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

• 批准号: 10179955
• 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
• 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/10179955
• 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 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; Laboratories; Life Expectancy; Link; Mediating; Membrane Glycoproteins; Meningoencephalitis; Monoclonal Antibodies; Mus; Naegleria; Naegleria fowleri; Nervous System Physiology; Neuraxis; Outcome; Parasites; Parasitic Diseases; Parasitic infection; Patients; Phenotype; Population; Recombinants; Specificity; Surface Antigens; Testing; Therapeutic; Therapeutic antibodies; Tissues; Treatment Efficacy; Vaccination; Variant; base; 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

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.

摘要： 真核病原体对中枢神经系统的机会性入侵要求高度协调但又有节制的多个 加强免疫反应。福氏奈格勒、棘阿米巴等胞外寄生虫感染中枢神经系统 和Balamuthia已被证明几乎不可能治疗，但针对N.fowleri的免疫导向疗法已经 这种可能性改变了几乎所有人都致命的疾病的进程。“吃脑的阿米巴”福勒氏杆菌是 引起一种称为原发性阿米巴脑膜脑炎的破坏性脑膜脑炎 (PAM)尽管进行了密集的临床干预和新的治疗方法，但几乎普遍是致命的(97%) 迫切需要采取措施。奈格勒-反应性抗体(Abs)对猪的保护作用 人类尚不清楚，但PAM的动物模型表明，接种疫苗和被动给予抗体 变化无常地延缓死亡并促进生存。胞外寄生虫不能简单地被抗体中和，但 相反，免疫依赖于免疫细胞的靶向抗体同型特异性效应机制。之后 寄生虫与抗体结合，与片段结晶性受体(FCRs)的同型特异性结合可以指导 特定细胞类型的效应器具有对抗寄生虫的功能。鸡新城疫杆菌特异性抗体反应的研究进展 没有严格地将抗体特异性与单个抗体同种类型的功能结果联系起来， 在理解抗体如何以最佳方式从体内消除寄生虫方面产生了关键差距 中枢神经系统(CNS)，同时不加重免疫病理。我们已经产生了一种单克隆抗体 在体外显示对寄生虫有很强的抗增殖作用的鸡圆环菌细胞表面抗原的特异性 并促进体内受感染宿主的存活。这项提案试图定义如何结合抗增殖 抗体和同种异型特异性结合可促进有效的细胞外免疫反应 中枢神经系统在维持神经保护的同时寄生。该项目的完成将定义新的治疗方法 治疗中枢神经系统感染的方法目前几乎没有有效的选择，结果非常糟糕。