Culina Slobodan, Gupta Nimesh, Boisgard Raphael, Afonso Georgia, Gagnerault Marie-Claude, Dimitrov Jordan, Østerbye Thomas, Justesen Sune, Luce Sandrine, Attias Mikhaël, Kyewski Bruno, Buus Søren, Wong F Susan, Lacroix-Desmazes Sebastien, Mallone Roberto
INSERM, U1016, Cochin Institute, Paris, France CNRS, UMR 8104, Cochin Institute, Paris, France Paris Descartes University, Sorbonne Paris Cité, Paris, France.
INSERM, UMRS 1138, Les Cordeliers Research Center, Paris, France Pierre et Marie Curie-Paris 6 University, Sorbonne Universities, UMRS 1138, Paris, France Paris Descartes University, UMRS 1138, Paris, France.
Diabetes. 2015 Oct;64(10):3532-42. doi: 10.2337/db15-0024. Epub 2015 Apr 27.
The first signs of autoimmune activation leading to β-cell destruction in type 1 diabetes (T1D) appear during the first months of life. Thus, the perinatal period offers a suitable time window for disease prevention. Moreover, thymic selection of autoreactive T cells is most active during this period, providing a therapeutic opportunity not exploited to date. We therefore devised a strategy by which the T1D-triggering antigen preproinsulin fused with the immunoglobulin (Ig)G Fc fragment (PPI-Fc) is delivered to fetuses through the neonatal Fc receptor (FcRn) pathway, which physiologically transfers maternal IgGs through the placenta. PPI-Fc administered to pregnant PPIB15-23 T-cell receptor-transgenic mice efficiently accumulated in fetuses through the placental FcRn and protected them from subsequent diabetes development. Protection relied on ferrying of PPI-Fc to the thymus by migratory dendritic cells and resulted in a rise in thymic-derived CD4(+) regulatory T cells expressing transforming growth factor-β and in increased effector CD8(+) T cells displaying impaired cytotoxicity. Moreover, polyclonal splenocytes from nonobese diabetic (NOD) mice transplacentally treated with PPI-Fc were less diabetogenic upon transfer into NOD.scid recipients. Transplacental antigen vaccination provides a novel strategy for early T1D prevention and, further, is applicable to other immune-mediated conditions.
1型糖尿病（T1D）中导致β细胞破坏的自身免疫激活的最初迹象出现在生命的最初几个月。因此，围产期为疾病预防提供了一个合适的时间窗口。此外，自身反应性T细胞的胸腺选择在此期间最为活跃，提供了一个迄今为止尚未利用的治疗机会。因此，我们设计了一种策略，通过该策略，与免疫球蛋白（Ig）G Fc片段融合的T1D触发抗原前胰岛素原（PPI-Fc）通过新生儿Fc受体（FcRn）途径递送至胎儿，该途径在生理上通过胎盘转运母体IgG。给怀孕的PPIB15-23 T细胞受体转基因小鼠施用PPI-Fc可通过胎盘FcRn有效地在胎儿中积累，并保护它们免受随后的糖尿病发展。保护依赖于迁移性树突状细胞将PPI-Fc转运至胸腺，并导致表达转化生长因子-β的胸腺来源的CD4(+)调节性T细胞增加，以及细胞毒性受损的效应性CD8(+) T细胞增加。此外，经PPI-Fc经胎盘处理的非肥胖糖尿病（NOD）小鼠的多克隆脾细胞在转移到NOD.scid受体中时致糖尿病性较低。经胎盘抗原疫苗接种为早期T1D预防提供了一种新策略，并且进一步适用于其他免疫介导的疾病。
