Treatment of Primary Amoebic Meningoencephalitis via Modulation of Antibody Effector Functions

通过调节抗体效应器功能治疗原发性阿米巴脑膜脑炎

基本信息

批准号：
10550175
负责人：
E. Ashley Moseman
金额：
$ 40.25万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10550175
关键词：
Acanthamoeba Amoeba genus Animal Model Antibodies Antibody Response Antibody Specificity Antibody-Dependent Enhancement Antibody-mediated protection Antiparasitic Agents Binding Biological Assay Brain Cell surface Cells Central Nervous System Central Nervous System Infections Cessation of life Clinical Coculture Techniques Complement Data Disease Eating Effector Cell Engineering Epitopes Equilibrium Fostering Goals Growth Human IgG1 Immune Immune response Immunity Immunoglobulin Class Switching Immunotherapeutic agent Immunotherapy In Vitro Individual Infection Intervention Intraventricular Invaded Laboratories Life Expectancy Link Mediating Membrane Glycoproteins Meningoencephalitis Monoclonal Antibodies Mus Naegleria Naegleria fowleri Nervous System Physiology Outcome Parasites Parasitic Diseases Parasitic infection Patients Phenotype Population Proliferating Recombinants Specificity Surface Antigens Testing Therapeutic Therapeutic antibodies Tissues Treatment Efficacy Vaccination Variant cell motility cell type clinically relevant cohort effective therapy extracellular functional outcomes immune activation immunopathology improved outcome in vivo intravital imaging mouse model neuroprotection neurotropic neutralizing antibody novel novel therapeutic intervention optimal treatments passive antibodies pathogen preservation pressure prevent primary amebic meningoencephalitis prophylactic receptor restraint

项目摘要

Abstract: Opportunistic CNS invasion by eukaryotic pathogens requires a highly coordinated, yet restrained, multi- pronged immune response. CNS Infection by extracellular parasites such as Naegleria fowleri, Acanthamoeba, and Balamuthia have proven nearly impossible to treat, yet immune directed therapies against N. fowleri have the potential alter the course of almost universally fatal disease. The “brain eating amoeba” N. fowleri is responsible for a devastating form of meningoencephalitis known as primary amoebic meningoencephalitis (PAM) that is almost universally fatal (>97%) despite intensive clinical intervention, and new therapeutic approaches are desperately needed. The protective relevance of Naegleria-reactive antibodies (Abs) in humans is unclear, but animal models of PAM suggest that vaccinations and passive Ab administration variably delay death and foster survival. Extracellular parasites cannot simply be neutralized by antibody, but rather immunity relies on targeting antibody isotype specific effector mechanisms from immune cells. After parasites are bound by antibody, isotype specific binding to fragment crystallizable receptors (FcRs) can direct cell type specific effector functions against parasites. Prior studies of N. fowleri specific antibody responses have not rigorously linked antibody specificity with the functional outcomes of individual\antibody isotypes, creating a critical gap in understanding how antibody can optimally eliminate parasites from the within the central nervous system (CNS) while not exacerbating immunopathology. We’ve generated a monoclonal Ab specific for N. fowleri cell surface antigens that has shown strong anti-proliferative effects on parasites in vitro and facilitates survival of infected hosts in vivo. This proposal seeks to define how combining anti-proliferative effects of antibody and isotype specific binding can facilitate effective immune response against extracellular CNS parasites while maintaining neuroprotection. Completion of this project will define new therapeutic approaches to CNS infections that currently have few effective options and very poor outcomes.

抽象的：真核病原体的机会主义中枢神经系统入侵需要高度协调但又恢复的多种多样的支撑免疫反应。通过细胞外寄生虫感染的中枢神经系统感染，例如Naegleria Fowleri，Acanthamoeba，事实证明，Balamuthia几乎不可能治疗，但免疫针对N. Fowleri的疗法已潜力改变了几乎普遍致命疾病的过程。 “大脑吃变态”N。Fowleri是负责脑膜脑炎的毁灭性形式，称为原发性脑膜脑炎（PAM）几乎是普遍致命的（> 97％）dospite强化临床干预和新疗法迫切需要方法。 Naegleria反应性抗体（ABS）的保护性相关性人类尚不清楚，但是PAM的动物模型表明疫苗接种和被动ab给药可变延迟死亡并促进生存。细胞外寄生虫不能简单地被抗体中和，而是免疫学依赖于靶向免疫细胞的抗体同种型特异性效应机制。后寄生虫由抗体结合，同种型特异性结合与碎片可结晶的受体（FCR）可以直接针对寄生虫的细胞类型特异性效应子功能。先前对牛氏猪笼草特异性抗体反应的研究没有将抗体的特异性与单个\抗体同型的功能结果进行严格关联，在理解抗体如何最佳地消除寄生虫中的关键差距中枢神经系统（CNS）不加重免疫病理学。我们产生了一个单克隆AB 针对牛氏猪笼草的特异并促进体内感染宿主的生存。该建议旨在定义如何结合反增殖抗体和同型特异性结合的作用可以促进对细胞外的有效免疫反应 CNS寄生虫保持神经保护作用。该项目的完成将定义新疗法目前几乎没有有效选择且结果非常差的中枢神经系统感染方法。