Inhibitory antibodies in hemophilia A.
OBJECTIVE
The review describes recent advances in our understanding of mechanisms leading to development of neutralizing antibodies following factor VIII (FVIII) replacement therapy for hemophilia A. Novel interventions with translational potential to lessen the incidence of these deleterious immune responses are discussed.


RESULTS
Genetic and environmental risk factors for inhibitor development, and cellular mechanisms leading to antibody production versus immune tolerance to FVIII, are increasingly coming into focus. Human and animal model studies are identifying T-cell and B-cell epitopes in FVIII and characterizing the presentation of naturally processed FVIII peptides on antigen-presenting cells (APCs). Novel methods to promote immune tolerance include decreasing FVIII uptake by APCs, modifying co-stimulatory pathways, inducing regulatory T-cell production, and presenting FVIII antigen to immature dendritic cells in a tolerance-promoting manner. A complementary approach to reduce inhibitor incidence is the design of less immunogenic FVIII proteins through epitope modification.


CONCLUSIONS
Studies of FVIII immunogenicity are revealing mechanisms of anti-FVIII immune responses, suggesting new approaches to reduce the incidence of inhibitors. Rational design of FVIII variants is producing less immunogenic proteins targeted to specific patient sub-populations. Future therapies will likely involve administration of less immunogenic FVIII proteins under conditions that promote immune tolerance.
Puget Sound Blood Center Research Institute, Seattle, Washington 98104, USA. KathleenP@psbc.org
Kathleen P
KP
Pratt
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D019774:Blood Coagulation Factor Inhibitors / Q000276:immunology*; D005169:Factor VIII / Q000276:immunology* / Q000627:therapeutic use; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D012307:Risk Factors; D013601:T-Lymphocytes / Q000276:immunology
D019774:Blood Coagulation Factor Inhibitors; D005169:Factor VIII