Rocuronium-specific antibodies drive perioperative anaphylaxis but can also function as reversal agents in preclinical models

IF 15.8 1区 医学 Q1 CELL BIOLOGY
Alice Dejoux, Qianqian Zhu, Christelle Ganneau, Odile Richard-Le Goff, Ophélie Godon, Julien Lemaitre, Francis Relouzat, François Huetz, Aurélien Sokal, Alexis Vandenberghe, Cyprien Pecalvel, Lise Hunault, Thomas Derenne, Caitlin M. Gillis, Bruno Iannascoli, Yidan Wang, Thierry Rose, Christel Mertens, Pascale Nicaise-Roland, NASA Study Group, Patrick England, Matthieu Mahévas, Luc de Chaisemartin, Roger Le Grand, Hélène Letscher, Frederick Saul, Cédric Pissis, Ahmed Haouz, Laurent L. Reber, Pascal Chappert, Friederike Jönsson, Didier G. Ebo, Gaël A. Millot, Sylvie Bay, Sylvie Chollet-Martin, Aurélie Gouel-Chéron, Pierre Bruhns
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引用次数: 0

Abstract

Neuromuscular blocking agents (NMBAs) relax skeletal muscles to facilitate surgeries and ease intubation but can lead to adverse reactions, including complications because of postoperative residual neuromuscular blockade (rNMB) and, in rare cases, anaphylaxis. Both adverse reactions vary between types of NMBAs, with rocuronium, a widely used nondepolarizing NMBA, inducing one of the longest rNMB durations and highest anaphylaxis incidences. rNMB induced by rocuronium can be reversed by the synthetic γ-cyclodextrin sugammadex. However, in rare cases, sugammadex can provoke anaphylaxis. Thus, additional therapeutic options are needed. Rocuronium-induced anaphylaxis is proposed to rely on preexisting rocuronium-binding antibodies. To understand the pathogenesis of rocuronium-induced anaphylaxis and to identify potential therapeutics, we investigated the memory B cell antibody repertoire of patients with suspected hypersensitivity to rocuronium. We identified polyclonal antibody repertoires with a high diversity among V(D)J genes without evidence of clonal groups. When recombinantly expressed, these antibodies demonstrated specificity and low affinity for rocuronium without cross-reactivity for other NMBAs. Moreover, when these antibodies were expressed as human immunoglobulin E (IgE), they triggered human mast cell activation and passive systemic anaphylaxis in transgenic mice, although their affinities were insufficient to serve as reversal agents. Rocuronium-specific, high-affinity antibodies were thus isolated from rocuronium-immunized mice. The highest-affinity antibody was able to reverse rocuronium-induced neuromuscular blockade in nonhuman primates with kinetics comparable to that of sugammadex. Together, these data support the hypothesis that antibodies cause anaphylactic reactions to rocuronium and pave the way for improved diagnostics and neuromuscular blockade reversal agents.
罗库溴铵特异性抗体会导致围手术期过敏性休克,但在临床前模型中也能起到逆转作用
神经肌肉阻滞剂(NMBA)可放松骨骼肌,从而促进手术并方便插管,但也可能导致不良反应,包括术后残留神经肌肉阻滞(rNMB)引起的并发症,以及极少数情况下的过敏性休克。这两种不良反应因 NMBA 类型而异,其中罗库溴铵是一种广泛使用的非去极化 NMBA,可诱导最长的 rNMB 持续时间和最高的过敏性休克发生率。然而,在极少数情况下,苏甘麦得可引发过敏性休克。因此,还需要其他治疗方案。有人提出,罗库溴铵诱发的过敏性休克依赖于预先存在的罗库溴铵结合抗体。为了了解罗库溴铵诱发过敏性休克的发病机理并确定潜在的治疗方法,我们研究了疑似对罗库溴铵过敏的患者的记忆 B 细胞抗体复合物。我们发现多克隆抗体复合物在 V(D)J 基因间具有高度多样性,但没有克隆群的迹象。重组表达时,这些抗体对罗库溴铵表现出特异性和低亲和性,而对其他 NMBAs 没有交叉反应。此外,当这些抗体表达为人类免疫球蛋白 E(IgE)时,它们会引发转基因小鼠的人类肥大细胞活化和被动性全身过敏性休克,尽管它们的亲和力不足以作为逆转剂。因此,我们从免疫了罗库溴铵的小鼠体内分离出了罗库溴铵特异性高亲和力抗体。亲和力最高的抗体能够逆转非人灵长类动物中洛库铵诱导的神经肌肉阻滞,其动力学与苏加麦克斯相当。这些数据共同支持了抗体导致罗库溴铵过敏反应的假设,并为改进诊断和神经肌肉阻滞逆转剂铺平了道路。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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