Factor VIII alloantibodies in hemophilia

Current Opinion in Hematology

Volumn 11, Issue 3, 2004, Pages 146-150

  Jacquemin, Marc G ^a   Saint Remy, Jean Marie R ^a  

^a UNIVERSITY OF LEUVEN   (Belgium)

Author keywords

Factor VIII; Inhibitors; Regulation; Therapy

Indexed keywords

ALLOANTIBODY; BLOOD CLOTTING FACTOR 8; MONOCLONAL ANTIBODY;

ANTIBODY PRODUCTION; ANTIGEN SPECIFICITY; B LYMPHOCYTE; CELL CLONING; DOWN REGULATION; EXPERIMENTAL MODEL; HEMOPHILIA; HEMOPHILIA A; HEMOSTASIS; IMMUNE RESPONSE; IMMUNIZATION; NONHUMAN; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE;

ANIMALS; ANTIBODY SPECIFICITY; FACTOR VIII; HEMOPHILIA A; HUMANS; ISOANTIBODIES; MICE; MODELS, ANIMAL;

EID: 3242723791     PISSN: 10656251     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.moh.0000130312.87668.bf     Document Type: Review

References (35)

1. Schwaab R, Brackmann HH, Meyer C, et al.: Haemophilia A: mutation type determines risk of inhibitor formation. Thromb Haemost 1995, 74:1402-1406.
2. Jacquemin MG, Desqueper BG, Benhida A, et al.: Mechanism and kinetics of factor VIII inactivation: study with an IgG4 monoclonal antibody derived from a hemophilia A patient with inhibitor. Blood 1998, 92:496-506.
3. Jacquemin MG, 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, 95:156-165.
4. Voorberg J, van den Brink EN: Phage display technology: a tool to explore the diversity of inhibitors to blood coagulation factor VIII. Semin Thromb Hemost 2000, 26:143-150.
5. van den Brink EN, Bril WS, Turenhout EA, 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.
6. Pratt KP, Shen BW, Takeshima K, et al.: Structure of the C2 domain of human factor VIII at 1.5 A resolution. Nature 1999, 402:439-442.
7. Spiegel PC Jr, Jacquemin M, Saint-Remy JMR, et al.: Structure of a factor VIII C2 domain:IgG4K Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII. Blood 2001, 98:13-19.
8. Lewis DA, Pound ML, Ortel TL: Contributions of Asn2198, Met2199, and Phe2200 in the factor VIII C2 domain to cofactor activity, phospholipid-binding, and von Willebrand factor-binding. Thromb Haemost 2003, 89:795-802.
9. Barrow RT, Healey JF, Jacquemin MG, et al.: Antigenicity of putative phospholipid membrane binding residues in factor VIII. Blood 2001, 97:169-174.
10. Jacquemin MG, De Maeyer M, d'Oiron R, et al.: Molecular mechanisms of mild and moderate haemophilia A. J Thromb Haemost 2003, 1:456-463.
11. d'Oiron R, Lavergne JM, Lavend'homme R, et al.: Deletion of alanine 2201 in the Factor VIII C2 domain results in mild hemophilia by impairing Factor VIII binding to von Willebrand Factor and phospholipids and destroys a major Factor VIII antigenic determinant involved in inhibitor development. Blood 2004, 103:155-157. This is the first demonstration that a single-amino-acid deletion in one of the phospholipid-binding sites of the C2 domain results in mild hemophilia by reducing the interaction of FVIII with both VWF and phospholipids.
12. Gilles JGG, Arnout J, Vermylen J, Saint-Remy JMR: Anti-Factor VIII antibodies of haemophiliac patients are directed primarily towards non-functional determinants and do not exhibit isotypic restriction. Blood 1993, 82:2452-2461.
13. Hu GL, Okita DK, Diethelm-Okita BM, Conti-Fine BM: Recognition of coagulation factor VIII by CD4+ T cells of healthy humans. J Thromb Haemost 2003, 1:2159-2166. This paper describes the first systematic approach to identifying human T-cell epitopes on the FVIII molecule. Using sets of peptides encompassing the entire FVIII sequence, the authors show that such epitopes are spread over FVIII, with no particular dominance. In addition, they show that healthy individuals also have specific T cells in the periphery, a finding in keeping with the fact that thymus T-cell repertoire selection involves only T cells with high affinity towards dominant epitopes.
14. Reding MT, Okita DK, Diethelm-Okita BM, et al.: Human CD4+ T-cell epitope repertoire on the C2 domain of coagulation factor VIII. J Thromb Haemost 2003, 1:1777-1784.
15. Jacquemin MG, Vantomme V, Buhot C, et al.: A single mutation Arg2150His regulates the T cell specificity for the factor VIII C1 domain: a molecular mechanism responsible for the higher incidence of inhibitor in mild/moderate hemophilia A patients with mutations in the Cl domain. Blood 2003, 101:1351-1358. This is the first evaluation at the clonal level of the human T-cell response towards FVIII. It shows that a single mutation in the carboxyterminal end of the C1 domain is enough to prevent the negative selection in the thymus of T cells of relevance to hemophilia A patients, insofar as such T cells drive the production of inhibitor antibodies.
16. Hay CRM, Ollier W, Pepper L, et al.: HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. Thromb Haemost 1997, 77:234-237.
17. Oldenburg J, Picard JK, Schwaab R, et al.: HLA genotype of patients with severe haemophilia A due to intron 22 inversion with and without inhibitors of factor VIII. Thromb Haemost 1997, 77:238-242.
18. Misra N, Bayry J, Pashov A, et al.: Restricted BV gene usage by factor VIII-reactive CD4+ T cells in inhibitor-positive patients with severe hemophilia A. Thromb Haemost 2003, 90:813-822.
19. Ling M, Duncan EM, Rodgers SE, et al.: Low detection rate of antibodies to non-functional epitopes on factor VIII in patients with hemophilia A and negative for inhibitors by Bethesda assay. J Thromb Haemost 2003, 1:2548-2553.
20. Raut S, Villard S, Grailly S, et al.: Anti-heavy-chain monoclonal antibodies directed to the acidic regions of the factor VIII molecule inhibit the binding of factor VIII to phospholipids and von Willebrand factor. Thromb Haemost 2003, 90:385-397. These unexpected findings indicate that antibodies directed towards FVIII heavy chain could directly or indirectly influence functions classically associated with the light chain.
21. Qian JJ, Borovok M, Bi L, et al.: Inhibitor antibody development and T cell response to human factor VIII in murine hemophilia A. Thromb Haemost 1999, 81:240-244.
22. Qian J, Collins M, Sharpe AH, Hoyer LW: Prevention and treatment of factor VIII inhibitors in murine hemophilia A. Blood 2000, 95:1324-1329.
23. Hausl C, Maier E, Schwarz HP, 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.
24. Hausl C, Ahmad RU, Schwarz HP, et al.: Preventing re-stimulation of memory B cells in hemophilia A: a potential new strategy for the treatment of antibody-dependent immune disorders? Blood 2004. In press. Epub ahead of print. An interesting study demonstrating that in the hemophilia A mouse model, the anti-FVIII response undergoes full memorization and can be reactivated through cognate or bystander interaction with T cells.
25. Doering C, Parker ET, Healey JF, et al.: Expression and characterization of recombinant murine factor VIII. Thromb Haemost 2002, 88:450-458.
26. Barrow RT, Healey JF, Gailani D, et al.: Reduction of the antigenicity of factor VIII toward complex inhibitory antibody plasmas using multiply-substituted hybrid human/porcine factor VIII molecules. Blood 2000, 95:564-568.
27. Parker ET, Healey JF, Barrow RT, et al.: Reduction of the inhibitory antibody response to human factor VIII in hemophilia A mice by mutagenesis of the A2 domain B cell epitope. Blood 2004. In press. Epub ahead of print. This paper shows that the substitution of three-amino-acid substitutions in the human A2 domain sequence by their porcine counterparts is enough to reduce not only antigenicity (ie, the binding of preformed anti-FVIII antibodies) but also immunogenicity upon injection in the hemophilia A mouse model.
28. van der Bom JG, Mauser-Bunschoten EP, Fischer K, van den Berg HM: Age at first treatment and immune tolerance to factor VIII in severe hemophilia. Thromb Haemost 2003, 89:475-479. This study reinforces previous findings suggesting that the risk of developing an inhibitor to FVIII is higher in young infants than later in life. If confirmed, these findings would have a considerable impact on treatment strategies.
29. Wing K, Ekmark A, Karlsson H, et al.: Characterization of human CD25+CD4+ T cells in thymus, cord and adult blood. Immunology 2002, 106:190-199.
30. Khoo UY, Proctor LE, Macpherson AJ: CD4+ Tcell down-regulation in human intestinal mucosa normally recognize the local commensal bacteria, but their responses are inhibited by local regulatory T cells in an interleukin-10 (IL-10) and/or transforming growth factor-b (TGF-b)-mediated manner. J Immunol 1997, 158:3626-3634.
31. Weiner HL: Oral tolerance: immune mechanisms and the generation of Th3-type TGF-beta-secreting regulatory cells. Microbes Infect 2001, 3:947-954.
32. Rawle FEM, Labelle AD, Postma L et al.: Oral administration of factor VIII contributes to the prevention of anti-factor VIII antibody development after protein infusion, and prolongs factor VIII transgene expression post-adenoviral gene transfer [abstract]. Blood 2003, 102:163a. This is the first published evidence that prolonged immune unresponsiveness to FVIII administration can be achieved through oral feeding with FVIII. The mechanisms of such a tolerance induction is unknown but likely involve the generation of regulatory TH3 cells. If confirmed, these findings would have a significant impact on therapy with FVIII infusion and on gene therapy.
33. Villard S, Lacroix-Desmazes S, Kieber-Emmons Th, et al.: Peptide decoys selected by phage display block in vitro and in vivo activity of a human anti-FVIII inhibitor. Blood 2003, 102:949-952.
34. Gilles JG, Grailly S, De Maeyer M, et al.: In vivo neutralization of C2 domain specific human anti-FVIII by an anti-idiotypic antibody. Blood 2004, 103:2617-2623. The hoped-for antigen-specific prevention or suppression of the anti-FVIII immune response finds here a first potential application. It is shown that single anti-idiotypic antibodies can neutralize both in vitro and in vivo the inhibitory activity of human high-affinity inhibitors. These findings bring hopes for the downregulation of inhibitors directed towards the FVIII C2 domain, which carries major B-cell epitopes.
35. Scott DW, Qian J, Lei TC: Gene therapy for tolerance to the C2 domain of Factor VIII [abstract]. Blood 2003, 102:163a. B cells engineered to express some of the FVIII domains induce a long-lasting state of unresponsiveness to specific immunization in the hemophilia A mouse model. Potential applications include the prevention of inhibitory antibodies but also of an immune response to vectors used for gene therapy.