Materno-Fetal Transfer of Preproinsulin Through the Neonatal Fc Receptor Prevents Autoimmune Diabetes

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity
  • Cell Proliferation
  • Dendritic Cells / physiology
  • Diabetes Mellitus, Type 1 / prevention & control*
  • Female
  • Gene Expression Regulation, Developmental / physiology
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Insulin / administration & dosage
  • Insulin / metabolism*
  • Maternal-Fetal Exchange / physiology*
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Placenta / metabolism
  • Pregnancy
  • Protein Precursors / administration & dosage
  • Protein Precursors / metabolism*
  • Receptors, Fc / genetics
  • Receptors, Fc / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Specific Pathogen-Free Organisms
  • Thymus Gland / physiology


  • Histocompatibility Antigens Class I
  • Insulin
  • Protein Precursors
  • Receptors, Fc
  • Recombinant Proteins
  • preproinsulin
  • Fc receptor, neonatal