PEPTIDE IMMUNODOMINANCE IS DETERMINED BY PFR DEPENDENCY

该提案将确定PFR对肽和蛋白质免疫原性的重要性。人们对开发基于肽的疫苗越来越感兴趣，以减少诱导针对免疫原同源宿主蛋白的自身免疫的可能性，或诱导可能加剧而不是减轻疾病的不适当免疫反应的可能性。该项目的长期目标是更深入地了解MHC II类结合表位周围肽侧残基（PFR）对T细胞反应的影响。这项提议的第一个目的是确定PFR影响T细胞反应和整体免疫原性的频率。这些研究将主要涉及小鼠T细胞杂交瘤的分析和体内免疫实验。第二个目标将是确定控制PFR如何增强和/或调节T细胞功能的机制。这些研究将包括前体频率测定、细胞因子分析和增殖研究，重点关注T细胞反应的动力学和大小。本文所描述的方法包括实验室常用的方法和将成为新的培训经验的方法。这一应用将确立PFR的免疫学意义，并对免疫调节、疫苗开发和基于肽的免疫治疗具有重要意义。

The proposal will determine the importance of PFR for peptide and protein immunogenicity. There is increasing interest in developing peptide-based vaccines in order to reduce the possibility of either inducing autoimmunity against a host protein homologous to the immunogen, or inducing an inappropriate immune response that may exacerbate rather than alleviate a disease. The long-term objective of this program is to gain a greater understanding of the influence that peptide flanking residues (PFR) surrounding MHC class II binding epitopes have on T cell responses in general. The first aim of this proposal will be to determine how frequently PFR affect T cell responses and overall immunogenicity. These studies will primarily involve analysis of murine T cell hybridomas and in vivo immunization experiments. The second aim will be to determine the mechanisms controlling how PFR potentiate and/or modulate T cell function. These studies will involve precursor frequency determination, cytokine analysis and proliferation studies to focus on kinetics and magnitude of T cell responses. The methods described herein include those that are common to the laboratory and those that will be new training experiences. This application will establish the immunological significance of PFR and has significant implications for immunoregulation, vaccine development and peptide-based immunotherapy.