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A. Varthaman et al.
ma.56,57 Thus, IgG purified from the plasma of healthy indi- viduals bind to murine monoclonal anti-FVIII IgG,56 and inhibit the binding of mouse monoclonal and human polyclonal anti-FVIII IgG to FVIII.58 Therapeutic prepara- tions of pooled normal IgG, intravenous immunoglobu- lins, contain both anti-FVIII IgG with inhibitory potential toward FVIII59 and anti-idiotypic antibodies capable of blocking disease-associated anti-FVIII antibodies.60 This suggests that ‘natural’ protective anti-idiotypic antibodies are produced spontaneously in healthy individuals and exert a tight control on potentially inhibitory ‘natural’ anti-FVIII IgG.
In conclusion, endogenous FVIII is not merely ignored by the immune system under physiological conditions. On the contrary, the homeostasis of FVIII recognition by the healthy immune system relies on an equilibrium between FVIII-specific T and B cells and FVIII-binding antibodies, and a counteractive tolerogenic response mediated by regulatory T cells and blocking anti-idiotypic antibodies (Figure 1).
Recognition of exogenous therapeutic factor VIII in patients with hemophilia A
FVIII inhibitors develop in 5 to 30% of patients depend- ing on the severity of hemophilia A. The abnormality in the F8 gene responsible for the disease is the strongest pre- dictor of alloimunization against therapeutic FVIII. In par- ticular, patients with severe hemophilia A, and among them patients lacking circulating FVIII:Ag, have the high- est incidence of FVIII inhibitor development.7 Conversely, patients with missense mutations have the lowest risk of developing FVIII inhibitors. This correlation illustrates the importance of the degree of education, either centrally in the thymus or at the periphery, of the immune system of the patients towards endogenous FVIII: the more the endogenously produced FVIII resembles the exogenously administered therapeutic FVIII, the lower the risk of devel- oping a neutralizing immune response.
The situation is not, however, so simple. For instance, some missense mutations responsible for mild/moderate hemophilia A are associated with rates of inhibitor devel- opment as elevated as those seen in FVIII:Ag-negative patients wih severe hemophilia A.61 This highlights the existence of confounding parameters such as the impaired secretion of some forms of mutated FVIII consecutive to their retention in the endoplasmic reticulum,62 thus lead- ing to poor antigen presentation resulting in absence of tolerance induction. Alternatively, missense mutations may create T-cell epitopes in the mutated endogenous FVIII which differ from those of therapeutic FVIII.63-67 In the latter case, the education of the immune system does not “fit” with the exogenously administered FVIII and reg- ulatory elements cannot be engaged in an adequate man- ner. More relevant to this review is the possibility that active tolerance to FVIII in treated patients may be impli- cated irrespective of the severity of the disease and irre- spective of the presence of the endogenous (mutated) FVIII protein. This hypothesis is supported by several lines of evidence.
Immunological assessment of therapeutic factor VIII in patients with hemophilia A
About half of all FVIII inhibitors that form have a low inhibitory titer, are clinically insignificant and usually dis- appear spontaneously.68 This is illustrated by the recent
SIPPET study in which 27% of the included patients with severe hemophilia A developed transient FVIII inhibitors in the initial months following first exposure to therapeu- tic FVIII.69 Immune recognition of FVIII in patients with severe hemophilia A is thus not necessarily pathogenic and can be controlled. In agreement, the presence of non- neutralizing anti-FVIII IgG has been described in inhibitor- negative patients as well as in patients after successful immune tolerance induction therapy.54 While the risk of inhibitor development in patients with severe hemophilia A is highest during the first 20 cumulated exposure days (i.e., within the first 3-4 years of life),70 an increased inci- dence of FVIII inhibitors at an older age has been reported.71 Incidentally, with age, tolerance mechanisms weaken and there is an increased risk of developing autoimmune manifestations.72 This observation pleads in favor of the existence of active tolerance to therapeutic FVIII in inhibitor-negative patients, which can be lost with age. Importantly, immune tolerance induction therapy successfully eradicates FVIII inhibitors in 60-70% of inhibitor-positive patients. Although the induction of active tolerance to FVIII during immune tolerance induc- tion therapy has, to our knowledge, never been demon- strated formally, the disappearance of detectable inhibitors and restoration of normal FVIII pharmacokinet- ics are associated in some patients with the persistence of FVIII-specific T cells,73 anti-FVIII IgG with neutralizing potential and concomitant induction of blocking anti-idio- typic antibodies.74 Lastly, the possible involvement of CD4+CD25+ regulatory T cells during an ongoing inhibito- ry anti-FVIII immune response was suggested in a patient with hemophilia A.64 Thus, tolerance to therapeutic FVIII does not merely rely on the elimination of FVIII-specific immune cells/antibodies. Collectively, these findings sug- gest the existence of an interplay between allogenic FVIII- specific immune cells/molecules and regulatory elements of the immune system, which is reminiscent of the home- ostatic immune assessment of endogenous FVIII that pre- vails under physiological conditions (illustrated in Figure 1 for patients with severe hemophilia A).
Exacerbated immune response or failed tolerance?
We observed a few years ago that a GT repeat polymor- phism in the promoter of the gene encoding the anti- inflammatory enzyme heme-oxygenase-1 (HO-1) is associ- ated with inhibitor development in patients with severe hemophilia A.75 Thus, in a retrospective cohort of 300 patients, those who developed FVIII inhibitors had a signif- icantly increased prevalence of longer GT stretches in the hmox1 gene promoter, known to impair the capacity of the cells to turn on expression of the gene.75 Conversely, patients with shorter GT repeats had a lower incidence of FVIII inhibitors. More recently, Matino et al. elegantly demonstrated that dendritic cells from patients who have developed FVIII inhibitors are less prone to express indoleamine 2,3-dioxygenase 1 (IDO1), following in vitro stimulation by CpG.76 IDO1 is a key regulatory enzyme involved in the degradation of tryptophan which supports regulatory T-cell functions and peripheral tolerance in adult life. Taken together with the observation that polymor- phisms in promoters of the pro/anti-inflammatory genes encoding tumor necrosis factor-alpha, interleukin-10 and cytotoxic T-lymphocyte antigen-4 are associated with FVIII inhibitor development,11-14 these findings suggest that the capacity of patients to induce the expression of the endoge-
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haematologica | 2019; 104(2)