Overcoming maternal antibody-mediated immunosuppression

克服母源抗体介导的免疫抑制

基本信息

批准号：
8534701
负责人：
JOSHY JACOB
金额：
$ 48.19万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-21 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8534701
关键词：
Address Adult Agammaglobulinemia Antibodies Antibody Affinity Antibody Formation Antibody Suppression Antigens Applications Grants Area B-Lymphocytes Birth Bone Marrow Breast Feeding Breeding CD4 Positive T Lymphocytes Child Complement Data Development Fc Receptor Gifts Grant Human Human Milk Immune Immune response Immune system Immunity Immunization Immunosuppression Infant Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H5N1 Subtype Knowledge Lead Life Macaca mulatta Maternal antibody Measles Mediating Memory Memory B-Lymphocyte Modeling Mothers Mus Neonatal Newborn Infant Particulate Placenta Plasma Cells Play Positioning Attribute Pre-Clinical Model Pregnancy Primates Research Resources Rodent Model Role Serological Side Structure of germinal center of lymph node Testing Time Universities Vaccinated Vaccination Vaccines Work base influenzavirus nonhuman primate population health prevent programs pup response vaccine development

项目摘要

DESCRIPTION (provided by applicant): Maternally derived antibodies are crucial for protecting infants during their first months of life. This is best exemplified in infants with agammaglobulinemia, who thrive during the first year of life but succumb to repeated infections after the levels of circulating maternal antibodies wane. There is however, one downside to maternal antibodies; they suppress vaccine-induced activation of the infant immune system. Because of this, many necessary and life-saving vaccines such as measles are given at delayed times, up to a year after birth. This leaves a wide window of time during which the infant is vulnerable to infection but unable to develop the antibody response necessary for its own protection. Understanding how to activate the infant immune system in the presence of maternal antibodies is a critical area of research because it could lead to the development of more efficacious infant vaccines. We reasoned that maternal antibody-mediated suppression could in part be due to the form of the antigen used for vaccination. Our preliminary data show that immunization with soluble but not particulate antigens lead to significant activation of the infant immune system. Based upon this, our central hypothesis is that maternal antibody mediated immunosuppression of the new born immune system can be overcome and that robust long-term protective immunity can be generated by immunizing the new born with soluble rather than particulate antigens. We will test our central hypothesis by pursuing three specific aims. In Aim 1, we will fully characterize the infant immune responses induced by soluble antigens in the presence of maternal antibodies. In Aim 2, we will probe the extent of this protective immunity using H1N1, H3N2 and H5N1 influenza virus challenge models. Finally, in Aim 3, we will determine the extent to which maternal antibody mediated suppression can be overcome in non-human primate, rhesus macaque infants. The proposed work is significant because knowledge gained from these studies will enable us to develop vaccines that overcome maternal antibody suppression and can be used to successfully vaccinate infants.

描述（由申请人提供）：母体得出的抗体对于在婴儿生命的头几个月中保护婴儿至关重要。这在患有agammaglobloblobloblemia的婴儿中最好地说明了这一点，他们在生命的第一年就蓬勃发展，但在循环母体抗体的水平下降后屈服于重复感染。但是，孕产妇抗体的缺点。它们抑制了疫苗诱导的婴儿免疫系统的激活。因此，许多必要的挽救生命的疫苗，例如麻疹，在出生后延迟的时间延迟。这留下了宽阔的时间窗口，在此期间婴儿容易感染，但无法发展自身保护所需的抗体反应。了解如何在孕产妇抗体的存在下激活婴儿免疫系统是一个关键的研究领域，因为它可能导致更有效的婴儿疫苗的发展。我们认为母体抗体介导的抑制可能部分是由于用于疫苗接种的抗原的形式。我们的初步数据表明，可溶性但不是颗粒抗原的免疫导致婴儿的显着激活免疫系统。基于此，我们的中心假设是可以克服母体抗体介导的新出生免疫系统的免疫抑制，并且可以通过免疫新生的可溶性而不是颗粒抗原来产生健壮的长期保护性免疫。我们将通过追求三个特定目标来检验中心假设。在AIM 1中，我们将在存在母体抗体的情况下完全表征可溶性抗原引起的婴儿免疫反应。在AIM 2中，我们将使用H1N1，H3N2和H5N1流感病毒挑战模型探测这种保护性免疫的程度。最后，在AIM 3中，我们将确定在非人类灵长类动物的恒河猕猴婴儿中可以克服母体抗体介导的抑制的程度。拟议的工作很重要，因为从这些研究中获得的知识将使我们能够开发克服母体抗体抑制的疫苗，并可用于成功接种婴儿。