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Modulation of humoral immunity to a ricin vaccine antigen by wild-type and mutant type II heat-labile enterotoxins.

机译：野生型和突变型II型热不稳定肠毒素对蓖麻毒蛋白疫苗抗原的体液免疫的调节。

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摘要

As incidents of bioterrorism increase across the globe, the need to develop safe and effective vaccines against potential biological agents is high. A large effort is currently underway to develop a safe and effective vaccine against ricin toxin, which has been identified as a weapon of mass destruction and potential bioterror weapon. One of the top candidate antigens (Ag) for the ricin vaccine is RiVax, an engineered detoxified ricin A-subunit. There is a concurrent search for novel adjuvants to augment the ricin vaccine for administration specifically in the skin.;The type II heat-labile enterotoxins (HLT) expressed by enterotoxigenic Escherichia coli were initially identified as potent mucosal adjuvants when administered by the intranasal (i.n.) route. Due to inherent toxicity, neuronal trafficking along the olfactory bulb, and neuroinflammatory propensities of HLT when administered intranasally, their use as adjuvants by this route has been discouraged. Nevertheless, this setback has fostered exploration of new, alternative routes of administration of HLT and for the development of detoxified, mutant HLT.;LT-IIb and LT-IIb(T13I) are the best studied members of the type II subfamily of HLT. In this study, the ability of LT-IIb and LT-IIb(T13I), a mutant HLT with alterations in receptor-binding affinity, to augment humoral immunity to a co-administered Ag (RiVax) by the intradermal (i.d.) route was evaluated. Results of this study demonstrated that LT-IIb and LT-IIb(T13I) possess potent i.d. adjuvant properties and enhance the production of RiVax-specific serum IgG antibodies (Ab). LT-IIb(T13I) is significantly less inflammatory than LT-IIb when administered into the skin. Strikingly, both LT-IIb and LT-IIb(T13I), when employed as i.d. adjuvants, enhanced the ability of RiVax to produce critical ricin-neutralizing Ab. Yet, when employed as intranasal adjuvants with RiVax, LT-IIb and LT-IIb(T13I) failed to enhance production of ricin-neutralizing Ab. Importantly, when subjected to ricin challenge, significantly more mice survived challenge when immunized by the i.d. route with RiVax and LT-IIb(T13I) in comparison to mice that received RiVax alone. Taken together, these data highlight the potent i.d. adjuvant properties of LT-IIb and LT-IIb(T13I) toward RiVax.;Further development of these adjuvants as clinical agents requires an identification of the mechanism(s) that underlie their immunoenhancing properties. Analysis of tissue fluid and serum from mice intradermally immunized with RiVax in combination with LT-IIb or LT-IIb(T13I) showed robust production of IL-6, a cytokine known to drive humoral immunity. I.d. immunization of IL-6 knockout mice with RiVax and LT-IIb or LT-IIb(T13I) resulted in significantly decreased RiVax-specific IgG Ab in comparison to their wild-type counterparts. I.d. administration of recombinant IL-6 with RiVax produced Ag-specific and ricin-neutralizing Ab to levels that were similar to those produced by i.d. immunization of mice with RiVax and LT-IIb. Finally, a cellular source of IL-6 induced by LT-IIb and LT-IIb(T13I) was identified as skin infiltrating neutrophils. Ablation of neutrophils was correlated with a decrease in RiVax-specific IgG Ab. These data provided strong evidence that IL-6 and infiltrating neutrophils are important components of the i.d. adjuvant response of LT-IIb enterotoxins.;In summation, the capacity of LT-IIb and LT-IIb(T13I) to function as i.d. adjuvants to enhance B cell activity and stimulate Ag-specific humoral immune responses is critical for subsequent development of effective protein subunit vaccines designed for administration into the skin. Overall, the non-toxic, low inflammatory nature of LT-IIb(T13I) combined with its potent adjuvant properties indicates that this mutant type II HLT is a novel, safe, and effective i.d. adjuvant with potential clinical utility.
机译：随着全球范围内生物恐怖主义事件的增多，迫切需要开发针对潜在生物制剂的安全有效疫苗。目前正在大力开发一种针对蓖麻毒素的安全有效疫苗，该疫苗已被确认为大规模杀伤性武器和潜在的生物恐怖武器。蓖麻毒蛋白疫苗的最佳候选抗原（Ag）之一是RiVax，它是一种工程化的解毒蓖麻毒蛋白A亚基。目前正在寻找新的佐剂来增强蓖麻毒蛋白疫苗，以特别地在皮肤中给药。肠毒素（经鼻内给药）最初由肠毒素产生的大肠杆菌表达的II型不耐热肠毒素（HLT）被认为是有效的粘膜佐剂。 ）路线。由于内在的毒性，沿嗅球的神经元运输以及鼻内给药时HLT的神经炎症倾向，不鼓励通过这种途径将其用作佐剂。然而，这种挫折促使人们探索了HLT的新的替代治疗途径，并促进了脱毒的突变HLT的发展。LT-IIb和LT-IIb（T13I）是HLT II型亚家族中研究最好的成员。在这项研究中，LT-IIb和LT-IIb（T13I）（一种具有受体结合亲和力改变的突变型HLT）通过皮内（id）途径增强对共同施用的Ag（RiVax）的体液免疫的能力是评估。这项研究的结果表明，LT-IIb和LT-IIb（T13I）具有强大的内径。佐剂特性，增强RiVax特异性血清IgG抗体（Ab）的产生。当施用于皮肤时，LT-IIb（T13I）的炎症性明显低于LT-IIb。引人注目的是，LT-IIb和LT-IIb（T13I）当用作i.d。佐剂，增强了RiVax产生关键的蓖麻毒素中和抗体的能力。然而，当与RiVax一起作为鼻内佐剂使用时，LT-IIb和LT-IIb（T13I）无法提高蓖麻毒素中和抗体的产量。重要的是，当接受蓖麻毒蛋白激发时，经内毒素免疫后，明显更多的小鼠存活了激发。与仅接受RiVax的小鼠相比，RiVax和LT-IIb（T13I）具有更好的免疫途径。这些数据加在一起显示了有效的内径LT-IIb和LT-IIb（T13I）对RiVax的佐剂特性;这些佐剂作为临床药物的进一步发展需要确定其免疫增强特性的基础机制。对使用RiVax与LT-IIb或LT-IIb（T13I）联合进行皮内免疫的小鼠的组织液和血清的分析显示，IL-6的产生强劲，IL-6是一种已知可驱动体液免疫的细胞因子。 ID。与野生型相比，用RiVax和LT-IIb或LT-IIb（T13I）免疫IL-6基因敲除小鼠可导致RiVax特异性IgG Ab明显降低。 ID。用RiVax施用重组IL-6可以产生与i.d.产生的相似的Ag特异性和蓖麻毒素中和的Ab。 RiVax和LT-IIb免疫小鼠。最后，LT-IIb和LT-IIb（T13I）诱导的IL-6的细胞来源被确定为皮肤浸润性中性粒细胞。中性粒细胞的消融与RiVax特异性IgG Ab的减少相关。这些数据提供了有力的证据，证明IL-6和浸润性中性粒细胞是内脏的重要组成部分。总的来说，LT-IIb和LT-IIb（T13I）的功能如前所述。增强B细胞活性并刺激Ag特异性体液免疫应答的佐剂对于设计用于皮肤给药的有效蛋白亚基疫苗的后续开发至关重要。总体而言，LT-IIb（T13I）的无毒，低炎症性及其有效的佐剂特性表明，该突变型II HLT是一种新颖，安全且有效的内毒素。具有潜在临床实用性的佐剂。

著录项

  • 作者

    Greene, Christopher John.;

  • 作者单位

    State University of New York at Buffalo.;

  • 授予单位 State University of New York at Buffalo.;
  • 学科 Immunology.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 136 p.
  • 总页数 136
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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