The FVIII2194–2213 peptide contains a dominant DR0101-restricted
T-cell epitope that was recognized by CD4+ T cells from two mild haemophilia A subjects with the A2201P missense substitution. We suggest that modification of this FVIII epitope could facilitate efforts to engineer versions of FVIII that would be less immunogenic Talazoparib for individuals who are DRB1*0101. The promiscuity of this epitope across other DRB1 types is under investigation. We thank Mr Charles Cooper, RN, for help with protocols, Ms Shelley Nakaya for carrying out FVIII genotyping assays, Ms. Laura Stewart for carrying out Bethesda assays, and all subjects for their voluntary blood donations. This work was supported by a Bayer Haemophilia Award (K. P. Pratt), a CSL Behring Haemophilia Research Award (K. P. Pratt), NIH R01-HL 071093-01 (A. R. Thompson), and NIH contract HHSN266200400028C (W. W. Kwok). It is an honour to dedicate this manuscript, with great respect, to Prof. Hans-Hermann Brackmann. Kathleen P. Pratt received unrestricted research awards from Bayer Healthcare Pharmaceuticals
and the CSL Behring Foundation that were applied to research described in this work. She was also reimbursed and paid an honorarium for speaking at the 2008 Baxter Hemophilia Update meeting in April 2008. The other authors stated Ixazomib that they had no interests which might be perceived as posing a conflict or bias. “
“Among the proposed predictors for immune tolerance induction (ITI) outcome, the therapeutic regimen – specifically the dose and frequency of administered factor VIII (FVIII) as well as FVIII product type – is intensely debated. Are there any advantages for low-dose regimens (50 IU FVIII kg−1 three times a week) over high-dose
regimens (200 IU FVIII kg day−1) or vice versa? Are von Willebrand factor PtdIns(3,4)P2 (VWF)-containing plasma-derived concentrates superior to recombinant FVIII concentrates for tolerance induction? A review of the available literature indicates that patients with good prognostic factors can achieve success with either low-dose or high-dose ITI regimens. Retrospective data suggest that patient characteristics such as maximum historical inhibitor titres and pre-ITI inhibitor titres are better predictors of treatment success than dose. Results of the prospective International ITI Study have recently become available. In inhibitor patients with good prognosis, success rates were similar between low-dose (50 IU FVIII kg−1 three times a week) and high-dose (200 IU FVIII kg−1 daily) regimens. However, patients receiving low-dose ITI took longer to achieve various ITI milestones and had a significantly higher bleed rate per month compared with the high-dose group (0.62 vs. 0.28; P = 0.00024), findings with important clinical implications.