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.

Materno-Fetal Transfer of Preproinsulin Through the Neonatal Fc Receptor Prevents Autoimmune Diabetes

“…In summary, the therapeutic mechanism was dependent on FcRn-mediated PPI-Fc transfer and cDC migration to the thymus and resulted in impaired Teff cytotoxicity and enhanced selection of thymic Tregs. Moreover, we recently applied a similar strategy of transplacental Ag-Fc administration in the CD4 + hemagglutinin (HA) 110-119 TCRtransgenic 6.5 mouse model (41) to fully dissect therapeutic mechanisms (20). HA-Fc ferrying to the thymus was also observed in this model, and three differences were highlighted.…”

“…Follow-up studies are needed to explore whether such protection is maintained in NOD mice prospectively observed for diabetes development. Of further note, applications could reach beyond autoimmunity, as this strategy was also effective at promoting neoAg-specific tolerance toward clotting factor VIII (FVIII) in FVIII 2/2 mice challenged with therapeutic FVIII (20). The possibility of employing a single PPI-Fc dose to induce long-lasting tolerance is attractive for translation to genetically at-risk children.…”

“…AF680-labeled PPI-Fc were injected into pregnant G9C8 mice at E18. In vivo imaging demonstrated selective PPI-Fc accumulation in the uterine horns ( mice (20). Interestingly however, PPI-Fc was detectable at the vascularized placental interface (Fig.…”

The European Hematology Association Roadmap for European Hematology Research: a consensus document

“…Several strategies are being investigated to reduce the immunogenicity of therapeutic factor VIII. These include alteration of factor VIII moieties implicated in its processing/recognition by immune effectors, control of the inflammatory status of the patients at the time of replacement therapy and induction of active immune tolerance, for example, upon oral or transplacental transfer of factor VIII, 293 or using cell therapy for tolerance induction.…”

The national blueprint for pregnancy/birth longitudinal cohorts to study factor VIII immunogenicity: NHLBI State of the Science (SOS) Workshop on factor VIII inhibitors

“…Materials transferred to the foetus by nondiffusional transport, such as immunoglobulin via neonatal Fc receptors, could exert immune effects and may offer mechanisms for transfer of drugs to the foetus . Maternal cells can also reach the foetus leading to chimerism .…”