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Diabetes. 2015 Oct;64(10):3532-42. doi: 10.2337/db15-0024. Epub 2015 Apr 27.

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

Author information

1
INSERM, U1016, Cochin Institute, Paris, France CNRS, UMR 8104, Cochin Institute, Paris, France Paris Descartes University, Sorbonne Paris Cité, Paris, France.
2
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.
3
CEA/DSV/IBM/SHFJ/U1023, Laboratory of Experimental Molecular Imaging, Orsay, France.
4
Department of International Health, Immunology and Microbiology, Panum Institute, Copenhagen, Denmark.
5
Division of Developmental Immunology, DKFZ, Heidelberg, Germany.
6
Institute of Molecular & Experimental Medicine, Cardiff University, Cardiff, U.K.
7
INSERM, U1016, Cochin Institute, Paris, France CNRS, UMR 8104, Cochin Institute, Paris, France Paris Descartes University, Sorbonne Paris Cité, Paris, France Department of Diabetology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France roberto.mallone@inserm.fr.

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.

PMID:
25918233
DOI:
10.2337/db15-0024
[Indexed for MEDLINE]
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