Autoimmune Oophoritis: Consequences of Gamete Vaccines

自身免疫性卵巢炎：配子疫苗的后果

• 批准号: 7008870
• 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/7008870
• 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）：我的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 ZP3 B 细胞表位 (335-342) 和外源 T 细胞表位的嵌合肽 (CP2) 已被证明是一种有效的疫苗，不会在成年动物中引起卵巢自身免疫性疾病。 CP2 免疫导致女性生育能力下降 70%，这是可逆的，并且她们的卵巢没有病变。然而，我们现在遇到了与 CP2 疫苗相关的新问题。尽管用 CP2 免疫的成年小鼠的卵巢没有出现病变，但其后代的卵巢出现了 AOD，并且在某些情况下出现了卵母细胞的损失。目前还不清楚为什么后代 AOD（自身免疫性卵巢疾病）仅发生在 B6AF 1 新生儿中，而不是其他 5 个近交系和 1 个远交系的新生儿中。我们也不明白为什么后代 AOD 只发生在具有针对一种 ZP3 B 细胞表位 [ZP3 (335-342)] 的抗体的小鼠中，而不是在具有针对另一个 ZP3 B 的抗体的小鼠中。 表位[ZP3(17I-180)]。这些发现提出了这样的假设：后代 AOD 代表了一种独特的事件，仅限于独特的小鼠品系，对独特的 ZP3 B 细胞表位作出反应。在本研究中，我们将确定后代 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。与此同时，我们的目标是鉴定新的卵母细胞抗原 (Ag)，并检查其作为新型、安全有效的 ZP 避孕疫苗中候选 Ag 的潜力。在目标 1 中，我们将确定子代 AOD 的自然史和普遍性、具有先前子代 AOD 的青春期后小鼠的生育力、小鼠新生儿对 CP2 抗体反应的变化以及灵长类动物中子代 AOD 的发生。目标 2 将鉴定新的 ZP B 细胞表位，这些表位可在不产生 AOD 的情况下实现避孕。在目标3中，我们将进一步研究子代AOD的机制，并确定子代AOD独特发生的机制。具体来说， 我们将确定对 CP2 免疫反应的免疫遗传学调节，以及 ZP Ab 的 B 细胞表位特异性对诱导子代 AOD 的影响。