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

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.

Maternally transferred anti-factor VIII IgG reduce the anti-factor VIII humoral immune response in factor VIII-deficient mice.

Replacement therapy with exogenous factor VIII (FVIII) to treat haemorrhages or used in prophylaxis induces inhibitory anti-FVIII immunoglobulin G (IgG) in some patients with haemophilia A. Therapeutic strategies to prevent the onset of the deleterious anti-FVIII immune response are still lacking. Maternal IgG is transferred to the offspring during fetal and neonatal life. While protecting the offspring from bacterial and viral infections, maternal IgG may alter the repertoires of T and B lymphocytes, and may impair vaccination in early infancy. Using haemophilic mice, we demonstrate that the transfer of maternal anti-FVIII IgG modulates the onset of anti-FVIII inhibitory IgG in early adulthood. The protective effect is reproduced upon reconstitution of naive mice with anti-FVIII IgG, suggesting that the reduced ability to mount an anti-FVIII immune response is the result of an interference between circulating anti-FVIII IgG and the administered FVIII rather than to a profound remodelling of lymphocyte repertoires occurring during the ontogeny of the immune system.

Induction of heme oxygenase-1 in factor VIII-deficient mice reduces the immune response to therapeutic factor VIII.

Replacement therapy with exogenous factor VIII (FVIII) to treat hemorrhages induces anti-FVIII inhibitory immunoglobulin G in up to 30% of patients with hemophilia A. Chronic inflammation associated with recurrent bleedings is a proposed risk factor for FVIII inhibitor development. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with potent anti-inflammatory activity. Here, we demonstrate that induction of HO-1 before FVIII administration drastically reduces the onset of the anti-FVIII humoral immune response. The protective effect was specific for HO-1 because it was reproduced on administration of the end products of HO-1 activity, carbon monoxide, and bilirubin, and prevented by the pharmacologic inhibition of HO-1 using tin mesoporphyrin IX. HO-1 induction was associated with decreased major histocompatibility complex class II expression by splenic antigen-presenting cells and reduced T-cell proliferation. Triggering the endogenous anti-inflammatory machinery before FVIII administration may represent a novel therapeutic option for preventing the development of FVIII inhibitors in hemophilia A patients.

A cellular viewpoint of anti-FVIII immune response in hemophilia A.

A large proportion of hemophilia A patients who receive replacement therapy, develop an immune response toward the infused factor VIII (FVIII). In this review, we discuss recent progress in several aspects of the anti-FVIII immune response, focusing on the sites of FVIII endocytosis (marginal zone of the spleen and bleeding site), the type of antigen-presenting cells (dendritic cells, macrophages and B cells) and endocytic receptors, implicated in FVIII presentation to T cells during primary and secondary immune response. Although it is becoming increasingly clear that regulatory T cells are involved in FVIII tolerance in healthy subjects and potentially in patients without inhibitors, we would like to demonstrate that little is known about the different T cells subsets and the cytokines network, which are also crucial for the development of allo- and autoimmune diseases. As more information on these issues becomes available, a better understanding of the role of each immune cells compartment in promoting FVIII tolerance or inhibitors development might lead to new strategies to promote FVIII tolerance in hemophilia A patients.