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A. Varthaman et al.
Collectively, the accumulated evidence favors the hypothesis that all hemophilia A patients treated with FVIII develop an immune response to therapeutic FVIII: mounting an immune response to exogenous FVIII is part of the normal recognition and assessment of an innocu- ous antigen. In this context, the immunological assess- ment of therapeutic FVIII does not require the presence of overt danger signals. The maturation of antigen-present- ing cells leading to the activation of naïve T cells specific for therapeutic FVIII is triggered in a bystander manner by a dynamic immune system confronted with an ever- changing environment. Furthermore, we propose that the onset of neutralizing antibodies to FVIII in a substantial number of patients results from these patients’ inability to develop a counteractive antigen-specific tolerogenic response, rather than from an exacerbated activation of the immune system at the time of FVIII administration. Consequently, instead of investigating why 5-30% of the patients develop an inhibitory response to FVIII, the sci- entific challenge is to understand why 5-30% of the patients fail to develop active immune tolerance to FVIII (depicted in Figure 2 for patients with the severe form of the disease). Such a change of perspective will have reper- cussions on the clinical management of patients. For instance, in inhibitor-positive patients the use of immunosuppressive drugs that favor the onset of T-cell- mediated tolerance77,78 should be privileged over that of drugs that simply shut off adaptive immunity. It will also foster the development of strategies to achieve FVIII-spe- cific immuno-tolerance. Of importance, prophylaxis with emicizumab, a recently marketed FVIII-bypassing agent, in previously untreated patients79 or in inhibitor-positive patients80 allows correction of coagulation while avoiding stimulation of the immune system with FVIII. It thus inherently prevents the immunological (re-)assessment of therapeutic FVIII and establishment of active tolerance. Consequences on the incidence of inhibitor development when the patients must receive therapeutic FVIII in the future will have to be monitored.
Conclusions
Studies in the past 15 years have focused on deciphering the signals that lead to the development of a pathogenic anti-FVIII immune response in 5-30% of patients with hemophilia A, as compared to the therapeutic FVIII being ‘ignored’ in the remaining patients receiving therapy. To our knowledge, there is no evidence supporting the hypothesis that therapeutic FVIII is ignored by the immune system in previously treated inhibitor-negative patients. Based on the available experimental findings and clinical observations, we propose that therapeutic FVIII is not ignored but is assessed by the immune system of all the patients exposed to this treatment. In most patients, immune FVIII assessment is accompanied by the induc- tion of antigen-specific counteractive tolerance mecha- nisms, which ensure that neutralizing anti-FVIII responses are not incited. In a subset of patients, however, the inabil- ity to develop such tolerance leads to the onset of clinical- ly relevant levels of neutralizing anti-FVIII antibodies. A better understanding of the counteractive tolerogenic response in play and of the genetic/environmental factors that prevent its induction in inhibitor-positive patients will have repercussions on the clinical management of patients and highlight new strategies to achieve active immune tolerance towards therapeutic FVIII.
Acknowledgments
This work was supported by INSERM, Centre National de la Recherche Scientifique and Sorbonne Université (Paris, France) and by the Innovative Medicines Initiative Joint Undertaking ABIRISK (Anti-Biopharmaceutical Immunization Risk) project under grant agreement #115303, the resources of which comprise financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and in-kind contribu- tions from EFPIA companies. AV was a recipient of an individual fellowship from the Marie Sklodowska-Curie Actions (grant number: 656757 - Tolltum - MSCA-IF-EF-ST). We thank Dr Kathleen Pratt for her critical reading of the manuscript.
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