Nanomedicine Research and Education Center, Semmelweis University, Budapest & Department Nanobiotechnology, Miskolc University, Miskolc, Hungary.
Mol Immunol. 2014 Oct;61(2):163-73. doi: 10.1016/j.molimm.2014.06.038. Epub 2014 Aug 12.
Intravenous injection of a variety of nanotechnology enhanced (liposomal, micellar, polymer-conjugated) and protein-based (antibodies, enzymes) drugs can lead to hypersensitivity reactions (HSRs), also known as infusion, or anaphylactoid reactions. The molecular mechanism of mild to severe allergy symptoms may differ from case to case and is mostly not known, however, in many cases a major cause, or contributing factor is activation of the complement (C) system. The clinical relevance of C activation-related HSRs, a non-IgE-mediated pseudoallergy (CARPA), lies in its unpredictability and occasional lethal outcome. Accordingly, there is an unmet medical need to develop laboratory assays and animal models that quantitate CARPA. This review provides basic information on CARPA; a short history, issues of nomenclature, incidence, classification of reactogenic drugs and symptoms, and the mechanisms of C activation via different pathways. It is pointed out that anaphylatoxin-induced mast cell release may not entirely explain the severe reactions; a "second hit" on allergy mediating cells may also contribute. In addressing the increasing requirements for CARPA testing, the review evaluates the available assays and animal models, and proposes a possible algorithm for the screening of reactogenic drugs and hypersensitive patients. Finally, an analogy is proposed between CARPA and the classic stress reaction, suggesting that CARPA represents a "blood stress" reaction, a systemic fight of the body against harmful biological and chemical agents via the anaphylatoxin/mast-cell/circulatory system axis, in analogy to the body's fight of physical and emotional stress via the hypothalamo/pituitary/adrenal axis. In both cases the response to a broad variety of noxious effects are funneled into a uniform pattern of physiological changes.
静脉注射各种纳米技术增强（脂质体、胶束、聚合物偶联）和基于蛋白质的（抗体、酶）药物可导致过敏反应（HSR），也称为输注或类过敏反应。从轻度到重度过敏症状的分子机制可能因病例而异，而且大多数情况下并不清楚，但在许多情况下，主要原因或促成因素是补体（C）系统的激活。C 激活相关 HSR，非 IgE 介导的假性过敏（CARPA）的临床相关性在于其不可预测性和偶尔致命的结果。因此，开发定量 CARPA 的实验室检测和动物模型存在未满足的医学需求。
本篇综述提供了 CARPA 的基本信息；简要的历史、命名问题、发生率、致反应性药物和症状的分类以及通过不同途径激活 C 的机制。指出过敏毒素诱导的肥大细胞释放可能不完全解释严重反应；过敏中介细胞的“二次打击”也可能有贡献。在满足对 CARPA 测试的需求不断增加的情况下，该综述评估了现有的检测和动物模型，并提出了一种可能的筛选致反应性药物和过敏患者的算法。
最后，在 CARPA 和经典应激反应之间提出了一个类比，表明 CARPA 代表了一种“血液应激”反应，即身体通过过敏毒素/肥大细胞/循环系统轴对抗有害的生物和化学制剂的全身性战斗，类似于身体通过下丘脑/垂体/肾上腺轴对抗身体和情绪压力的战斗。在这两种情况下，对各种有害影响的反应都被汇集到一种统一的生理变化模式中。
