Immunobiology of Inhibitor Development in Hemophilia A

 

 Buy Article Permissions and Reprints

ABSTRACT

After treatment with factor (F) VIII concentrate a significant number of patients with hemophilia A develop inhibitory antibodies that neutralize FVIII. Epitope mapping revealed that antibodies bind to selected regions within the A2, A3, and C2 domains of FVIII. Anti-A2 and anti-A3 antibodies interfere with assembly of FVIIIa with FIXa, whereas anti-C2 antibodies impede the interaction of FVIII with phospholipids. The immunologic mechanisms underlying inhibitor development in hemophilia A have not been fully elucidated. FVIII is recognized by the immune system as a foreign antigenic substance that evokes the T cell-dependent formation of high-affinity antibodies. Clonal analysis of B cell responses in hemophilia A patients has given further insight into the epitope specificity and molecular characteristics of FVIII inhibitors. Costimulatory blockade of FVIII-reactive T cells in a mouse model for hemophilia A has suggested new approaches for treatment of inhibitor patients. In this article, recent studies on the immunobiology of FVIII inhibitors are summarized and discussed with reference to their potential impact on treatment and prevention of immune responses in patients with hemophilia.

REFERENCES

• 1 Hoyer L W. Hemophilia.  N Engl J Med . 1994;  330 38-47
  CrossrefPubMedGoogle Scholar
• 2 Mannucci P M, Tuddenham E GD. The hemophilias-from royal genes to gene therapy.  N Engl J Med . 2001;  344 1773-1779
  CrossrefPubMedGoogle Scholar
• 3 Healey J F, Lubin I M, Nakai H. et al . Residues 484-508 contain a major determinant of the inhibitory epitope in the A2 domain of human factor VIII.  J Biol Chem . 1995;  270 14505-14509
  CrossrefPubMedGoogle Scholar
• 4 Healey J F, Barrow R T, Tamim H M. et al . Residues Glu2181-Val2243 contain a major determinant of the inhibitory epitope in the C2 domain of human factor VIII.  Blood . 1998;  92 3701-3709
  PubMedGoogle Scholar
• 5 Fijnvandraat K, Celie P HN, Turenhout E AM. et al . A human allo-antibody interferes with binding of factor IXa to the factor VIII light chain.  Blood . 1998;  91 2347-2352
  PubMedGoogle Scholar
• 6 Zhong D, Saenko E L, Shima M, Felch M, Scandella D. Some human inhibitor antibodies interfere with factor VIII binding to factor IX.  Blood . 1998;  92 136-142
  PubMedGoogle Scholar
• 7 Fay P L, Scandella D. Human inhibitors specific for the factor VIII A2 domain disrupt the interaction between the subunit and factor IXa.  J Biol Chem . 1999;  274 29826-29830
  CrossrefPubMedGoogle Scholar
• 8 Arai M, Hoyer L W, Scandella D. Molecular basis of factor VIII inhibition by human antibodies-antibodies that bind to the factor VIII light chain prevent the interaction of factor VIII with phospholipids.  J Clin Invest . 1989;  83 1978-1984
  PubMedGoogle Scholar
• 9 Lacroix-Desmazes S, Moreau A, Sooryanarayana. et al . Catalytic activity of antibodies against factor VIII in patients with hemophilia A.  Nat Med . 1999;  5 1044-1047
  PubMedGoogle Scholar
• 10 Algiman M, Dietrich G, Nydegger U E. et al . Natural antibodies to factor VIII (antihemophilic factor) in healthy individuals.  Proc Natl Acad Sci USA . 1992;  89 3795-3799
  CrossrefPubMedGoogle Scholar
• 11 Gilles J G, Saint-Remy J M. Healthy subjects produce both anti-factor VIII and specific anti-factor VIII idiotypic antibodies.  J Clin Invest . 1994;  94 1496-1505
  PubMedGoogle Scholar
• 12 Moreau A, Lacroix-Desmazes S, Stieltjes N. et al . Antibodies to the FVIII light chain that neutralize FVIII procoagulant activity are present in plasma of nonresponder patients with severe hemophilia A and in normal polyclonal human IgG.  Blood . 2000;  95 3435-3441
  PubMedGoogle Scholar
• 13 Jacquemin M G, Desqueper B G, Benhida A. et al . Mechanism and kinetics of factor VIII inactivation: study with an IgG4 monoclonal antibody derived from a hemophilia A patient with an inhibitor.  Blood . 1998;  92 496-506
  PubMedGoogle Scholar
• 14 Spiegel P C, Jacquemin M, Saint-Remy J MR, Stoddard B L, Pratt K. Structure of a factor VIII C2 domain-immunoglobulin G4κ Fab complex: identification of an inhibitory antibody on the surface of factor VIII.  Blood . 2001;  98 13-19
  CrossrefPubMedGoogle Scholar
• 15 Barrow R T, Healey J F, Jacquemin M, Saint-Remy J MR, Lollar P. Antigenicity of putative phospholipid membrane binding residues in factor VIII.  Blood . 2001;  97 169-174
  CrossrefPubMedGoogle Scholar
• 16 Jacquemin M, Benhida A, Peerlinck K. et al . A human antibody directed to the factor VIII C1 domain inhibits factor VIII cofactor activity and binding to von Willebrand factor.  Blood . 2000;  95 156-163
  PubMedGoogle Scholar
• 17 Santagostino E, Gringeri A, Tagliavacca L. et al . Inhibitors to factor VIII in a family with mild hemophilia: molecular characterization and response to factor VIII and desmopressin.  Thromb Haemost . 1995;  74 619-621
  PubMedGoogle Scholar
• 18 Peerlinck K, Jacquemin M, Arnout J. et al . Anti-factor VIII antibody inhibiting allogeneic but not autologous factor VIII in patients with mild hemophilia A.  Blood . 1999;  93 2267-2273
  PubMedGoogle Scholar
• 19 Fijnvandraat K, Turenhout E AM, van den Brink N E. et al . The missense mutation Arg ⁵⁹³→Cys is related to antibody formation in a patient with mild hemophilia A.  Blood . 1997;  89 4371-4377
  PubMedGoogle Scholar
• 20 van den Brink N E, Turenhout E AM, Davies J. et al . Human antibodies with specificity for the C2 domain of factor VIII are derived from VH1 germline genes.  Blood . 2000;  95 558-563
  PubMedGoogle Scholar
• 21 van den Brink N E, Turenhout E AM, Bank C MC. et al . Molecular analysis of human anti-factor VIII antibodies by V gene phage display identifies a new epitope in the acidic region following the A2 domain.  Blood . 2000;  96 540-545
  PubMedGoogle Scholar
• 22 van den Brink N E, Turenhout E AM, Bovenschen N. et al . Multiple VH genes are used to assemble human antibodies directed towards the A3-C1 domains of factor VIII.  Blood . 2001;  97 966-972
  CrossrefPubMedGoogle Scholar
• 23 Voorberg J, van den Brink N E. Phage display technology: a tool to explore the diversity of inhibitors to blood coagulation factor VIII.  Semin Thromb Hemost . 2000;  26 143-150
  Article in Thieme ConnectPubMedGoogle Scholar
• 24 van den Brink N E, Bril W S, Turenhout E A. et al . Two classes of germline genes both derived from the V(H) 1 family direct the formation of human antibodies that recognize distinct antigenic sites in the C2 domain of factor VIII.  Blood . 2002;  99 2828-2834
  CrossrefPubMedGoogle Scholar
• 25 Barrow R T, Healey J F, Gailiani D, Scandella D, Lollar P. Reduction of the antigenicity of factor VIII towards complex inhibitory antibody plasmas using multiply-substituted hybrid human/porcine factor VIII molecules.  Blood . 2000;  95 564-568
  PubMedGoogle Scholar
• 26 Nogami K, Shima M, Giddings J C. et al . Circulating factor VIII immune complexes in patients with type 2 acquired hemophilia A and protection from activated protein C-mediated proteolysis.  Blood . 2001;  97 669-677
  CrossrefPubMedGoogle Scholar
• 27 McMillan C W, Shapiro S S, Whitehurst D. et al . The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors.  Blood . 1988;  71 344-348
  PubMedGoogle Scholar
• 28 Schwaab R, Brackmann H H, Meyer C. et al . Mutation type determines risk of inhibitor formation.  Thromb Haemost . 1995;  74 1402-1406
  PubMedGoogle Scholar
• 29 Fakharzadeh S, Kazazian H H. Correlation between factor VIII genotype and inhibitor development in hemophilia A.  Semin Thromb Hemost . 2000;  26 167-171
  Article in Thieme ConnectPubMedGoogle Scholar
• 30 Goodeve A, Williams I, Bray G L. et al . Relationship between factor VIII mutation type and inhibitor development in a cohort of previously untreated patients treated with recombinant factor VIII (Recombinate).  Thromb Haemost. 200;  83 844-848
  PubMedGoogle Scholar
• 31 Singer S T, Addieggo Jr E J, Reason D C, Lucas A H. T lymphocyte proliferative responses induced by recombinant factor VIII in hemophilia A patients with inhibitors.  Thromb Haemost . 1996;  76 17-22
  PubMedGoogle Scholar
• 32 Reding M T, Wu H, Krampf M. et al . Sensitization of CD4+ T cells to coagulation factor VIII: response in congenital and acquired hemophilia patients and in healthy subjects.  Thromb Haemost . 2000;  84 643-652
  PubMedGoogle Scholar
• 33 Bi L, Lawler A M, Antonarakis S E. et al . Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A.  Nat Genet . 1995;  10 119-121
  CrossrefPubMedGoogle Scholar
• 34 Bi L, Sarkar R, Naas T. et al . Further characterization of factor VIII-deficient mice created by gene targeting: RNA and protein studies.  Blood . 1996;  88 3446-3450
  PubMedGoogle Scholar
• 35 Sarkar R, Gao G, Chirmule N. et al . Partial correction of murine hemophilia A with neo-antigenic murine factor VIII.  Hum Gene Ther . 2000;  11 881-894
  CrossrefPubMedGoogle Scholar
• 36 Qian J, Borovok M, Bi L, Kazazian H H, Hoyer L W. Inhibitor antibody development and T cell response to human factor VIII in murine hemophilia A.  Thromb Haemost . 1999;  81 240-244
  PubMedGoogle Scholar
• 37 Reipert B M, Ahmad R U, Turecek P L. et al . Characterization of antibodies induced by human factor VIII in a murine knockout model of hemophilia A.  Thromb Haemost . 2000;  84 826-832
  PubMedGoogle Scholar
• 38 Hausl C, Maier E, Schwarz H P. et al . Long-term persistence of anti-factor VIII antibody-secreting cells in hemophilic mice after treatment with human factor VIII.  Thromb Haemost . 2002;  87 840-845
  PubMedGoogle Scholar
• 39 Wu H, Reding M, Qian J. et al . Mechanism of the immune response to human factor VIII in murine hemophilia A.  Thromb Haemost . 2001;  85 125-133
  PubMedGoogle Scholar
• 40 Rossi G, Sarkar J, Scandella D. Long-term induction of immune tolerance after blockade of CD40-CD40L interaction in a mouse model of hemophilia A.  Blood . 2001;  97 2750-2757
  CrossrefPubMedGoogle Scholar
• 41 Sasgary M, Ahmad R U, Schwarz H P, Turecek P, Reipert B M. Single cell analysis of factor VIII-specific T cells in hemophilic mice after treatment with human factor VIII.  Thromb Haemost . 2002;  87 266-272
  PubMedGoogle Scholar
• 42 Chambers C A. The expanding world of co-stimulation: the two-signal model revisited.  Trends Immunol . 2001;  22 217-223
  CrossrefPubMedGoogle Scholar
• 43 Coyle A J, Gutierrez-Romas J-C. The expanding B7 superfamily: increasing complexity in costimulatory signals regulating T cell function.  Nat Immunol . 2001;  2 203-209
  CrossrefPubMedGoogle Scholar
• 44 Blazar B R, Taylor P A, Linsley P S, Vallera D A. In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice.  Blood . 1994;  83 3815-3825
  PubMedGoogle Scholar
• 45 Qian J, Collins M, Sharpe A, Hoyer L W. Prevention and treatment of factor VIII inhibitors in murine hemophilia A.  Blood . 2000;  95 1324-1329
  PubMedGoogle Scholar
• 46 Kirk A D, Burkly L C, Batty D S. et al . Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates.  Nat Med . 1999;  5 686-693
  PubMedGoogle Scholar
• 47 Qian J, Burkly L C, Smith E P. et al . Role of CD154 in the secondary immune response: the reduction of pre-existing splenic germinal centers and anti-factor VIII inhibitor titer.  Eur J Immunol . 2000;  30 2548-2554
  CrossrefPubMedGoogle Scholar
• 48 Reipert B M, Sasgary M, Ahmad R U. et al . Blockade of CD40/CD40 ligand interactions prevents induction of factor VIII inhibitors in hemophilic mice but does not induce lasting immune tolerance.  Thromb Haemost . 2002;  86 1345-1352
  PubMedGoogle Scholar
• 49 Ewenstein B M, Hoots W K, Lusher J M. et al . Inhibition of CD40 ligand (CD154) in the treatment of factor VIII inhibitors.  Haematologica . 2000;  85 35-39
  PubMedGoogle Scholar
• 50 Kawai T, Andrews D, Colvin R B, Sachs D H, Cosimi A B. Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand (Letter).  Nat Med . 2000;  6 114
  PubMedGoogle Scholar
• 51 Brackmann H H, Gormsen J. Massive factor VIII infusion in haemophiliacs with factor VIII inhibitor, high responder (Letter).  Lancet . 1977;  8044 933
  PubMedGoogle Scholar
• 52 Mauser-Bunschoten E P, Hieuwenhuis H K, Roosendaal G, van den Berg M H. Low-dose immune tolerance induction in hemophilia A patients with inhibitors.  Blood . 1995;  86 983-988
  PubMedGoogle Scholar