Using natural antibodies to improve vaccines

使用天然抗体改进疫苗

• 批准号: 8610225
• 负责人: John J Iacomini
• 金额: $ 13.87万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2014-03-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610225
• 关键词: Adjuvant; Affect; Antibodies; Antibody Repertoire; Antibody Specificity; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Binding; Bovine Serum Albumin; Carbohydrates; Cells; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Effectiveness; Epitopes; Generations; Human; Hybridomas; ITGAX gene; Immunity; Immunization; Immunocompromised Host; Immunoglobulin M; Immunoglobulins; Immunosuppression; Immunosuppressive Agents; Individual; Infection; Knock-in Mouse; Lethal Dose 50; Light; Listeria monocytogenes; Lymphoid Follicle; MHC Class I Genes; Maintenance; Memory; Modification; Murine leukemia virus; Mus; Organ Transplantation; Ovalbumin; Play; Pongidae; Primates; Recombinants; Regimen; Role; Solid; T cell response; T-Lymphocyte; Testing; Transformed Cell Line; Vaccination; Vaccine Research; Vaccines; Virus; base; clinically relevant; immunogenic; immunogenicity; improved; in vivo; novel; novel vaccines; pathogen; public health priorities; public health relevance; response; secondary infection; vaccine efficacy; variable region gene

DESCRIPTION (provided by applicant): Natural antibodies play a major role in providing protective host immunity. A significant portion of natural antibodies present in all humans, apes and Old World primates are specific for the carbohydrate antigen Gal11-3Gal21-4GlcNAc-R, or 1Gal. Indeed, 1Gal-specific natural antibodies comprise one to eight percent of circulating immunoglobulin in humans. Based on the universal high-titer presence of these antibodies, we hypothesized that it might be possible to utilize this pre-existing antigen-specific repertoire to augment the immunogenicity of antigens in order to improve the efficacy of vaccines. To test this hypothesis, we used 1Gal-deficient mice (GT0 mice), which like humans produce 1Gal-specific natural antibodies, to analyze whether conjugation of a poorly immunogenic antigen, such as bovine serum albumin (BSA), to 1Gal could affect its immunogenicity in vivo. Immunization of GT0 mice with BSA conjugated to 1Gal (1Gal-BSA) led to a T and B cell response to BSA that was significantly greater than that observed following immunization of control mice without the need for adjuvant. The ability to produce 1Gal-specific antibodies also led to an enhanced cytotoxic T lymphocyte anti-virus response following challenge of mice with murine leukemia virus- transformed cell lines expressing 1Gal. These data suggest that pre-existing 1Gal-specific antibodies encoded for in the natural antibody repertoire can be used to increase B and T cell responses to poorly immunogenic antigens that have been modified to express 1Gal epitopes without the need for adjuvant. The central hypothesis of this proposal is therefore that this pre-existing antibody repertoire can be used to improve vaccine strategies for pathogens. The specific aims are: to determine the mechanism by which 1Gal-specific natural antibodies increase the immunogenicity of antigens modified to express 1Gal; determine if pre-existing 1Gal-specific natural antibodies can be used to improve vaccines for pathogens, and; determine the effectiveness of immunization with 1Gal-modified antigens in immunocompromised hosts.

描述（由申请人提供）：天然抗体在提供保护性宿主免疫力方面发挥着重要作用。所有人类、猿类和旧世界灵长类动物中存在的天然抗体的很大一部分对碳水化合物抗原 Gal11-3Gal21-4GlcNAc-R 或 1Gal 具有特异性。事实上，1Gal 特异性天然抗体占人体循环免疫球蛋白的百分之一到百分之八。基于这些抗体普遍存在的高滴度，我们假设有可能利用这种预先存在的抗原特异性库来增强抗原的免疫原性，从而提高疫苗的功效。为了检验这一假设，我们使用 1Gal 缺陷型小鼠（GT0 小鼠）（它们与人类一样产生 1Gal 特异性天然抗体）来分析免疫原性较差的抗原（如牛血清白蛋白 (BSA)）与 1Gal 的结合是否会影响其体内免疫原性。用与 1Gal 缀合的 BSA (1Gal-BSA) 免疫 GT0 小鼠，导致 T 细胞和 B 细胞对 BSA 的反应显着高于免疫对照小鼠（无需佐剂）后观察到的反应。在用表达1Gal的鼠白血病病毒转化细胞系攻击小鼠后，产生1Gal特异性抗体的能力还导致细胞毒性T淋巴细胞抗病毒反应增强。这些数据表明，天然抗体库中编码的预先存在的 1Gal 特异性抗体可用于增强 B 和 T 细胞对免疫原性较差的抗原的反应，这些抗原已被修饰为表达 1Gal 表位，而无需佐剂。因此，该提案的中心假设是，这种预先存在的抗体库可用于改进病原体的疫苗策略。具体目标是：确定1Gal特异性天然抗体增加修饰表达1Gal的抗原免疫原性的机制；确定是否可以使用现有的 1Gal 特异性天然抗体来改进病原体疫苗；确定 1Gal 修饰抗原在免疫受损宿主中的免疫效果。