VACCINE STRATEGIES TO ENHANCE CD4+ T CELL PRIMING

基础免疫学的最新进展使我们对 影响宿主对感染性疾病免疫反应的因素 病原体 将这些知识应用于疾病的设计 特定的疫苗有望对我们的健康产生重大影响 能够成功地使人们对许多病原体免疫。 不 细胞在免疫应答的调节中占据中心位置， 抗原，影响抗体产生，巨噬细胞和粒细胞 功能和自然杀伤细胞活性。 此外，T细胞可能 直接作为效应细胞发挥作用，提供抗微生物活性 通过感染宿主细胞的裂解或通过 能够干扰入侵细胞增殖的细胞因子 有机体 这项研究的主要目的是增强免疫力， 使用旨在增强T细胞对特异性抗原的应答的策略， 细胞反应。 体外研究表明，T细胞反应不同， 定量和定性取决于1）肽-MHC的密度 抗原呈递细胞表面上的复合物，和2） 与T细胞结合递送至T细胞的共刺激信号 受体结合 我们已经制定了改变这两个参数的策略 在重组疫苗的情况下体内。 通过修饰抗原， 含有溶酶体靶向序列，抗原加工可以改变， 导致与MHC II类的关联增加，以呈递给 CD 4 +T细胞。 通过表达抗原沿着共刺激分子或 通过使用细胞因子，T细胞应答的性质可能受到有利的影响。 使用甲型流感和人乳头瘤病毒（HPV）作为模型病原体， 将产生重组牛痘病毒构建体， 用于检测疾病特异性抗原（流感）的策略 血凝素和HPV-16 E7），重点是随后的性质， 反应和保护的幅度产生的体内 挑战. 这些策略可以直接与其他路线进行比较。 抗原递送和贩运正在研究的建议， Drs. Ahearn和Siliciano。

Recent advances in basic immunology have led to an increased understanding of the factors influencing the host immune response to infectious pathogens. The application of this knowledge to the design of disease specific vaccines holds the promise of significantly impacting on our ability to successfully immunize people against numerous pathogens. T cells occupy a central position in the regulation of the immune response to antigen, influencing antibody production, macrophage and granulocyte function, and natural killer cell activity. In addition, T cells may function directly as effector cells, providing anti microbial activity through the lysis of infected host cells or through the elaboration of cytokines capable of interfering with the propagation of the invading organism. The broad objective of this study is to augment the immune response to specific antigens using strategies aimed at enhancing the T cell response. Studies in vitro indicate that T cell responses vary quantitatively and qualitatively depending on 1) the density of peptide-MHC complexes on the surface of antigen presenting cells, and 2) the nature of co-stimulatory signals delivered to the T cell in conjunction with T cell receptor engagement. We have developed strategies to alter both parameters in vivo in the context of recombinant vaccines. By modifying antigen to contain lysosomal targeting sequences, antigen processing may be altered, leading to increased association with MHC class II for presentation to CD4+T cells. By expressing antigen along with co-stimulatory molecules or cytokines, the nature of the T cell response may be favorably influenced. Using influenza A and human papillomavirus (HPV) as model pathogens, recombinant vaccinia virus constructs will be created enabling these strategies to be tested for disease specific antigens (influenza hemagglutinin and HPV-16 E7), focusing on the nature of the ensuing response and the magnitude of protection generated against an in vivo challenge. These strategies may be directly compared to other routes of antigen delivery and trafficking being investigated in the proposals of Drs. Ahearn and Siliciano.