Quantitative mechanistic model reveals key determinants of placental IgG transfer and informs prenatal immunization strategies.
Quantitative mechanistic model reveals key determinants of placental IgG transfer and informs prenatal immunization strategies.
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定量机制模型揭示了胎盘 IgG 转移的关键决定因素，并为产前免疫策略提供了信息。
DOI：
10.1101/2023.04.18.537285
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Dolatshahi,Sepideh
中科院分区：
文献类型：
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作者：
Erdogan,RemziyeR;Dolatshahi,Sepideh
经胎盘抗体转移在新生儿免疫形成中至关重要。最近，产前母体免疫已被用于促进病原体特异性免疫球蛋白G（IgG）转移到胎儿。抗体转移涉及多种因素，但这些关键调节因子如何共同作用以引发选择性转移与母亲工程疫苗有关，以最佳地免疫新生儿。在这里，我们提出了第一个定量机制模型来揭示胎盘抗体转移的决定因素，并告知个性化的免疫方法。我们确定内皮细胞表达的胎盘FcγRIIb是受体介导的转移的限制因子，在促进IgG1、IgG3和IgG4亚类优先转运中发挥关键作用，但对IgG2无影响。综合计算模型和体外实验表明，IgG亚类丰度，Fc受体（FcR）结合亲和力，FcR丰度在合体滋养层和内皮细胞有助于亚类间的竞争和潜在的病人间和病人内的抗体转移异质性。我们开发了一个硅化产前疫苗试验床，通过将母体接种的计算模型与使用破伤风、白喉和无细胞百日咳（Tdap）疫苗作为案例研究的胎盘转移模型相结合。模型模拟揭示了精确的产前免疫机会，占患者的预期妊娠期长度，胎盘大小，和FcR表达通过调节疫苗的时机，剂量和佐剂。这种计算方法提供了新的观点，在人类母胎抗体转移的动态和潜在的途径，以优化产前疫苗接种，促进新生儿免疫。
Transplacental antibody transfer is crucially important in shaping neonatal immunity. Recently, prenatal maternal immunization has been employed to boost pathogen-specific immunoglobulin G (IgG) transfer to the fetus. Multiple factors have been implicated in antibody transfer, but how these key regulators work together to elicit selective transfer is pertinent to engineering vaccines for mothers to optimally immunize their newborns. Here, we present the first quantitative mechanistic model to uncover the determinants of placental antibody transfer and inform personalized immunization approaches. We identified placental FcγRIIb expressed by endothelial cells as a limiting factor in receptor-mediated transfer, which plays a key role in promoting preferential transport of subclasses IgG1, IgG3, and IgG4, but not IgG2. Integrated computational modeling andin vitroexperiments reveal that IgG subclass abundance, Fc receptor (FcR) binding affinity, and FcR abundance in syncytiotrophoblasts and endothelial cells contribute to inter-subclass competition and potentially inter- and intra-patient antibody transfer heterogeneity. We developed anin silicoprenatal vaccine testbed by combining a computational model of maternal vaccination with this placental transfer model using the tetanus, diphtheria, and acellular pertussis (Tdap) vaccine as a case study. Model simulations unveiled precision prenatal immunization opportunities that account for a patient’s anticipated gestational length, placental size, and FcR expression by modulating vaccine timing, dosage, and adjuvant. This computational approach provides new perspectives on the dynamics of maternal-fetal antibody transfer in humans and potential avenues to optimize prenatal vaccinations that promote neonatal immunity.