Page 176 - Haematologica August 2018

M.T. Georgescu et al.
could likely have been used in the E16KO mouse model, we wanted a consistent treatment protocol across the two strains. There is no conceptual reason that lower per- weight FVIII doses would result in evasion of the toler- ance-promoting mechanisms.
The use of high FVIII doses over consecutive treatment days simulated “peak treatment moments” known to be associated with an increased risk of inhibitors.10 However, this intense initial exposure to FVIII was not given because of a hemorrhagic event, which from a clinical point of view is unrealistic. Patients often receive more intense ini- tial exposures to FVIII to treat life-threatening bleeding, when inflammation may be present and could enhance the immune response to FVIII. We cannot infer that Dex would exert the same effect in these scenarios. However, animal models may be of limited utility in studying these more clinically relevant circumstances. For example, rodent studies have not consistently identified an associa- tion between hemarthrosis48,49 and anti-FVIII immune responses. Ultimately, clinical studies will be needed to answer the most important questions about the use of Dex in patients with severe HA.
Conclusions
Our experiments show that Dex, when administered during an intense initial exposure to FVIII, diminishes the anti-FVIII immune response in E17KO/hMHC and E16KO HA mice. In addition, this treatment protocol promotes durable and antigen-specific immunologic tolerance to FVIII in E17KO/hMHC mice. This effect appears to be mediated by alterations in lymphocyte populations and thymic gene expression. Clinical studies are needed to determine if this approach can be translated into clinical practice to prevent the devastating occurrence of FVIII inhibitors for which we currently offer no mitigation strat- egy, even in high-risk patients. Ready access to Dex and other glucocorticoids, ease of administration, and exten- sive clinical experience with these drugs will make such clinical studies very feasible.
Funding
This project was supported in part by Operating and Foundation grants from The Canadian Institutes of Health Research (MOP10912, FDN-154285). DL is the recipient of a Canada Research Chair in Molecular Hemostasis.
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