TY - JOUR
T1 - Inhibitory antibodies in hemophilia A
AU - Pratt, Kathleen P.
PY - 2012/9
Y1 - 2012/9
N2 - Purpose of review: 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. Recent findings: 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. Summary: 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.
AB - Purpose of review: 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. Recent findings: 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. Summary: 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.
KW - antidrug antibodies
KW - hemophilia A
KW - inhibitors
KW - therapeutic proteins
UR - http://www.scopus.com/inward/record.url?scp=84865418932&partnerID=8YFLogxK
U2 - 10.1097/MOH.0b013e328356ed37
DO - 10.1097/MOH.0b013e328356ed37
M3 - Review article
C2 - 22814650
AN - SCOPUS:84865418932
SN - 1065-6251
VL - 19
SP - 399
EP - 405
JO - Current Opinion in Hematology
JF - Current Opinion in Hematology
IS - 5
ER -