FOCUSING IMMUNITY vs BOTULINUM TOXIN WITH CYTOKINE DNA

使用细胞因子 DNA 聚焦免疫与肉毒杆菌毒素

• 批准号: 7193447
• 负责人: DAVID S STRAYER
• 金额: $ 50.04万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7193447
• 关键词: Adenovirus Vector; Adenoviruses; Animals; Antibodies; Antibody Formation; Antigens; Bioterrorism; Botulinum Toxins; Breathing; C-terminal; Condition; Data; Dose; Effectiveness; Gene Delivery; Germ; Goals; Growth Factor; Immune response; Immunity; Immunization; Immunoglobulin G; Immunology; In Vitro; Interleukin-4; Interleukin-5; Laboratories; Measures; Mediating; Mucosal Immunity; Peptides; Plasmids; Process; Protocols documentation; Recombinants; Research; Safety; Secretory Immunoglobulin A; Serotyping; Serum; Signal Transduction; Standards of Weights and Measures; System; Terrorism; Testing; Therapeutic; Therapeutic Uses; Time; Toxic effect; Toxin; Treatment Protocols; Vaccination; Weight; aerosolized; base; cytokine; design; holotoxins; human TGFB1 protein; improved; in vivo; secretory immune system; vaccination strategy; vector

DESCRIPTION (provided by applicant): The toxin of Clostridium botulinum, particularly administered by inhalation, is a potential weapon of bioterrorism and germ warfare, and protecting people from the potentially devastating effects of its use is a high priority. At the same time, botulinum toxin (BT) has very important medicinal uses as an antispasmotic agent. We propose a collaborative project to use gene delivery of cDNAs encoding BT, serotype A (BT/A), antigens, to be given in tandem with cDNAs encoding cytokines that preferentially stimulate secretory IgA antibody (SIgA) responses. The goal of these studies is develop immunization regimens that protect from inhalational BT without precluding the important therapeutic uses of this agent. We will use both plasmid and recombinant adenoviral gene delivery vehicles to deliver both the heavy chain of BT (HC). Antibody elicited by HC protects from challenge with the complete toxin. These vectors will also deliver DNAs encoding cytokines that preferentially weight immune responses in favor of SIgA, at the expense of serum IgG antibody: transforming growth factor-beta1 and interleukins-4 and -5 (IL-4, IL-5). Our main hypothesis is: Immunizing regimens using cytokines that favor SIgA can elicit protective mucosal immunity to BT without system antibody. To test this hypothesis we propose four aims. We will: 1. Produce plasmid and adenovirus expression constructs to deliver BT/A-HC and cvtokine cDNAs. 2. Define parameters of local and svstemic immunity to BT, elicited by plasmid and rAd vectors. 3. Add cytokine-carrying vectors, individually and then in combinations, to these immunization regimens. 4. Modify expression constructs and administration regimens to optimize selectivity, protection, and safety. Thus, we will apply current understanding of the signaling mechanisms that occur during the activation of the secretory immune system to the need to protect people from the potential weaponization of botulinum toxin without limiting its important therapeutic applications.

描述（由申请人提供）：肉毒梭菌的毒素，尤其是通过吸入管理，是生物恐怖主义和细菌战的潜在武器，保护人们免受其使用的潜在毁灭性影响，这是优先的重中之重。同时，肉毒杆菌毒素（BT）具有非常重要的药用用途，作为杂质者。我们提出了一个协作项目，以使用编码BT，血清型A（BT/A）和抗原的cDNA递送，与编码细胞因子的CDNA同时给出，该细胞因子优先刺激分泌IgA抗体（SIGA）反应。这些研究的目的是开发免疫方案，可防止吸入BT，而不排除该药物的重要治疗用途。我们将同时使用质粒和重组腺病毒基因递送车辆来交付重链BT（HC）。 HC引起的抗体可通过完整的毒素保护挑战。这些载体还将提供编码的DNA，以优先考虑SIGA的细胞因子，以血清IgG抗体为代价：转化生长因子-beta1和interleukins-4和-5（IL-4，IL-4，IL-5）。我们的主要假设是： 使用有利于SIGA的细胞因子进行免疫治疗方案，可以在没有系统抗体的情况下对BT产生保护性粘膜免疫。 为了检验这一假设，我们提出了四个目标。我们将： 1。产生质粒和腺病毒表达构建体，以提供BT/A-HC和CVTokine CDNA。 2。将局部和SVSTEMINIC免疫的参数定义为BT，由质粒和RAD载体引起。 3。将细胞因子携带的向量单独地添加到这些免疫方案中。 4。修改表达构建体和管理方案，以优化选择性，保护和安全性。 因此，我们将应用对分泌免疫系统激活期间发生的信号传导机制的当前理解，以保护人们免受肉毒杆菌毒素潜在的武器化的影响，而不会限制其重要的治疗应用。