Materno-Fetal Transfer of Preproinsulin Through the Neonatal Fc Receptor Prevents Autoimmune Diabetes.
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.
INSERM, U1016, Cochin Institute, Paris, France CNRS, UMR 8104, Cochin Institute, Paris, France Paris Descartes University, Sorbonne Paris Cité, Paris, France.
Slobodan
S
Culina
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.
Nimesh
N
Gupta
CEA/DSV/IBM/SHFJ/U1023, Laboratory of Experimental Molecular Imaging, Orsay, France.
Raphael
R
Boisgard
INSERM, U1016, Cochin Institute, Paris, France CNRS, UMR 8104, Cochin Institute, Paris, France Paris Descartes University, Sorbonne Paris Cité, Paris, France.
Georgia
G
Afonso
INSERM, U1016, Cochin Institute, Paris, France CNRS, UMR 8104, Cochin Institute, Paris, France Paris Descartes University, Sorbonne Paris Cité, Paris, France.
Marie-Claude
MC
Gagnerault
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.
Jordan
J
Dimitrov
Department of International Health, Immunology and Microbiology, Panum Institute, Copenhagen, Denmark.
Thomas
T
Østerbye
Department of International Health, Immunology and Microbiology, Panum Institute, Copenhagen, Denmark.
Sune
S
Justesen
INSERM, U1016, Cochin Institute, Paris, France CNRS, UMR 8104, Cochin Institute, Paris, France Paris Descartes University, Sorbonne Paris Cité, Paris, France.
Sandrine
S
Luce
INSERM, U1016, Cochin Institute, Paris, France CNRS, UMR 8104, Cochin Institute, Paris, France Paris Descartes University, Sorbonne Paris Cité, Paris, France.
Mikhaël
M
Attias
Division of Developmental Immunology, DKFZ, Heidelberg, Germany.
Bruno
B
Kyewski
Department of International Health, Immunology and Microbiology, Panum Institute, Copenhagen, Denmark.
Søren
S
Buus
Institute of Molecular & Experimental Medicine, Cardiff University, Cardiff, U.K.
F Susan
FS
Wong
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.
Sebastien
S
Lacroix-Desmazes
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.
Roberto
http://orcid.org/0000-0002-9846-8861
R
Mallone
D000818:Animals; D015551:Autoimmunity; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism*; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011498:Protein Precursors / Q000008:administration & dosage / Q000378:metabolism*; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D013950:Thymus Gland / Q000502:physiology
D015395:Histocompatibility Antigens Class I; D007328:Insulin; D011498:Protein Precursors; D011961:Receptors, Fc; D011994:Recombinant Proteins; C013737:preproinsulin; C100688:Fc receptor, neonatal