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: 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
• 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

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： 真核病原体侵入中枢神经系统需要一个高度协调，但受限制的， 免疫反应。细胞外寄生虫（例如福氏耐格里原虫、棘阿米巴原虫）引起的中枢神经系统感染， 和Balamuthia已被证明几乎不可能治疗，但针对N.福勒里有 这种可能性改变了几乎普遍致命的疾病的进程。“食脑变形虫”N。福莱里群岛 导致了一种毁灭性的脑膜脑炎，称为原发性阿米巴脑膜脑炎 (PAM)尽管进行了密集的临床干预， 迫切需要采取各种办法。耐格里属反应性抗体（Abs）在 人类尚不清楚，但PAM的动物模型表明，接种疫苗和被动Ab给药 延缓死亡，促进生存。细胞外寄生虫不能简单地被抗体中和， 相反，免疫依赖于来自免疫细胞的靶向抗体同种型特异性效应器机制。后 寄生虫被抗体结合，同种型特异性结合片段可结晶受体（FcRs）可以指导 针对寄生虫的细胞类型特异性效应器功能。以往的研究N. Fowleri特异性抗体应答 没有严格地将抗体特异性与单个抗体同种型的功能结果联系起来， 在理解抗体如何最佳地从体内消除寄生虫方面造成了一个关键的差距。 中枢神经系统（CNS），而不加剧免疫病理学。我们制造了一种单克隆抗体 对N. Fowleri细胞表面抗原在体外对寄生虫显示出强的抗增殖作用 并促进受感染宿主在体内的存活。该提案旨在确定如何结合抗增殖 抗体和同种型特异性结合的作用可以促进针对细胞外 中枢神经系统寄生虫，同时保持神经保护。该项目的完成将定义新的治疗方法， 目前治疗CNS感染的有效方法很少，结果也很差。