The mucosal immune system: from fundamental concepts to vaccine development

BCG, a live attenuated tubercle bacillus, is the most widely used vaccine in the world and is also a useful vaccine vehicle for delivering protective antigens of multiple pathogens. Extrachromosomal and integrative expression vectors carrying the regulatory sequences for major BCG heat-shock proteins have been developed to allow expression of foreign antigens in BCG. These recombinant BCG strains can elicit long-lasting humoral and cellular immune responses to foreign antigens in mice.

This study determined the difference in rate of degradation between pure polymers of lactic acid (pla), glycolic acid (PGA), and various ratios of copolymers of these two substances. Fast-cured and slow-cured polyglycolide was compared with copolymers of glycolide/lactide intermixed in ratios of 75:25, 50:50, and 25:75, as well as pure polylactide. A total of 420 rats were implanted with carbon-14 and tritium-labeled polymers in bone and soft tissue. At intervals of 1, 2, 3, 5, 7, 9, and 11 months, groups of five animals with the implants in bone and five with the implants in the abdominal wall were sacrificed. The implant area as well as tissue from the liver, spleen, kidney, lung and some muscle tissue was analyzed for radioactivity along with the urine and feces collected throughout the experiment. Half-lives of the different polymers and copolymers were calculated from the radioactivity present in the implant area for each time interval. Half-life of the polymers and copolymers decreased from 5 months for 100% PGA to 1 week with 50:50 PGA:PLA copolymer and rapidly increased to 6.1 months for 100% PLA. Fast-cured PGA had a half-life in tissue of 0.85 months. No difference in rate of degradation was seen in soft tissue or bone. No significant radioactivity was detected in urine, feces, or tissue samples. From this study, it is concluded that control of degradation rate of the implant could best be attained by varying the composition of PLA and PGA between 75% and 100% PLA along with a corresponding 25% to 0% PGA. This would provide a half-life range of the implant of from 2 weeks to 6 months.

The selective induction of antibodies in external secretions is desirable for the prevention of various systemic as well as predominantly mucosa-restricted infections. An enormous surface area of mucosal membranes is protected primarily by antibodies that belong, in many species, to the IgA isotype. Such antibodies are produced locally by large numbers of IgA-containing plasma cells distributed in subepithelial spaces of mucosal membranes and in the stroma of secretory glands. In humans and in some animal species, plasma-derived IgA antibodies do not enter external secretions in significant quantities and systemically administered preformed IgA antibodies would be of little use for passive immunization. Systemic administration of microbial antigens may boost an effective S-IgA immune response only in a situation whereby an immunized individual had previously encountered the same antigen by the mucosal route. Local injection of antigen in the vicinity of secretory glands is usually accompanied by an undesirable concomitant systemic response and frequently requires the addition of adjuvants that are unacceptable for administration in humans. Immunization routes that involve ingestion or possibly inhalation of antigens lead to the induction of not only local but also generalized immune responses manifested by the parallel appearance of S-Iga antibodies to ingested or inhaled antigens in secretions of glands distant from the site of immunization. Based on extensive studies in animal models as well as in humans, convincing evidence is available that antigen-sensitized and IgA-committed precursors of plasma cells from GALT are disseminated to the gut, other mucosa-associated tissues, and exocrine glands. However, due to the limited absorption of desired antigens from the gut lumen of orally immunized individuals, repeated large doses of antigens are required for an effective S-IgA response. Novel antigen delivery systems for the stimulation of such responses are currently being examined in several laboratories. Live attenuated or genetically manipulated bacteria expressing other microbial antigens have also been used for selective colonization of gut-associated lymphoid tissues. Unique antigen packaging and the use of adjuvants suitable for oral administration hold promise for an efficient antigen delivery to critical tissues in the intestine and deserve extensive exploration. The oral immunization route appears to have many advantages over systemic immunization.(ABSTRACT TRUNCATED AT 400 WORDS)