title: Regulation of immune responses to protein therapeutics by transplacental induction of T cell tolerance.
abstract: Central tolerance plays a key role in modulating immune responses to self and exogenous antigens. The absence of self-antigen expression, as in patients with genetic deficiencies, prevents the development of antigen-specific immune tolerance. Hence, a substantial number of patients develop neutralizing antibodies to the corresponding protein therapeutics after replacement treatment. In this context, the administration of missing antigens during fetal development, a key period for self-tolerance establishment, should confer early and long-lasting antigen-specific tolerance. To this end, we exploited the physiological pathway of the neonatal Fc receptor (FcRn) through which maternal immunoglobulins are transplacentally transferred to fetuses. We demonstrate that Fc-fused antigens administered to pregnant mice reach fetal lymphoid organs in an FcRn-dependent manner, accumulate in antigen-presenting cells of myeloid origin, and promote the generation of both thymic and peripheral antigen-specific regulatory T cells. This strategy was successfully pursued in a mouse model of hemophilia A, where maternofetal transfer of the Fc-fused immunodominant domains of coagulation factor VIII conferred antigen-specific tolerance. Transplacental tolerance induction with Fc-fused proteins may thus prove valuable to prevent alloimmunization after replacement protein therapy for congenital deficiencies.
authors.affiliation: INSERM, U1138, F-75006 Paris, France. Centre de Recherche des Cordeliers (CRC), Equipe - Immunopathology and Therapeutic Immunointervention, F-75006 Paris, France. Sorbonne Universités, Université Pierre et Marie Curie (UPMC)-Paris 6, UMR S 1138 and UMR S CR7, F-75006 Paris, France.
authors.forename: Nimesh
authors.initials: N
authors.lastname: Gupta
authors.affiliation: INSERM, U1016, Institut Cochin, F-75014 Paris, France. CNRS, UMR8104, F-75014 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, F-75006 Paris, France.
authors.forename: Slobodan
authors.initials: S
authors.lastname: Culina
authors.affiliation: INSERM, U1138, F-75006 Paris, France. Centre de Recherche des Cordeliers (CRC), Equipe - Immunopathology and Therapeutic Immunointervention, F-75006 Paris, France. Sorbonne Universités, Université Pierre et Marie Curie (UPMC)-Paris 6, UMR S 1138 and UMR S CR7, F-75006 Paris, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Meslier
authors.affiliation: INSERM, U1138, F-75006 Paris, France. Centre de Recherche des Cordeliers (CRC), Equipe - Immunopathology and Therapeutic Immunointervention, F-75006 Paris, France. Sorbonne Universités, Université Pierre et Marie Curie (UPMC)-Paris 6, UMR S 1138 and UMR S CR7, F-75006 Paris, France.
authors.forename: Jordan
authors.initials: J
authors.lastname: Dimitrov
authors.affiliation: Université François-Rabelais de Tours, CNRS, Génétique, Immunothérapie, Chimie et Cancer (GICC), UMR 7292, F-37032 Tours, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Arnoult
authors.affiliation: INSERM, U1138, F-75006 Paris, France. Centre de Recherche des Cordeliers (CRC), Equipe - Immunopathology and Therapeutic Immunointervention, F-75006 Paris, France. Sorbonne Universités, Université Pierre et Marie Curie (UPMC)-Paris 6, UMR S 1138 and UMR S CR7, F-75006 Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Delignat
authors.affiliation: INSERM, U1138, F-75006 Paris, France. Centre de Recherche des Cordeliers (CRC), Equipe - Immunopathology and Therapeutic Immunointervention, F-75006 Paris, France. Sorbonne Universités, Université Pierre et Marie Curie (UPMC)-Paris 6, UMR S 1138 and UMR S CR7, F-75006 Paris, France.
authors.forename: Bagirath
authors.initials: B
authors.lastname: Gangadharan
authors.affiliation: INSERM, U1138, F-75006 Paris, France. Centre de Recherche des Cordeliers (CRC), Equipe - Immunopathology and Therapeutic Immunointervention, F-75006 Paris, France. Sorbonne Universités, Université Pierre et Marie Curie (UPMC)-Paris 6, UMR S 1138 and UMR S CR7, F-75006 Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Lecerf
authors.affiliation: Laboratory of Experimental Immunology, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Sune
authors.initials: S
authors.lastname: Justesen
authors.affiliation: Université François-Rabelais de Tours, CNRS, Génétique, Immunothérapie, Chimie et Cancer (GICC), UMR 7292, F-37032 Tours, France. CHRU de Tours, Laboratory of Immunology, F-37044 Tours, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gouilleux-Gruart
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC)-Paris 6, UMR S 1138 and UMR S CR7, F-75006 Paris, France. CNRS, ERL 8255, INSERM U1135, F-75013 Paris, France.
authors.forename: Benoit L
authors.initials: BL
authors.lastname: Salomon
authors.affiliation: Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.affiliation: INSERM, U1138, F-75006 Paris, France. Centre de Recherche des Cordeliers (CRC), Equipe - Immunopathology and Therapeutic Immunointervention, F-75006 Paris, France. Sorbonne Universités, Université Pierre et Marie Curie (UPMC)-Paris 6, UMR S 1138 and UMR S CR7, F-75006 Paris, France. Laboratoire International Associé IMPACT (INSERM, France-Indian Council of Medical Research, India), F-75006 Paris, France.
authors.forename: Srinivas V
authors.initials: SV
authors.lastname: Kaveri
authors.affiliation: INSERM, U1016, Institut Cochin, F-75014 Paris, France. CNRS, UMR8104, F-75014 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, F-75006 Paris, France. Assistance Publique Hôpitaux de Paris, Service de Diabétologie, Hôpital Cochin, F-75014 Paris, France.
authors.forename: Roberto
authors.initials: R
authors.lastname: Mallone
authors.affiliation: INSERM, U1138, F-75006 Paris, France. Centre de Recherche des Cordeliers (CRC), Equipe - Immunopathology and Therapeutic Immunointervention, F-75006 Paris, France. Sorbonne Universités, Université Pierre et Marie Curie (UPMC)-Paris 6, UMR S 1138 and UMR S CR7, F-75006 Paris, France. Laboratoire International Associé IMPACT (INSERM, France-Indian Council of Medical Research, India), F-75006 Paris, France. sebastien.lacroix-desmazes@crc.jussieu.fr.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lacroix-Desmazes
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D004705:Endocytosis; D005169:Factor VIII / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D006467:Hemophilia A / Q000628:therapy; D007108:Immune Tolerance; D008431:Maternal-Fetal Exchange; D051379:Mice; D010920:Placenta / Q000276:immunology*; D011247:Pregnancy; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; C078147:F8 protein, human; D005169:Factor VIII