CHILDHOOD IMMUNIZATION FOR DENTAL CARIES

变形链球菌是与人类龋齿相关的主要微生物。 变形链球菌（MS）定植并开始积聚在大多数18至36个月大的儿童的牙齿表面。 致龋链球菌积累的一个关键组成部分是葡聚糖的形成，葡聚糖是通过MS葡糖基转移酶（GTF）对蔗糖的催化作用合成的。 葡聚糖通过提供致龋性变形链球菌的结合位点以及改变牙菌斑的孔隙度来增加变形链球菌的致病潜力。 MS中的GTF可诱导免疫应答，抑制GTF催化活性，保护啮齿动物免受龋齿，并干扰人类中固有MS的再积累。 虽然不确定，但保护作用可能涉及抑制GTF的催化和/或葡聚糖结合活性。 我们的儿童龋齿疫苗的开发方法是制备生物可蚀性聚（d，l-丙交酯-共-乙交酯）（PLGA）的微粒，其中包括GTF和明胶作为生物粘附剂，用于鼻腔给药。 与鼻粘膜的粘附增加了微粒的通过时间，并促进了这些含GTF微粒的吸收，从而增加了微粒被诱导免疫组织摄取的可能性。 我们已经证明，这些微粒产生升高的唾液伊加和血清IgG，以响应鼻腔给药的速率显着大于未掺入的GTF所观察到的。 II期策略旨在优化I期开发的PLGA/GTF/明胶系统，并在使用大鼠模型的挑战试验中证明对龋齿的保护作用。建议的商业应用通过口服或鼻腔递送的儿童免疫接种是受欢迎的途径，因为它们简单、快速并且减少了注射对儿童的创伤。 粘膜免疫的增强递送系统的商业潜力是巨大的：普遍的儿童免疫实际上可以消除儿童时期的蛀牙及其相关问题。 此外，开发用于粘膜诱导免疫的更有效的递送系统将广泛应用于除龋齿之外的粘膜感染。

Mutans streptococci are the principal microorganisms associated with dental caries in humans. Mutans streptococci (MS) colonize and begin to accumulate on the tooth surfaces of most children between the ages of approximately 18 and 36 months of age. A critical component in the accumulation of cariogenic streptococci is the formation of glucan, which is synthesized by the catalytic action of MS glucosyltransferases (GTF) on sucrose. Glucan increases the pathogenic potential of mutans streptococci by providing binding sites for cariogenic mutans streptococci as well as changing the porosity of dental plaque. GTF from MS can induce an immune response that inhibits GTF catalytic activity, protect rodents from dental caries, and interfere with the reaccumulation of indigenous MS in humans. Although uncertain, it is likely that protection involves inhibition of the catalytic and/or glucan binding activities of GTF. Our approach to the development of childhood vaccine for dental caries is to prepare microparticles of the bioerodible poly(d,l-lactide-co-glycolide) (PLGA), including therein both GTF and gelatin as a bioadhesive, for nasal administration. Adhesion to the nasal mucosa increases the transit time of the microparticles and facilitates absorption of these GTF-containing microparticles, thereby increasing the potential for uptake of microparticles to inductive immune tissue. We have demonstrated that these microparticles produce elevated salivary IgA and serum IgG in response to nasal administration to rates significantly greater than observed for unincorporated GTF. The Phase II strategy is directed to opitmizing the PLGA/GTF/gelatin system developed in Phase I and demonstrating protection against dental caries in a challenge test using the rat model. PROPOSED COMMERCIAL APPLICATION Childhood immunization by oral or nasal delivery are the favored routes because they are simple, rapid and reduce the trauma to the child occasioned by injection. The commercial potential of an enhanced delivery system for mucosal immunization is enormous: universal childhood immunization could virtually eliminate tooth decay and its associated problems in childhood. Further, the development of a more efficient delivery system for mucosal induction of immunity would find broad application to mucosal infections other than dental caries.