Autoimmune Oophoritis: Consequences of Gamete Vaccines

自身免疫性卵巢炎：配子疫苗的后果

• 批准号: 6847457
• 负责人: KENNETH S.K. TUNG
• 金额: $ 24.13万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-27 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6847457
• 关键词: antibody; autoimmune disorder; chimeric proteins; cooperative study; egg /ovum; immunogenetics; immunoregulation; laboratory mouse; nondrug contraceptive; ovary disorder; vaccine development

DESCRIPTION (provided by applicant): A major long-term goal of my laboratory is to develop a safe and effective human contraceptive vaccine. To this end, we have taken a two pronged approach: 1) To develop an effective method of reversible contraception, and 2) To assure safety of the vaccine by identifying and resolving potential problems associated with contraceptive vaccination. A chimeric peptide (CP2) that contained a native ZP3 B cell epitope (335-342) and a foreign T cell epitope has proved to be an efficacious vaccine that does not in duce ovarian autoimmune disease in adult animals. CP2 immunization led to 70% reduction in female fertility that was reversible, and their ovaries were free of pathology. However, we have now encountered a new problem associated with the CP2 vaccine. Although the ovaries of adult mice immunized with CP2 were free of pathology, the ovaries of their progeny developed AOD, and in some cases there was loss of oocytes. It is unclear is why progenic AOD [autoimmune ovary disease] should occur only in B6AF 1 neonates but not the neonate of five other inbred strains and one outbred strain. Nor do we understand why progenic AOD should occur only in mice with Ab to one ZP3 B cell epitope [ZP3 (335-342)] but not with Ab to anotherZP3 B epitope [ZP3 (l7I-l80)]. These findings have prompted the hypothesis that progenic AOD represents a unique occurrence confined to a unique mouse strain in response to a unique ZP3 B cell epitope. In the proposed research, we will determine the generalizability of progenic AOD, understand the mechanism of neonatal ovarian injury, elucidate the basis for its unique occurrence, and define its long-term effect. At the same time, our goal is to identify new oocyte antigen (Ag) and examine their potential as candidate Ag in a new, safe and effective ZP contraceptive vaccine. In Aim 1, we will determine the natural history and generalizability of progenic AOD, the fertility of postpubertal mice with a antecedent progenic AOD, the variations in the murine neonatal response to CP2 antibody, and the occurrence of progenic AOD in the primate. Aim 2 will identify new ZP B cell epitopes that confer contraception without progenic AOD. In Aim 3, we will further investigate the mechanism of progenic AOD, and identify the mechanism responsible for the unique occurrence of progenic AOD. Specifically, we will determine the immunogenetic regulation of the immune response to CP2, and the influence of the B cell epitope specificity of the ZP Ab on the induction of progenic AOD.

描述（由申请人提供）：我实验室的一个主要长期目标是开发一种安全有效的人类避孕疫苗。为此，我们采取了双管齐下的方法：1）开发一种有效的可逆避孕方法，2）通过识别和解决与避孕疫苗接种相关的潜在问题来确保疫苗的安全性。含有天然ZP 3 B细胞表位（335-342）和外源T细胞表位的嵌合肽（CP 2）已被证明是一种有效的疫苗，在成年动物中不会引起卵巢自身免疫性疾病。CP 2免疫导致雌性生育力降低70%，这是可逆的，并且它们的卵巢没有病变。然而，我们现在遇到了与CP 2疫苗相关的新问题。尽管用CP 2免疫的成年小鼠的卵巢没有出现病理变化，但其后代的卵巢却出现了AOD，并且在某些情况下出现了卵母细胞丢失。目前尚不清楚为什么前基因性自身免疫性卵巢疾病只发生在B6 AF 1新生儿中，而不是其他五个近交系和一个远交系的新生儿。我们也不理解为什么前代AOD只发生在具有针对一个ZP 3 B细胞表位[ZP 3（335-342）]的Ab而不发生在具有针对另一个ZP 3 B的Ab的小鼠中 表位[ZP 3（171 - 180）]。这些发现提示了这样的假设，即前代AOD代表了仅限于响应于独特ZP 3 B细胞表位的独特小鼠品系的独特发生。在拟议的研究中，我们将确定progenic AOD的普遍性，了解新生儿卵巢损伤的机制，阐明其独特发生的基础，并确定其长期影响。同时，我们的目标是确定新的卵母细胞抗原（Ag），并检查其作为候选抗原在新的，安全和有效的ZP避孕疫苗的潜力。在目的1中，我们将确定的自然历史和progenic AOD的普遍性，生育力的青春期后小鼠与先行progenic AOD，在小鼠新生儿的反应CP 2抗体的变化，并发生progenic AOD在灵长类动物。目的2将鉴定新的ZP B细胞表位，其赋予避孕作用而不具有前基因AOD。在目标3中，我们将进一步研究前代AOD的机制，并确定前代AOD独特发生的机制。具体地说， 我们将确定对CP 2的免疫应答的免疫遗传学调节，以及ZP Ab的B细胞表位特异性对前基因AOD诱导的影响。