Tolerance Induction and The Immunobiology of Factor VIII in Hemophilia A
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The development of inhibitory antibodies to the factor VIII (FVIII) protein is the greatest complication in the management of hemophilia A patients. These antibodies, which form in approximately 25% of patients, neutralize the procoagulant activity of FVIII. There are limited treatment options to manage FVIII “inhibitors”, and this significantly increases morbidity within the hemophilia population. Therefore, understanding the immunobiology of FVIII, and developing safe, efficacious therapies to induce immunological tolerance to FVIII is a clinical priority. In 2010, there is no therapy available to prevent the formation of FVIII inhibitors in boys with hemophilia. Therefore, we evaluated the efficacy of anti-CD3 to induce tolerance to FVIII in a prophylactic setting. Low-dose anti-CD3 significantly increased the level CD4+CD25+ T regulatory cells, and prevented formation of inhibitors in >80% in hemophilia A mice. Depleting CD4+CD25+ cells in vivo completely abrogated tolerance. Furthermore, cytokine production by splenocytes from tolerant mice were shifted toward a Th1 response. Anti-CD3 therefore represents one of the most efficacious pre-clinical therapies for FVIII tolerance induction. Surgery is widely regarded in the hemophilia community as a trigger for inducing de novo inhibitor formation. There is, however, only conflicting clinical evidence, and no basic science data to lend support to this clinical hypothesis. Therefore, we developed a novel surgical procedure in hemophilia A mice to study the influence of surgery on FVIII immunogenicity. We found that surgery induced a systemic proinflammatory response (upregulated plasma IL-1 and IL-6), but surprisingly the immunogenicity of FVIII was not enhanced when infused at the perioperative time. These results are significant, however, because they suggest that surgery is not as important for de novo inhibitor formation as previously thought. Finally, it is unknown whether central tolerance to FVIII shapes the peripheral T cell repertoire. Therefore, we studied the murine thymus for evidence of FVIII expression. Whole thymus expressed FVIII mRNA but not protein. FVIII mRNA expression in the thymus was due, at least in part, by the thymic epithelium (CD45-/loEpCAM+). In FVIII-/-AIRE+/-, the immunogenicity of FVIII appeared to be unaltered. This study is the first to investigate a possible role for central tolerance to FVIII.