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Thromb Haemost 1999; 81(02): 240-244
DOI: 10.1055/s-0037-1614450
Review Articles
Schattauer GmbH

Inhibitor Antibody Development and T Cell Response to Human Factor VIII in Murine Hemophilia A

Jiahua Qian
1   From the Holland Laboratory, American Red Cross, Rockville, MD, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, and the Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
,
Marina Borovok
1   From the Holland Laboratory, American Red Cross, Rockville, MD, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, and the Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
,
Lei Bi
1   From the Holland Laboratory, American Red Cross, Rockville, MD, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, and the Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
,
Haig H. Kazazian Jr.
1   From the Holland Laboratory, American Red Cross, Rockville, MD, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, and the Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
,
Leon W. Hoyer
1   From the Holland Laboratory, American Red Cross, Rockville, MD, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, and the Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
› Author Affiliations
Further Information

Publication History

Received18 May 1998

Accepted after resubmission22 October 1998

Publication Date:
08 December 2017 (online)

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Summary

In order to understand better the mechanism of inhibitor formation in hemophilia A patients, we have characterized the immune response to human factor VIII in a murine model of hemophilia A. Mice with severe factor VIII deficiency caused by targeted gene disruptions in exons 16 and 17 were injected intravenously with human factor VIII. Anti-factor VIII was absent or was detected at only very low levels in hemophilic mice of both strains after a single injection of 0.2 μg factor VIII, but it was present in most mice after a second exposure. Subsequent exposures led to high titer anti-factor VIII antibodies in both ELISA and inhibitor assays. A human factor VIII-specific T cell proliferative response was detected with spleen cells obtained three days after a single injection with human factor VIII, before mice had detectable anti-factor VIII antibodies. Subsequent exposures to factor VIII were followed by an increased T cell proliferative response. These studies indicate that murine hemophilia A is a good model for the study of the immune response to human factor VIII, especially the role of the T cell in the early steps in inhibitor antibody formation.

 

  • References

  • 1 Hoyer LW. In: The incidence of factor VIII inhibitors in patients with severe hemophilia A. Aledort LM, Hoyer LW, Lusher JM, Reisner HM, White GC. eds. Inhibitors to coagulation factors New York: Plenum; 1995: p. 35-45.
    Google Scholar
  • 2 Hoyer LW. Why do so many haemophilia A patients develop an inhibitor?. Br J Haem 1995; 90: 498-501.
    CrossrefPubMedGoogle Scholar
  • 3 Scandella D. Human antibodies which inactivate factor VIII: their epitope specificity and biochemical and functional characteristics. Int J Ped Hematol Oncol 1994; 1: 437-47.
    PubMedGoogle Scholar
  • 4 Singer ST, Addiego JE, Jr. Reason DC, Lucas A. T lymphocyte proliferative responses induced by recombinant factor VIII in hemophilia A patients with inhibitors. Thromb Haemost 1996; 76: 17-22.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Newton-Nash DK, Gill JC, Foster PA. Cellular immune responses to coagulation factor VIII in F.VIII inhibitor patients. Aledort LM, Hoyer LW, Lusher JM, Reisner HM, White II. eds. Inhibitors to Coagulation Factors. New York: Plenum Press; 1995: p. 285.
    Google Scholar
  • 6 Bi L, Lawler AM, Antonarakis SE, High KA, Gearhart JD, Kazazian Jr. Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. Nature Genetics 1995; 10: 119-21.
    CrossrefPubMedGoogle Scholar
  • 7 Bi L, Sarkar R, Naas T, Lawler AM, Pain J, Shumaker SL, Bedian V, Kazazian Jr. HH. Further characterization of factor VIII-deficient mice created by gene targeting: RNA and protein studies. Blood 1996; 88: 3446-50.
    PubMedGoogle Scholar
  • 8 Elder B, Lakich D, Gitschier J. Sequence of the murine factor VIII cDNA. Genomics 1993; 16: 374-9.
    CrossrefPubMedGoogle Scholar
  • 9 Saenko EL, Shima M, Gilbert GE, Scandella D. Slowed release of throm-bin-cleaved factor VIII from von Willebrand factor by a monoclonal and a human antibody is a novel mechanism for factor VIII inhibition. J Biol Chem 1996; 271: 27424-31.
    CrossrefPubMedGoogle Scholar
  • 10 Kasper CK, Aledort LM, Counts RB, Edson JR, Fratantoni J, Green D, Hampton JW, Hilgartner MW, Lazerson J, Levine PH. et al A more uniform measurement of factor VIII inhibitors. Thromb et Diath Haem 1975; 34: 875-6.
    PubMedGoogle Scholar
  • 11 Lollar P, Parker ET, Curtis JE, Helgerson SL, Hoyer LW, Scott ME, Scandella D. Inhibition of factor VIIIa by human anti-A2 subunit antibodies. J Clin Invest 1994; 93: 2497-504.
    CrossrefPubMedGoogle Scholar
  • 12 Muchitsch E-M, Turecek PL, Gritsch H, Richter G, Pichler L, Schwarz HP. Factor VIII deficiency in knock-out mice is associated with spontaneous bleeding. Thromb Haemost 1997; 77 (Suppl. 01) Suppl. 230.
    PubMedGoogle Scholar
  • 13 Hoyer LW. Hemophilia A. N Engl J Med 1994; 330: 38-47.
    CrossrefPubMedGoogle Scholar
  • 14 Oldenburg J, Picard JK, Brackmann HH, Tuddenham EGD, Simpson E. HLA genotype of patients with severe haemophilia A due to intron 22 inversion with and without inhibitors of factor VIII. Thromb Haemost 1997; 77: 238-42.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Hay CRM, Ollier W, Pepper L, Cumming A, Keeney S, Goodeve AC, Col-vin BT, Hill FGH, Preston FE, Peake IR. HLA class II profile: A weak determinant of factor VIII inhibitor development in severe haemophilia A. Thromb Haemost 1997; 77: 234-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 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 factor VIII concentrate. Thromb Haemost 1993; 69: 115-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Rosendaal FR, Nieuwenhuis HK, van den Berg HM, Heijboer H, Mauser-Bunschoten EP, van der Meer J, Smit C, Strengers PFW, Briet E. Dutch Hemophilia Study Group. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in the Netherlands. Blood 1993; 81: 2180-6.
    PubMedGoogle Scholar
  • 18 Peerlinck K, Arnout J, di Giambattista M, Gilles JG, Laub R, Jacquemin M, Saint-Remy J-MR, Vermylen J. Factor VIII inhibitors in previously treated haemophilia A patients with a double viruS-inactivated plasma derived factor VIII concentrate. Thromb Haemost 1997; 77: 80-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Dazzi F, Rosato A, Tison T, Vianello F, Radossi P, Girolami A. An animal model to explore the molecular basis of factor VIII (FVIII) inhibitor formation: Evidence of anti-FVIII T-cell response and importance of administration route. Thromb Haemost 1995; 73: 1026.
    PubMedGoogle Scholar
  • 20 Jarvis MA, Levin LG, Harrison JA, DePianto DJ, Suzuki CM, Ziaja CL, Brown JE, Jolly KW, Reisner HM, Abildgaard CF. et al 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Woods A, Chen HY, Trumbauer ME, Sirotina A, Cummings R, Zaller DM. Human major histocompatibility complex class II-restricted T cell responses in transgenic mice. J Expt Med 1994; 180: 173-81.
    CrossrefPubMedGoogle Scholar
  • 22 Tuddenham EGD, Schwaab R, Seehafer J, Millar DS, Gitschier J, Higuchi M, Bidichandani S, Connor JM, Hoyer LW, Yoshioka A. et al Haemophilia A: Database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition. Nucl Acids Res 1994; 22: 3511-33.
    CrossrefPubMedGoogle Scholar
  • 23 Boguniewicz M, Sunshine GH, Borel Y. Role of the thymus in natural tolerance to an autologous protein antigen. J Expt Med 1989; 169: 285-90.
    CrossrefPubMedGoogle Scholar
  • 24 Lin RH, Stockinger B. T cell immunity or tolerance as a consequence of self antigen presentation. Eur J Immunol 1989; 19: 105-10.
    CrossrefPubMedGoogle Scholar
  • 25 Stockinger B, Lin RH, Grant C. Presentation of a circulating self protein (C5) to MHC class II restricted T cells. Inter Rev Immunol 1993; 10: 357-64.
    PubMedGoogle Scholar
  • 26 Goodnow CC. Balancing immunity, autoimmunity, and self-tolerance. Ann NY Acad Sci 1997; 815: 55-66.
    CrossrefPubMedGoogle Scholar
  • 27 Pulendran B, van Driel R, Nossal GJ. Immunological tolerance in germinal centres. Immunology Today 1997; 18: 27-32.
    PubMedGoogle Scholar
  • 28 Stockinger B, Grant CF, Hausmann B. Localization of self antigen: implications for antigen presentation and induction of tolerance. Eur J Immunol 1993; 23: 6-11.
    CrossrefPubMedGoogle Scholar
  • 29 Van Den Berg CW, Hofhuis FMA, Rademaker PM, Van Dijk H. Induction of active immunological hypo/non-responsiveness to C5 in adult C5-deficient DBA/2 mice. Immunology 1991; 74: 380-5.
    PubMedGoogle Scholar