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.
journal_name
Sci Transl Medjournal_title
Science translational medicineauthors
Gupta N,Culina S,Meslier Y,Dimitrov J,Arnoult C,Delignat S,Gangadharan B,Lecerf M,Justesen S,Gouilleux-Gruart V,Salomon BL,Scott DW,Kaveri SV,Mallone R,Lacroix-Desmazes Sdoi
10.1126/scitranslmed.aaa1957subject
Has Abstractpub_date
2015-02-18 00:00:00pages
275ra21issue
275eissn
1946-6234issn
1946-6242pii
7/275/275ra21journal_volume
7pub_type
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