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

Abstract
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.
AuthorsSlobodan Culina, Nimesh Gupta, Raphael Boisgard, Georgia Afonso, Marie-Claude Gagnerault, Jordan Dimitrov, Thomas Østerbye, Sune Justesen, Sandrine Luce, Mikhaël Attias, Bruno Kyewski, Søren Buus, F Susan Wong, Sebastien Lacroix-Desmazes, Roberto Mallone
JournalDiabetes (Diabetes) Vol. 64 Issue 10 Pg. 3532-42 (Oct 2015) ISSN: 1939-327X [Electronic] United States
PMID25918233 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
Chemical References
  • Histocompatibility Antigens Class I
  • Insulin
  • Protein Precursors
  • Receptors, Fc
  • Recombinant Proteins
  • preproinsulin
  • Fc receptor, neonatal
Topics
  • Animals
  • Autoimmunity
  • Cell Proliferation
  • Dendritic Cells (physiology)
  • Diabetes Mellitus, Type 1 (prevention & control)
  • Female
  • Gene Expression Regulation, Developmental (physiology)
  • Histocompatibility Antigens Class I (genetics, metabolism)
  • Humans
  • Insulin (administration & dosage, metabolism)
  • Maternal-Fetal Exchange (physiology)
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Placenta (metabolism)
  • Pregnancy
  • Protein Precursors (administration & dosage, metabolism)
  • Receptors, Fc (genetics, metabolism)
  • Recombinant Proteins (genetics, metabolism)
  • Specific Pathogen-Free Organisms
  • Thymus Gland (physiology)

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