Using natural antibodies to improve vaccines

描述（由申请人提供）：天然抗体在提供保护性宿主免疫中起主要作用。在所有人类、猿类和东半球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特异性的。事实上，1gal特异性天然抗体占人体循环免疫球蛋白的1%到8%。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，从而提高疫苗的效力。为了验证这一假设，我们使用了与人类一样产生1Gal特异性天然抗体的1Gal缺陷小鼠（GT0小鼠）来分析一种低免疫原性抗原（如牛血清白蛋白（BSA））与1Gal结合是否会影响其体内免疫原性。用BSA偶联1Gal （1Gal-BSA）免疫GT0小鼠可引起T细胞和B细胞对BSA的应答，显著高于不需要佐剂的对照小鼠免疫后观察到的应答。在用表达1Gal的小鼠白血病病毒转化细胞系攻击小鼠后，产生1Gal特异性抗体的能力也导致细胞毒性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B细胞和T细胞对低免疫原性抗原的反应，这些抗原已被修饰为表达1Gal表位，而不需要佐剂。因此，该建议的中心假设是，这种预先存在的抗体库可用于改进针对病原体的疫苗策略。具体目的是：确定1Gal特异性天然抗体提高表达1Gal修饰抗原的免疫原性的机制；确定预先存在的1gal特异性天然抗体是否可用于改进病原体疫苗；在免疫功能低下的宿主中确定1gal修饰抗原免疫的有效性。

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.