INDUCTION OF MUCOSAL IMMUNITY BY PARENTERAL INOCULATION

作为一名有公共卫生背景的儿科医生，我对 疫苗的研发由来已久。在为保罗博士工作的同时 在费城儿童医院的实验室里，我有 发现寄主-病原学基础科学之间的密切联系 互动和应用新获得的知识来发展 候选疫苗将非常令人兴奋。我在追寻被指导者 临床科学家发展奖(K08)，以促进我的研究和 具备黏膜免疫学和疫苗学领域的分析技能。这个 PSA允许通过由以下内容组成的计划获得这些技能 免疫学和病毒学的课程和进步的研究计划 如下所述。 几十年来，肠外免疫一直被用来刺激保护 从复制位置仅受限制的各种感染 到粘膜表面(如流感和百日咳)。尽管许多人最近 努力的重点是粘膜免疫，以诱导免疫 粘膜病原体，这类疫苗的成功研发已经 慢的。此外，一些观察结果表明， 新的和优化的现有非肠道疫苗可能已经 过早地被遗弃。 肌肉(IM)接种肠道病原体的小鼠， 轮状病毒，诱导肠道产生病毒特异性IgA和Ig G 淋巴细胞。肠外免疫诱导粘膜损伤的能力 免疫反应避免了阻碍发展的几个问题 口服疫苗的数量。这些观察结果将延伸到 回答以下问题：1)相对容量是什么 口服或IM接种以诱导病毒特异性体液和细胞 肠道淋巴细胞间的免疫反应？在多大程度上 这些反应的诱导取决于病毒的性质(例如， 感染性与非感染性)？2)IM的相对容量是多少 或者口服轮状病毒疫苗来预防轮状病毒的挑战？ 3)IM接种通过什么机制诱导免疫 肠道表面的反应？4)病毒蛋白被识别吗？ 通过病毒特异性体液和细胞免疫反应改变 与口服接种相比，我的情况如何？

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?