It is well established that mice which do not produce endogenous factor VIII (fVIII−/−) can manifest a robust immune response to exogenous fVIII treatments. They form B-cell and T-cell responses even when they encounter fVIII through traditionally tolerogenic routes (e.g., intravenous or intraperitoneal). In the fVIII−/− mouse, repeated administration of recombinant human fVIII has emerged as a useful model for studying the physiologic response in hemophilic patients iatrogenically immunized to therapeutic factor VIII treatments. While environmental factors likely offer some co-stimulatory signals, nonetheless, the ability to respond effectively in the absence of extrinsic adjuvant begs the questions of what is the “danger signal” required for immune responsiveness to fVIII? We have previously shown that when factor VIII is heat inactivated (56°, 30′), it completely losses function and much of its immunogenicity (
Disclosures: No relevant conflicts of interest to declare.
(Supported by NIH RO1 HL061883, NIH T32 HL007698, and a Predoctoral fellowship from the American Heart Association.)