Characterization of Antibodies Induced by Human Factor VIII in a Murine Knockout Model of Hemophilia A

Birgit M. Reipert; Rafi U. Ahmad; Peter L. Turecek; Hans P. Schwarz

doi:10.1055/s-0037-1614124

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2000; 84(05): 826-832
DOI: 10.1055/s-0037-1614124

Review Article

Schattauer GmbH

Characterization of Antibodies Induced by Human Factor VIII in a Murine Knockout Model of Hemophilia A

Birgit M. Reipert

¹From the Baxter Hyland Immuno, Vienna, Austria

,

Rafi U. Ahmad

¹From the Baxter Hyland Immuno, Vienna, Austria

,

Peter L. Turecek

¹From the Baxter Hyland Immuno, Vienna, Austria

,

Hans P. Schwarz

¹From the Baxter Hyland Immuno, Vienna, Austria

› Institutsangaben

Abstract

Summary

To investigate the usefulness of factor VIII (FVIII) knockout mice as an animal model of hemophilia A, we characterized the antibody response in FVIII knockout mice to recombinant human FVIII, administered intravenously or subcutaneously with or without adjuvant, and compared results to those in normal mice. Anti-factor VIII antibodies were detected after both intravenous and subcutaneous administration, with the highest titers after subcutaneous administration plus adjuvant. Depending on the administration strategy, knockout mice formed antibodies more rapidly and developed higher titers of inhibitory antibodies (Bethesda) than normal mice, suggesting differences in epitope specificity. Blotting thrombin cleavage products separated by gel electrophoresis showed that both strains developed antibodies against the nonfunctional B domain as well as against functional domains of factor VIII. The antibodies were mainly of the IgG1 subclass and resembled type I antibodies in hemophilia A.

Key words

Hemophilia A - animal model - knockout mice - factor VIII - antibodies

Volltext

Referenzen

References
1 Hoyer LW. The incidence of factor VIII inhibitors in patients with severe hemophilia A. In: Inhibitors to coagulation factors. Aledort LM, Hoyer LW, Lisher JM, Reisner HM, White GC. eds. New York: Plenum; 1995: 35-45.
2 Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Güngör T, Krackhardt B, Kornhuber B. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-8.
3 Peerlinck K, Arnout J, Gilles JG, Saint-Remy JM, Vermylen J. A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurized fector VIII concentrate. Thromb Haemost 1993; 69: 115-8.
4 Peerlinck K, Arnout J, Di Giambattista M, Gilles JG, Laub R, Jacquemin M, Saint-Remy JM, Vermylen J. Factor VIII inhibitors in previously treated hemophilia A patients with a double virus-inactivated plasma derived factor VIII concentrate. Thromb Haemost 1997; 77: 80-6.
5 de Biasi R, Rocino A, Carola A, Mannucci PM. Inhibitor development surveillance in hemophilia A patients shifted to recombinant factor VIII (rFVIII) preparations: A prospective multicenter Italian study (Abstract). Haemophilia 1998; 04: 231.
6 Bi L, Lawler AM, Antonarakis SE, High KA, Gearhart JD, Kazazian Jr HH. Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. Nature Genetics 1995; 10: 119-21.
7 Qian J, Borovok M, Bi L, Kazazian Jr HH, Hoyer LW. Inhibitor development and T cell response to human factor VIII in murine haemophilia A. Thromb Haemost 1999; 81: 240-4.
8 Qian J, Collins M, Sharpe AH, Hoyer LW. Prevention and treatment of factor VIII inhibitors in murine hemophilia A. Blood 2000; 95: 1324-9.
9 Bi L, Sarkar R, Naas T, Lawler AM, Pain J, Shumaker SL, Bedian V, Kazazian HH. Further characterization of factor VIII-deficient mice created by gene targeting:RNA and protein studies. Blood 1996; 88: 3446-50.
10 Muchitsch EM, Turecek PL, Zimmermann K, Pichler L, Auer W, Richter G, Gritsch H, Schwarz HP. Phenotypic expression of murine hemophilia (Letter). Thromb Haemost 1999; 82: 1371-3.
11 Reipert BM, Ahmad R, Olas K, Gritsch H, Turecek PL, Schwarz HP. Toleranzinduktion gegen humanen Faktor VIII in Mäusen – Untersuchungen zur Toleranzaufhebung durch denaturierten Faktor VIII. In: 29. Hämophilie-Symposium, Hamburg 1998. Scharrer I, Schramm W. eds. Berlin: Springer; 2000: 147-53.
12 Kasper CK, Aledort LM, Counts RB. A more uniform measurement of factor VIII inhibitors. Thromb Diath Heamorr 1975; 34: 869-72.
13 Biggs R, Austen DEG, Denson KWE, Rizza CR, Borrett R. The mode of action of antibodies which destroy factor VIII. I. Antibodies which have second-order concentration graphs. Br J Hematol 1972; 23: 125-35.
14 Biggs R, Austen DEG, Denson KWE, Borrett R, Rizza CR. The mode of action of antibodies which destroy factor VIII. II. Antibodies which give complex concentration graphs. Br J Hematol 1972; 23: 137-55.
15 Elder B, Lakich D, Gitschier J. Sequence of the murine factor VIII cDNA. Genomics 1993; 16: 374-9.
16 Jarvis MA, Levin LG, Harrison JA, DePianto DJ, Suzuki CM, Ziaja CL, Brown JE, Jolly KW, Reisner HM, Abildgaard CF, Powell JS. Induction of human factor VIII inhibitors in rats by immunization with human recombinant factor VIII: a small animal model for humans with high responder inhibitor phenotype. Thromb Haemost 1996; 75: 318-25.
17 Levin LG, Jarvis M, Powell J, Harrison JA, Reisner HM. Induction of human factor VIII inhibitors in rats 2: fine mapping of rat anti-human rFVIII antibodies. Thromb Haemost 1996; 76: 998-1003.
18 Gilles JG, Arnout J, Vermylen J, Saint-Remy JM. Anti-factor VIII antibodies in hemophiliac patients are frequently directed towards nonfunctional determinants and do not exhibit isotypic restrictions. Blood 1993; 82: 2452-61.
19 Fulcher CA, de Graaf SMahoney, Roberts JR, Kasper CA, Zimmerman TS. Localization of human factor VIII inhibitor epitopes to two polypeptide fragments. Proc Natl Acad Sci USA 1985; 82: 7728-32.
20 Nakai H, Mondorf W, Saenko EL, Scandella D. The presence of anti-A1 and B domain antibodies in factor VIII inhibitor patients (Abstract). Blood 1995; 86 (Suppl. 01) 190a.
21 Gawryl MS, Hoyer LW. Inactivation of Factor VIII coagulant activity by two different types of human antibodies. Blood 1982; 60: 1103-9.
22 Fulcher CA, De Graaf SMahoney, Zimmerman TS. FVIII inhibitor subclass and FVIII polypeptide specificity determined by immunoblotting. Blood 1987; 69: 1475-80.
23 Kavanagh M, Wood C, Davidson J. The immunological characterization of human antibodies to factor VIII isolated by affinity chromatography. Thromb Haemost 1981; 45: 60-4.
24 Stevens TL, Bossie A, Sanders VM, Fernandez-Botran R, Coffman RL, Mosmann TR, Vitetta ES. Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Nature 1988; 334: 255-8.
25 Mosmann TR, Coffman RL. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol 1989; 46: 111-47.