INDUCTION OF MUCOSAL IMMUNITY BY PARENTERAL INOCULATION

作为一名具有公共卫生背景的儿科医生，我对 疫苗开发由来已久。 在保罗医生工作期间 在费城儿童医院的奥菲特实验室， 发现了寄主-病原体基础科学之间的密切关系 互动和应用新获得的知识， 候选疫苗非常令人兴奋。 我追求的是 临床科学家发展奖（K08），以促进我的研究和 粘膜免疫学和疫苗学领域的分析技能。 的 PSA允许通过由以下内容组成的计划获得这些技能： 免疫学和病毒学课程和一个渐进的研究计划 如下所述。 几十年来，肠胃外免疫一直被用来刺激保护 从各种各样的感染，其复制位点仅限于 到粘膜表面（例如，流感和百日咳）。 虽然最近许多 努力集中在粘膜免疫以诱导免疫， 粘膜病原体，这种疫苗的成功开发， 慢了 此外，一些观察表明， 新的和现有的胃肠外疫苗的优化可能已经 过早被抛弃 用肠道病原体肌内（IM）接种小鼠， 轮状病毒，诱导肠道产生病毒特异性IgA和IgG 淋巴细胞 胃肠外免疫诱导粘膜免疫的能力 免疫反应消除了几个阻碍发展的问题， 口服疫苗。 这些观察将通过以下方式加以扩展： 解决以下问题：1）什么是相对容量 经口或IM接种，以诱导病毒特异性体液和细胞 肠道淋巴细胞的免疫反应 到什么程度 这些应答的诱导依赖于病毒的性质（例如， 传染性与非传染性）？ 2)IM的相对容量是多少 或口服轮状病毒疫苗以预防轮状病毒攻击？ 3)IM接种通过什么机制诱导免疫 肠道表面的反应 4)病毒蛋白被识别出来了吗 通过病毒特异性体液和细胞免疫反应的改变， IM与口服接种相比？

As a pediatrician with a background in public health, my interest in vaccine development has been longstanding. While working in Dr. Paul Offit's laboratory at The Children's Hospital of Philadelphia, I have found the close relationship between the basic science of host-pathogen interactions and the application of newly-acquired knowledge to develop candidate vaccines to be very exciting. I am pursuing the Mentored Clinical Scientist Development Award (K08) to further my research and analytic skills in the areas of mucosal immunology and vaccinology. The PSA allows for acquisition of these skills through a program composed of coursework in immunology and virology and a progressive research program as outlined below. Parenteral immunization has for decades been used to stimulate protection from a variety of infections whose site of replication is limited solely to mucosal surfaces (e.g., influenza and pertussis). Although many recent efforts have focused on mucosal immunization to induce immunity from mucosal pathogens, the successful development of such vaccines has been slow. Additionally, several observations suggest that the development of new and the optimization of existing parenteral vaccines may have been prematurely abandoned. Intramuscular (IM) inoculation of mice with the intestinal pathogen, rotavirus, induces production of virus-specific IgA and IgG by intestinal lymphocytes. The capacity of parenteral immunization to induce a mucosal immune response obviates several issues which have impeded the development of orally-administered vaccines. These observations will be extended by addressing the following questions: 1) What are the relative capacities of oral or IM inoculation to induce virus-specific humoral and cellular immune responses among intestinal lymphocytes? To what extent is induction of these responses dependent upon the nature of the virus (e.g., infectious vs. noninfectious)? 2) What are the relative capacities of IM or oral inoculation of rotavirus to protect against rotavirus challenge? 3) By what mechanism or mechanisms does IM inoculation induce an immune response at the intestinal surface? 4) Are the viral proteins recognized by virus-specific humoral and cellular immune responses altered following IM as compared with oral inoculation?