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Sci Transl Med. 2015 Feb 18;7(275):275ra21. doi: 10.1126/scitranslmed.aaa1957.

Regulation of immune responses to protein therapeutics by transplacental induction of T cell tolerance.

Author information

1
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.
2
INSERM, U1016, Institut Cochin, F-75014 Paris, France. CNRS, UMR8104, F-75014 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, F-75006 Paris, France.
3
Université François-Rabelais de Tours, CNRS, Génétique, Immunothérapie, Chimie et Cancer (GICC), UMR 7292, F-37032 Tours, France.
4
Laboratory of Experimental Immunology, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
5
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.
6
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.
7
Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
8
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.
9
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.
10
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.

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.

PMID:
25696000
DOI:
10.1126/scitranslmed.aaa1957
[Indexed for MEDLINE]

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