IMMUNOMODULATORY EFFECTS OF CPG DNA

说明(摘自申请者摘要)：CpG DNA具有免疫调节作用 最终可能对多种治疗方法有用的效果 应用，如癌症和过敏的疫苗接种和免疫治疗。 拟议工作的总体目标是了解CPG可能会如何改变 对多糖(PS)和PS-蛋白结合抗原的体液免疫，以及 为了更好地了解CpG DNA如何改变抗原处理和 T细胞的多肽表位的呈递。 申请者的第一个具体目标是确定CpG DNA对 对碳水化合物多糖(PS)和多肽表位的反应 糖结合疫苗。CpG寡核苷酸(ODN)对血管内皮细胞生长的影响 PS免疫原和PS-蛋白结合物(PS偶联到A)诱导的免疫 载体蛋白)，以及载体蛋白将被检测。这个 申请者假设CpG ODN将增强对 糖结合疫苗的碳水化合物表位，并可能改变抗体 被激发的同种类型(例如，在小鼠中诱导IgG2a反应)。 建议进行实验以测试CpG ODN是否可以增强抗原特异性 PS抗原单独诱导的IgM反应以及CpG是否诱导改变 在对PS免疫原的反应中，伴随着同型转换。驾驭 CpG ODN增强对PS抗原的体液免疫能力将使 微囊化细菌(肺炎链球菌， 流感嗜血杆菌等)。 申请者的第二个具体目标是确定CpG DNA对 巨噬细胞处理和呈递外源蛋白抗原， 在体外培养树突状细胞和B细胞，并确定其机制 CpG DNA介导了这种效应。对第二类MHC(MHC-II)抗原的影响 将在系统中使用独立的 可检测其提呈的抗原提呈细胞和模型抗原 通过T细胞杂交瘤对特定抗原肽的反应。影响 CpG DNA对表面肽的半衰期：MHC-II复合体， MHC-II的合成和表达，以及抗原加工的组成部分 将对机器进行检查。

DESCRIPTION (adapted from applicant's abstract): CpG DNA has immunomodulatory effects that may eventually be useful for a wide variety of therapeutic applications, such as vaccination and immunotherapy for cancer and allergy. The overall goals of the proposed work are to understand how CpG may alter humoral immunity to polysaccharide (PS) and PS-protein conjugate antigens, and to better understand how CpG DNA may alter antigen processing and the presentation of peptide epitopes to T cells. The applicant's first specific aim is to determine the effects of CpG DNA on responses to polysaccharide (PS) and peptide epitopes of carbohydrate and glycoconjugate vaccines. The effects of CpG oligodeoxynucleotides (ODN) on immunity induced by PS immunogens and PS-protein conjugates (PS coupled to a carrier protein), as well as the carrier protein will be tested. The applicants hypothesize that CpG ODN will enhance humoral responses to carbohydrate epitopes of glycoconjugate vaccines and may alter the antibody isotypes that are elicited (e.g. to induce IgG2a responses in mice). Experiments are proposed to test whether CpG ODN can enhance antigen-specific IgM responses induced by PS antigen alone, and whether CpG-induced alterations in responses to PS immunogen are accompanied by isotype switching. Harnessing the ability of CpG ODN to enhance humoral immunity to PS antigens would allow the development of improved vaccines for encapsulated bacteria (S. pneumoniae, H. influenzae, etc.). The applicant's second specific aim is to determine the effects of CpG DNA on the processing and presentation of exogenous protein antigens by macrophages, dendritic cells and B cells in vitro, and to determine the mechanism whereby CpG DNA mediates such effects. Effects on class II MHC (MHC-II) antigen processing and presentation will be examined in a system using isolated antigen presenting cells and model antigens whose presentation can be detected by T cell hybridomas responding to specific antigenic peptides. The influence of CpG DNA on factors such as half life of surface peptide:MHC-II complexes, MHC-II synthesis and expression, and components of antigen processing machinery will be examined.