Mechanism of the immune response to human factor VIII in murine hemophiliaA

Mice genetically deficient in factor VIII (fVIII) are a model of hemophilia A. As a first step to reproduce in this mouse model what occurs over time in hemophilia A patients treated with human fVIII (hfVIII), we have investi gated the time course and the characteristics of their immune response to h fVIII, after multiple intravenous injections. Anti-hfVIII antibodies appear ed after four to five injections. They were IgG1 and to a lesser extent 1gG 2, indicating that they were induced by both Th2 and Th1 cells. Inhibitors appeared after six injections. CD4(+) enriched splenocytes, from hfVIII-tre ated mice proliferated in response to fVIII and secreted IL-10: in a few mi ce they secreted also IFN-gamma and in one mouse IL-4, but never IL-2. A hf VIII-specific T cell line derived from hfVIII-treated mice secreted both IL -4 and LFN-gamma, suggesting that it included both Th1 and Th2 cells. CD4enriched splenocytes of hfVIII-treated mice recognized all hfVIII domains. Thus, hemophilic mice develop an immune response to hfVIII administered int ravenously similar to that of hemophilia A patients. Their anti-hfVIII anti bodies can be inhibitors and belong to IgG subclasses homologous to those o f inhibitors in hemophilic patients; their anti-hfVIII CD4(+) cells recogni ze a complex repertoire and both Th1 and Th2 cytokines, and especially IL-1 0, may drive the antibody synthesis.