Passive Immunization for Neurotropic Virus Infection

嗜神经病毒感染的被动免疫

• 批准号: 7386584
• 负责人: Douglas Craig Hooper
• 金额: $ 26.61万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386584
• 关键词: Active Immunization; Active immunity; Adoptive Transfer; Adult; Adverse effects; Aerosols; Allergic; Animals; Antibodies; Antibody Formation; Antigens; Area; B-Lymphocyte Subsets; B-Lymphocytes; Bioterrorism; Blood - brain barrier anatomy; Blood Circulation; Breathing; CD4 Positive T Lymphocytes; Cells; Chiroptera; Development; Disease; Exclusion; Exposure to; Hand; Human; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunoglobulin Fragments; Individual; Infection; Inflammatory Response; Knockout Mice; Mediating; Mus; National Institute of Allergy and Infectious Disease; Neurons; Numbers; Passive Immunization; Peripheral; Permeability; Probability; Process; Prophylactic treatment; Protocols documentation; Rabies; Rabies virus; Reagent; Recording of previous events; Relative (related person); Research Personnel; Risk; Role; Structure; Therapeutic; Time; Tissues; Toxin; Vaccination; Variant; Virus; Virus Diseases; Virus Replication; antibody engineering; base; beryllium trifluoride; cell type; congenic; desire; improved; infected B cell; knockout gene; neurotropic virus; neutralizing antibody; pathogen; prevent; programs; relating to nervous system; response; size

DESCRIPTION (provided by applicant): Passive immunization, the administration of pre-formed antigen-specific antibody, provides considerable advantages over active immunization as an immune state can essentially be provided on demand with a lessened chance of an inadequate response or side effects. While passive immunization has proven benefits for peripheral challenge, it is problematic for neurotrophic pathogens because of the blood-brain barrier (BBB), a specialization of the neurovasculature that protects CMS tissues from circulating cells and factors including antibodies. As is apparent from the number of neurotrophic viruses classified as NIAID priority pathogens, these are particularly suitable for bioterrorism. Included among this group is rabies virus (RV), which due to the emergence of bat RV variants that cause rabies in humans without overt evidence of exposure, has become a greater threat for use as a bioweapon. Rabies has a long history of successful post-exposure prophylaxis using a combination of passive and active immunization. The possibility that similar but improved therapies may be useful for bat-RV and other neurotrophic viruses prompts the need for a better understanding of the mechanisms of post-exposure prophylaxis. Clearance of RV from the infected CMS requires the administration of particular subsets of neutralizing antibodies as well as some aspect of the adaptive immune response which we speculate is the induction of blood-brain barrier (BBB) permeability. Using adoptive transfer of isolated, congenic T and B cell subsets into gene knockout mice that fail to mediate blood-brain barrier (BBB) permeability changes when infected with RV, we will identify the cell type(s) responsible for the loss of BBB integrity as well as the mechanisms involved. By transfer of known protective RV-specific antibodies engineered to express different Ig heavy chains, chemically prepared antibody fragments, or B cells into RV-infected, B cell-deficient mice, we will determine the structure of rabies-neuroprotective antibodies and the means of their delivery to the CMS. The ultimate aim of this project is to provide a protocol whereby exposure to neurotrophic viruses can be treated by passive immunization when contact with the agent is imminent or has recently occurred.

描述（由申请人提供）：被动免疫，预先形成的抗原特异性抗体的给药提供了与主动免疫相当可观的优势，因为可以根据需要提供免疫状态，而降低了反应不足或副作用的机会。虽然被动免疫已被证明对外围挑战有效，但由于血脑屏障（BBB），这对于神经营养病原体是有问题的，这是神经血管内部的专业化，可保护CMS组织免受循环细胞和抗体的因素的影响。从归类为NIAID优先病原体的神经营养病毒的数量中可以明显看出，这些病毒特别适合生物恐怖。该组中包括狂犬病病毒（RV），由于蝙蝠RV变种的出现，导致人类狂犬病而没有公开暴露的证据，它已成为生物武器的更大威胁。狂犬病具有悠久的成功暴露后预防历史，结合了被动免疫和主动免疫。类似但改进的疗法可能对BAT-RV和其他神经营养病毒有用的可能性促使需要更好地了解暴露后预防的机制。从受感染的CMS中清除RV需要对中和抗体的特定亚群以及适应性免疫反应的某些方面进行施用，我们推测，这是诱导血脑屏障（BBB）渗透性的诱导。利用分离的，偶然的T和B细胞子集转移到基因基因敲除小鼠中，这些小鼠无法介导血脑屏障（BBB）的通透性在感染RV时会发生变化，我们将确定负责BBB完整性丧失的细胞类型以及所涉及的机制。通过将已知的保护性RV特异性抗体转移，该抗体设计用于表达不同的Ig重链，化学准备的抗体片段或B细胞中，我们将确定狂犬病 - 神经保护抗体的结构以及其递送到CMS的平均值。该项目的最终目的是提供一项方案，即当与代理接触即将接触或最近发生时，可以通过被动免疫接触神经营养病毒。