Strain Variation in the Immune Response to Human Factor VIII in Normal and Hemophilic Mice.

Approximately 25–30% of Hemophilia A patients make inhibitors after treatment with therapeutic Factor VIII (fVIII). The ability to predict which patients may respond with inhibitors would be important in order to identify suitable patients for tolerance therapies prior to exposure to fVIII and the development of high inhibitor titers. Advances in identifying the nature of the fVIII mutations (inversion, stop codons, etc), HLA linkage and other factors have suggested these as important predictors of inhibitor responsiveness. As a step toward identifying other genetic factors that may predispose for inhibitor formation, we immunized both fVIII−/ − (knockout; C57Bl background) and fVIII sufficient mice of different MHC backgrounds with human fVIII (i.e. therapeutic doses, intravenously in saline with no adjuvant). Our hypothesis was that fVIII sufficient mice would only respond to epitope differences between human and mouse fVIII and that this response would be more sensitive to genetic variation. Our results showed a clear hierarchy of responsiveness both in terms of T-cell proliferation and ELISA titers in the following order: CAST/Ei>BALB/c>B10.A; CBA>C57Bl/6. Despite being bred on a C57Bl (low responder) background, knockout mice made the strongest response to human fVIII, presumably due to the lack of tolerance to mouse epitopes. These results suggest that MHC plays a role in fVIII responsiveness, as it does in the response to fIX or fVIII delivered via an adenovirus vector (http://www.abstracts-on-line.com/abstracts/hemphiladelphia03; Lozier, 2003;