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Immune response to FVIII in hemophilia patients
nous anti-inflammatory machinery and/or regulatory path- ways plays a key role in the ability of their immune system to control the response to the administered therapeutic FVIII. In order to test our hypothesis, a re-evaluation of existing cohorts of patients with hemophilia A would help to investigate whether patients who have developed a neu- tralizing anti-FVIII immune response have a generally more potent capacity to mount immune responses after vaccina- tion, or are more resistant to common viral or bacterial infections, than inhibitor-negative patients.
Reconsidering the immune response to therapeutic factor VIII
In the last 15 years, attempts to elucidate the reason(s) for which 5-30% of patients with hemophilia A develop an immune response to therapeutic FVIII, while 70-95% of them do not, and to decipher the nature of the danger
signals that are adjuvants to the inhibitory anti-FVIII immune response have remained largely inconclusive. Observations over the years demonstrate that endogenous FVIII is not ignored by the immune system under physio- logical conditions but is immunologically assessed, lead- ing to its homeostatic recognition based on counteracting reactive and tolerogenic adaptive immune effectors. Non- neutralizing FVIII-reactive antibodies are found in virtual- ly all patients with hemophilia A; clinically irrelevant inhibitory antibodies are transiently detected in a substan- tial number of patients after their first exposures to thera- peutic FVIII; and FVIII inhibitors may arise at an age when immune regulatory mechanisms are compromised (Figure 1). Furthermore, the development of FVIII inhibitors is associated with a hampered ability of the organism to activate HO-1 or IDO1-dependent anti-inflammatory/ tolerogenic mechanisms.
Figure 2. Immune response to factor VIII in patients with severe hemophilia A. (A) Classically, deciphering the immunogenicity of therapeutic factor VIII (FVIII) in patients with severe hemophilia A is addressed by investigating the reasons for which 20-30% of the patients develop an immune response to exogenous FVIII, while the remaining patients do not (adapted from Gouw et al.).24 (B) We propose that the immune system of all patients treated with FVIII reacts to the clotting factor. In 70-80% of the cases, this immunological assessment of therapeutic FVIII results in the establishment of active immune tolerance that relies on an equilibrium between FVIII-specific immune effector and regulatory elements. However, for reasons that are yet to be deciphered, the remaining patients fail to turn on appropriate anti-inflammatory/tolerogenic mechanisms. Anti-FVIII IgG: anti-factor VIII immunoglobulin G; aFVIII T cell: factor VIII-reactive T cell; Treg: regulatory T cell; anti-Id IgG: anti-idiotypic immunoglobulin G.
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