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Immune response to FVIII in hemophilia patients
trastuzumab (0.1 cell/million CD4+ T cells).50 Taken together, these findings suggest inefficient negative selec- tion of FVIII-reactive T cells in the thymus, despite the reported expression of FVIII mRNA in medullary thymic epithelial cells from healthy individuals.51
An additional, striking finding is that half of the detect- ed FVIII-specific CD4+ T cells have a memory phenotype,47 suggesting that immune responses to endogenous FVIII are ongoing under physiological conditions and are regu- lated to avoid deleterious autoreactivity. Indeed, the detection of regulatory T cells concomitant to that of FVIII-reactive T cells had been suggested in two independ- ent studies, though the specificity of the regulatory T cells for FVIII was not demonstrated. Hu et al. reported increased ratios of transforming growth factor-beta-pro- ducing T helper 3 regulatory cells over interferon-gamma- producing T helper 1 cells or interleukin-4-producing T helper 2 cells among CD4+ T cells from heathy donors, as compared to CD4+ T cells from patients with FVIII inhibitors.45 In parallel, Kamate et al. observed that elimi-
nation of natural CD4+CD25+ regulatory T cells from peripheral blood cells of healthy individuals increases the otherwise poorly detectable FVIII-induced activation of CD4+ T cells in vitro.52
Recognition of endogenous factor VIII by immunoglobulins under physiological conditions
The presence of natural anti-FVIII IgG in the blood of healthy donors was described for the first time by the group of MD Kazatchkine.53 In their seminal work, IgG- dependent FVIII neutralization was detected in the plasma of 17% of the donors. Subsequently, Reipert’s group con- firmed the presence of anti-FVIII antibodies in about 19% of healthy individuals, characterized by a highest preva- lence of IgG1, IgG3 and IgA subclasses with low apparent binding equilibrium affinities for FVIII in the nanomolar range.54,55 Interestingly, and reminiscent of the situation in the T-cell compartment of the immune system, the recog- nition of endogenous FVIII by immunoglobulins is subject to regulation by anti-idiotypic antibodies in normal plas-
Figure 1. Immune recognition of factor VIII in health and disease. Healthy donors. At the humoral level, tolerance to factor VIII (FVIII) under physiological conditions relies on an equilibrium between the recognition of FVIII by naturally occurring potentially inhibitory anti-FVIII antibodies and their control by blocking anti-idiotypic antibodies. Blocking anti-idiotypic antibodies may also regulate B-cell clones that secrete FVIII-specific autoantibodies. At the T-cell level, natural FVIII-reactive T cells may be down-regulated by natural regulatory T cells (Tregs; i.e., CD4+CD25+FoxP3+ Tregs) and/or by induced transforming growth factor-beta-secreting Tregs. In rare cases, and in particular in aging individuals, tolerance may fail and a neutralizing immune response to endogenous FVIII may develop - a condition referred to as acquired hemophilia. Patients with congenital hemophilia A. Based on the available evidence, we propose that a similar equilibrium between FVIII-reactive and FVIII- protective immune elements guarantees tolerance to therapeutic FVIII in inhibitor-negative patients, either upon spontaneous induction of immune tolerance at the time of initiation of FVIII treatment (i.e., in 70-80% of patients with the severe form of the disease), or after a drastic boost of the immune system in patients under- going successful immune tolerance induction (ITI) (i.e., in about 70% of inhibitor-positive patients with severe hemophilia A undergoing ITI). As is the case in healthy individuals, immune tolerance to FVIII may be lost upon aging.71 Of note, 10% of the patients (30% of the inhibitor-positive patients with severe hemophilia A in whom ITI fails) are not able to develop immune tolerance to FVIII, even after intensive desensitization protocols. Inh+: inhibitor-positive; Inh-: inhibitor-negative; ITI: immune tolerance induction; anti-Id IgG: anti-idiotypic immunoglobulin G; aFVIII T cell: factor VIII-reactive T cell.
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