal environment, such as iron. It is now almost axiomatic that in order to be efficacious, vaccines against enteric infection must be able to stimulate the local gut mucosal immune system, and that this goal is usually better achieved by administering the vaccines by the oral route rather than parenterally. Based on the concept of a common mucosal immune system through which activated lymphocytes from the gut can disseminate immunity also to other mucosal and glandular tissues there is currently also much interest in the possibility to develop oral vaccines against e.g. infections in the respiratory and urogenital tracts. It has previously been widely assumed that only live vaccines would efficiently stimulate a gut mucosal immune response. However, an oral cholera vaccine, composed of the nontoxic B subunit of cholera toxin in combination with killed whole cell (WC) cholera vibrios has been shown to stimulate a strong intestinal SIgA antibody response associated with long-lasting protection against cholera. We have used this new cholera subunit vaccine and developed ELISPOT methods for examining at the clonal B and T cell level the dynamics of intestinal and extra-intestinal immune responses in humans after enteric immunizations. With the aid of recombinant DNA engineering we have also been able to produce the B and WC vaccine components in a single step as well as, through genetic fusions, to provide B subunit with peptide extensions corresponding to foreign antigen epitopes: several vaccine candidates prepared along these lines are currently being tested.