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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.
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https://hal-univ-tours.archives-ouvertes.fr/hal-02425481
Contributor : Valérie Gouilleux <>
Submitted on : Monday, December 30, 2019 - 3:45:39 PM
Last modification on : Friday, September 18, 2020 - 2:35:03 PM

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Nimesh Gupta, Slobodan Culina, Yann Meslier, Jordan Dimitrov, Christophe Arnoult, et al.. Regulation of immune responses to protein therapeutics by transplacental induction of T cell tolerance. Science Translational Medicine, American Association for the Advancement of Science, 2015, 7 (275), pp.275ra21-275ra21. ⟨10.1126/scitranslmed.aaa1957⟩. ⟨hal-02425481⟩

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