Using natural antibodies to improve vaccines

使用天然抗体改进疫苗

基本信息

批准号：
8215634
负责人：
John J Iacomini
金额：
$ 40.69万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-15 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8215634
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: The development of novel immunization strategies against emerging pathogens remains a high public health priority throughout the world. In this proposal we will examine whether pre-existing natural antibody specificities can be used to develop potentially novel vaccine strategies.

描述（由申请人提供）：天然抗体在提供保护性宿主免疫方面起着重要作用。所有人类，猿类和旧世界灵长类动物中存在的大部分天然抗体都是针对碳水化合物抗原GAL11-3GAL21-4GLCNAC-R或1GAL的特异性的。实际上，1GAL特异性的天然抗体占人类循环免疫球蛋白的一到8％。基于这些抗体的通用高敏作，我们假设有可能利用这种先前存在的抗原特异性库来增强抗原的免疫原性，以提高疫苗的功效。为了检验这一假设，我们使用了1GAL缺陷的小鼠（GT0小鼠），就像人类产生1GAL特异性天然抗体一样，分析了对牛血清白蛋白（BSA）等免疫原性抗原的结合是否可能影响其在Vivo中的免疫原性。用偶联到1GAL（1GAL-BSA）的BSA对GT0小鼠的免疫接种导致T和B细胞对BSA的反应，该反应明显大于对对照小鼠免疫而无需辅助助剂后观察到的。产生1GAL特异性抗体的能力还导致了在用鼠白血病病毒转化为1GAL的小鼠挑战后，小鼠挑战后，细胞毒性T淋巴细胞抗病毒反应增强。这些数据表明，在天然抗体库中编码的预先存在的1GAL特异性抗体可用于增加对不需要佐剂的不需要的1GAL表达的B和T细胞对不良免疫原性抗原的反应。因此，该提案的核心假设是，这种现有的抗体库可用于改善病原体的疫苗策略。具体目的是：确定1GAL特异性抗体会增加改性以表达1Gal的抗原的免疫原性的机制；确定是否可以使用预先存在的1GAL特异性天然抗体来改善病原体的疫苗，并且；确定免疫功能低下宿主中用1GAL修饰抗原免疫的有效性。公共卫生相关性：针对新兴病原体的新型免疫策略的发展仍然是全世界的高公共卫生优先事项。在此提案中，我们将研究是否可以使用预先存在的天然抗体特异性来开发潜在的新型疫苗策略。