Autoimmune Oophoritis: Consequences of Gamete Vaccines

自身免疫性卵巢炎：配子疫苗的后果

• 批准号: 6667129
• 负责人: KENNETH S.K. TUNG
• 金额: $ 23.02万
• 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/6667129
• 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(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ZP3B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，在成年动物中不会导致卵巢自身免疫性疾病。CP2免疫使女性生育力下降70%，这是可逆的，她们的卵巢没有病理变化。然而，我们现在遇到了一个与CP2疫苗相关的新问题。CP2免疫的成年小鼠虽然卵巢无病变，但其子代的卵巢发生了AOD，在某些情况下出现卵母细胞丢失。目前尚不清楚为什么原生性AOD[自身免疫性卵巢疾病]只发生在B6AF1新生儿中，而不是其他五个近交系和一个近交系的新生儿。我们也不知道为什么原生性AOD只发生在对一个ZP3 B细胞表位[ZP3(335-342)]有抗体的小鼠身上，而不是对另一个ZP3 B细胞表位有抗体的小鼠身上 表位[ZP3(17I-180)]。这些发现提出了一种假设，即原基因AOD代表着独特的小鼠品系对独特的ZP3B细胞表位的独特反应。在拟议的研究中，我们将确定原生性AOD的概括性，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，我们的目标是鉴定新的卵母细胞抗原(Ag)，并检测它们作为候选抗原在新的、安全有效的ZP避孕疫苗中的潜力。在目标1中，我们将确定前源性AOD的自然历史和概括性，先天AOD的青春期后小鼠的生育力，小鼠对CP2抗体的反应的变化，以及前源性AOD在灵长类中的发生情况。目的2将确定新的ZP B细胞表位，在没有AOD的情况下提供避孕。在目标3中，我们将进一步研究原生性AOD的机制，并找出导致原生性AOD独特发生的机制。具体来说， 我们将确定对CP2免疫应答的免疫遗传调节，以及ZP抗体的B细胞表位特异性对原源性AOD诱导的影响。