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年龄在大约18至36个月之间的儿童的牙齿表面。龋齿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葡萄糖基转移酶（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。来自MS的GTF可以诱导免疫反应，抑制GTF的催化活性，保护啮齿动物免受龋齿的侵害，并干扰人类本地MS的再积累。虽然不确定，但很可能保护涉及抑制GTF的催化和/或葡聚糖结合活性。我们开发儿童龋齿疫苗的方法是制备生物可降解聚（d，l-丙交酯-羟基乙酸酯）（PLGA）的微粒，其中包括GTF和明胶作为生物粘合剂，用于鼻腔给药。与鼻黏膜的粘附增加了微颗粒的运输时间，促进了这些含gtf的微颗粒的吸收，从而增加了微颗粒被诱导免疫组织吸收的可能性。我们已经证明，这些微颗粒在鼻腔给药后产生的唾液IgA和血清IgG的升高率明显高于未掺入的GTF。第二阶段的策略是优化第一阶段开发的PLGA/GTF/明胶系统，并在使用大鼠模型的攻毒试验中展示对龋齿的保护作用。口服或鼻腔给药是儿童免疫接种的首选途径，因为它们简单、快速，并且减少了注射对儿童造成的创伤。增强粘膜免疫输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，开发一种更有效的粘膜免疫诱导输送系统将广泛应用于除龋齿以外的粘膜感染。

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.