Relevance of the Materno-Fetal Interface for the Induction of Antigen-Specific Immune Tolerance
Abstract
Background: Transplacental delivery of maternal IgG provides humoral protection during
the first months of life until the newborn’s immune system reaches maturity. The maternofetal
interface has been exploited therapeutically to replace missing enzymes in the fetus, as
shown in experimental mucopolysaccharidoses, or to shape adaptive immune repertoires
during fetal development and induce tolerance to self-antigens or immunogenic therapeutic
molecules.
Objective: To investigate whether proteins that are administered to pregnant mice or
endogenously present in their circulation may be delivered through the placenta.
Methods: We engineered monovalent IgG (FabFc) specific for different domains of human
factor VIII (FVIII), a therapeutically relevant model antigen. The FabFc were injected with
exogenous FVIII to pregnant severe hemophilia A mice or to pregnant mice expressing human
FVIII following AAV8-mediated gene therapy. FabFc and FVIII were detected in the pregnant
mice and/or fetuses by ELISA and immunohistochemistry.
Results: Administration of FabFc to pregnant mice mediated the materno-fetal delivery of
FVIII in a FcRn-dependent manner. FVIII antigen levels achieved in the fetuses represented
10% of normal plasma levels in the human. We identify antigen/FabFc complex stability,
antigen size and shielding of promiscuous protein patches, as key parameters to foster optimal
antigen delivery.
Conclusions: Our results pave the way towards the development of novel strategies for the in
utero delivery of endogenous maternal proteins to replace genetically deficient fetal proteins
or to educate the immune system and favor active immune tolerance upon protein encounter
later in life.
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