Tolerance induction in hemophilia: innovation and accomplishments

Abstract

Purpose of review: Hemophilia is an X-linked blood coagulation genetic disorder, which can cause significant disability. Replacement therapy for coagulation factor VIII (hemophilia A) or factor IX (hemophilia B) may result in the development of high-affinity alloantibodies ('inhibitors') to the replacement therapy, thus making it ineffective. Therefore, there is interest in directing immunological responses towards tolerance to infused factors.

Recent findings: In this review, we will discuss latest advancements in the development of potentially less immunogenic replacement clotting factors, optimization of current tolerance induction protocols (ITI), preclinical and clinical data of pharmacological immune modulation, hepatic gene therapy, and the rapidly advancing field of cell therapies. We will also evaluate publications reporting data from preclinical studies on oral tolerance induction using chloroplast-transgenic (transplastomic) plants.

Summary: Until now, no clinical prophylactic immune modulatory protocol exists to prevent inhibitor formation to infused clotting factors. Recent innovative technologies provide hope for improved eradication and perhaps even prevention of inhibitors.

Figure 1.

Overview of key cellular components that modulate inhibitor formation in hemophilia. Professional antigen presenting cells (APCs) such as dendritic cells present peptides derived from FVIII or FIX via their MHC II molecules to CD4⁺ T cells. These may differentiate into T helper cells and aid in the activation of B cells (which in turn produce the inhibitory antibodies). Peptide presentation by APCs to CD4⁺ T cells may also result in the induction of Tregs (regulatory CD4⁺ T cells) that actively suppress immune responses. Inhibitor development is largely dependent on CD4⁺ T cell help, which can, however, be suppressed by Tregs. Factors that lead to CD4⁺ T cell anergy (unresponsiveness) or their deletion also contribute to the prevention of the immune response. It is unclear whether Tregs can directly interact with and suppress activated B cells from differentiating into memory B cells or directly suppress inhibitor-producing plasma cells. High antigen doses directly inhibit memory B cells, leading to down-regulation of inhibitor formation.

Figure 2.

Experimental approaches to promote tolerance to clotting factor therapy that may serve to replace or supplement conventional ITI. In vivo gene transfer into the tolerogenic liver microenvironment using either AAV or lentiviral vectors promoted tolerance in several pre-clinical models. The immunomodulatory drug rapamycin, either alone or encapsulated in nanoparticles, is tolerogenic when co-administered with antigen. Fc-conjugation of FVIII/FIX may not only increase half-life in circulation but also facilitate tolerance induction. Oral administration of lettuce-encapsulated clotting factor leads to tolerance, which is mediated by the induction of at least two types of Tregs. Cellular therapy with either ex vivo expanded Tregs, engineered Tregs expressing specific TCRs, or CAR-Tregs that have receptor specificity to clotting factor without MHC restriction, have all been shown to promote tolerance in animal models of hemophilia.