Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France.
Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires de Paris Centre-Université de Paris, Cochin Hospital, Service de Diabétologie et Immunologie Clinique, Paris, France.
Front Immunol. 2021 Aug 10;12:616215. doi: 10.3389/fimmu.2021.616215. eCollection 2021.
Tolerogenic vaccinations using beta-cell antigens are attractive for type 1 diabetes prevention, but clinical trials have been disappointing. This is probably due to the late timing of intervention, when multiple auto-antibodies are already present. We therefore devised a strategy to introduce the initiating antigen preproinsulin (PPI) during neonatal life, when autoimmunity is still silent and central tolerance mechanisms, which remain therapeutically unexploited, are more active. This strategy employs an oral administration of PPI-Fc, i.e. PPI fused with an IgG Fc to bind the intestinal neonatal Fc receptor (FcRn) that physiologically delivers maternal antibodies to the offspring during breastfeeding. Neonatal oral PPI-Fc vaccination did not prevent diabetes development in PPI T-cell receptor-transgenic G9C8.NOD mice. However, PPI-Fc was efficiently transferred through the intestinal epithelium in an Fc- and FcRn-dependent manner, was taken up by antigen presenting cells, and reached the spleen and thymus. Although not statistically significant, neonatal oral PPI-Fc vaccination delayed diabetes onset in polyclonal .NOD mice that spontaneously develop accelerated diabetes. Thus, this strategy shows promise in terms of systemic and thymic antigen delivery the intestinal FcRn pathway, but the current PPI-Fc formulation/regimen requires further improvements to achieve diabetes prevention.
使用β细胞抗原的耐受疫苗接种对 1 型糖尿病的预防具有吸引力，但临床试验结果令人失望。这可能是由于干预时间较晚，此时已经存在多种自身抗体。因此，我们设计了一种策略，即在自身免疫仍处于静默状态且尚未得到治疗性利用的中枢耐受机制更活跃的新生儿期引入起始抗原前胰岛素原（PPI）。该策略采用口服 PPI-Fc，即将 PPI 与 IgG Fc 融合，以结合肠道新生儿 Fc 受体（FcRn），在母乳喂养期间将母体抗体生理性地传递给后代。在 PPI T 细胞受体转基因 G9C8.NOD 小鼠中，新生儿口服 PPI-Fc 疫苗接种并不能预防糖尿病的发生。然而，PPI-Fc 以 Fc 和 FcRn 依赖的方式有效地通过肠上皮细胞转运，被抗原呈递细胞摄取，并到达脾脏和胸腺。尽管没有统计学意义，但新生儿口服 PPI-Fc 疫苗接种可延迟自发性发生加速糖尿病的多克隆.NOD 小鼠的糖尿病发病。因此，这种策略在通过肠道 FcRn 途径进行全身和胸腺抗原传递方面具有一定前景，但目前的 PPI-Fc 制剂/方案需要进一步改进以实现糖尿病预防。
