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Thromb Haemost 2015; 114(02): 268-276
DOI: 10.1160/TH14-09-0789
Coagulation and Fibrinolysis
Schattauer GmbH

Danger signal-dependent activation of human dendritic cells by plasma-derived factor VIII products

Lilija Miller
1   Junior Research Group “Novel Vaccination Strategies and Early Immune Responses”, Paul-Ehrlich-Institut, Langen, Germany
,
Sabrina Weissmüller
1   Junior Research Group “Novel Vaccination Strategies and Early Immune Responses”, Paul-Ehrlich-Institut, Langen, Germany
,
Eva Ringler
1   Junior Research Group “Novel Vaccination Strategies and Early Immune Responses”, Paul-Ehrlich-Institut, Langen, Germany
,
Peter Crauwels
2   Division of Immunology, Paul-Ehrlich-Institut, Langen, Germany
,
Ger van Zandbergen
2   Division of Immunology, Paul-Ehrlich-Institut, Langen, Germany
,
Rainer Seitz
3   Division of Haematology / Transfusion Medicine, Paul-Ehrlich-Institut, Langen, Germany
,
Zoe Waibler
1   Junior Research Group “Novel Vaccination Strategies and Early Immune Responses”, Paul-Ehrlich-Institut, Langen, Germany
,
the ABIRISK consortium › Author Affiliations Financial support: The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°[115303], resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution.
Further Information

Publication History

Received: 22 September 2014

Accepted after major revision: 16 March 2015

Publication Date:
01 December 2017 (online)

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Summary

Treatment of haemophilia A by infusions of the clotting factor VIII (FVIII) results in the development of inhibitors/anti-drug antibodies in up to 25 % of patients. Mechanisms leading to immunogenicity of FVIII products are not yet fully understood. Amongst other factors, danger signals as elicited upon infection or surgery have been proposed to play a role. In the present study, we focused on effects of danger signals on maturation and activation of dendritic cells (DC) in the context of FVIII application. Human monocyte-derived DC were treated with FVIII alone, with a danger signal alone or a combination of both. By testing more than 60 different healthy donors, we show that FVIII and the bacterial danger signal lipopolysaccharide synergise in increasing DC activation, as characterised by increased expression of co-stimulatory molecules and secretion of pro-inflammatory cytokines. The degree and frequency of this synergistic activation correlate with CD86 expression levels on immature DC prior to stimulation. In our assay system, plasma-derived but not recombinant FVIII products activate human DC in a danger signal-dependent manner. Further tested danger signals, such as R848 also induced DC activation in combination with FVIII, albeit not in every tested donor. In our hands, human DC but not human B cells or macrophages could be activated by FVIII in a danger signal-dependent manner. Our results suggest that immunogenicity of FVIII is a result of multiple factors including the presence of danger, predisposition of the patient, and the choice of a FVIII product for treatment.

Keywords

Haemophilia A - inhibitors - danger signals - dendritic cells - early immune responses

 

  • References

  • 1 Sethu S, Govindappa K, Alhaidari M. et al. Immunogenicity to biologics: mechanisms, prediction and reduction. Arch Immunol Ther Exp 2012; 60: 331-344.
    CrossrefPubMedGoogle Scholar
  • 2 Baker MP, Reynolds HM, Lumicisi B. et al. Immunogenicity of protein therapeutics: The key causes, consequences and challenges. Self Nonself 2010; 01: 314-322.
    CrossrefPubMedGoogle Scholar
  • 3 Gouw SC, van der Bom JG, Ljung R. et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368: 231-239.
    CrossrefPubMedGoogle Scholar
  • 4 Mannucci PM, Tuddenham EG. The hemophilias--from royal genes to gene therapy. N Engl J Med 2001; 344: 1773-1779.
    CrossrefPubMedGoogle Scholar
  • 5 Bolton-Maggs Paula H B, Pasi KJ. Haemophilias A and B. Lancet 2003; 361: 1801-1809.
    CrossrefPubMedGoogle Scholar
  • 6 Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev 2013; 27: 179-184.
    CrossrefPubMedGoogle Scholar
  • 7 Iorio A, Halimeh S, Holzhauer S. et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010; 08: 1256-1265.
    CrossrefPubMedGoogle Scholar
  • 8 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 09: 418-435.
    CrossrefPubMedGoogle Scholar
  • 9 Strauss T, Lubetsky A, Ravid B. et al. Recombinant factor concentrates may increase inhibitor development: a single centre cohort study. Haemophilia 2011; 17: 625-629.
    CrossrefPubMedGoogle Scholar
  • 10 Mancuso ME, Mannucci PM, Rocino A. et al. Source and purity of factor VIII products as risk factors for inhibitor development in patients with hemophilia A. J Thromb Haemost 2012; 10: 781-790.
    CrossrefPubMedGoogle Scholar
  • 11 Butenas S, Krudysz-Amblo J, Rivard GE. et al. Product-dependent anti-factor VIII antibodies. Haemophilia 2013; 19: 619-625.
    CrossrefPubMedGoogle Scholar
  • 12 White GC, Kempton CL, Grimsley A. et al. Cellular immune responses in hemophilia: why do inhibitors develop in some, but not all hemophiliacs?. J Thromb Haemost 2005; 03: 1676-1681.
    CrossrefPubMedGoogle Scholar
  • 13 Gouw SC, van den Berg JG, van den Berg MH. et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood 2012; 119: 2922-2934.
    CrossrefPubMedGoogle Scholar
  • 14 Gouw SC, van der Bom JG, van den Berg MH. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood 2007; 109: 4648-4654.
    CrossrefPubMedGoogle Scholar
  • 15 Kurnik K, Bidlingmaier C, Engl W. et al. New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development. Haemophilia 2010; 16: 256-262.
    CrossrefPubMedGoogle Scholar
  • 16 Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol 2010; 125: S33.
    CrossrefPubMedGoogle Scholar
  • 17 Schülke S, Waibler Z, Mende M. et al. Fusion protein of TLR5-ligand and allergen potentiates activation and IL-10 secretion in murine myeloid DC. Mol Immunol 2010; 48: 341-350.
    CrossrefPubMedGoogle Scholar
  • 18 Stojdl DF, Lichty BD, ten Oever BR. et al. VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell 2003; 04: 263-275.
    CrossrefPubMedGoogle Scholar
  • 19 Qadura M, Waters B, Burnett E. et al. Recombinant and plasma-derived factor VIII products induce distinct splenic cytokine microenvironments in hemophilia A mice. Blood 2009; 114: 871-880.
    CrossrefPubMedGoogle Scholar
  • 20 Pfistershammer K, Stöckl J, Siekmann J. et al. Recombinant factor VIII and factor VIII-von Willebrand factor complex do not present danger signals for human dendritic cells. Thromb Haemost 2006; 96: 309-316.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Adkins JN, Varnum SM, Auberry KJ. et al. Toward a human blood serum proteome: analysis by multidimensional separation coupled with mass spectrometry. Mol Cell Proteomics 2002; 01: 947-955.
    CrossrefPubMedGoogle Scholar
  • 22 Skupsky J, Zhang A, Su Y. et al. A role for thrombin in the initiation of the immune response to therapeutic factor VIII. Blood 2009; 114: 4741-4748.
    CrossrefPubMedGoogle Scholar
  • 23 Rosenberg AS. Effects of protein aggregates: An immunologic perspective. AAPS J 2006; 08: E501.
    CrossrefPubMedGoogle Scholar
  • 24 Hilmenyuk T, Bellinghausen I, Heydenreich B. et al. Effects of glycation of the model food allergen ovalbumin on antigen uptake and presentation by human dendritic cells. Immunology 2010; 129: 437-445.
    CrossrefPubMedGoogle Scholar
  • 25 Delignat S, Repessé Y, Navarrete A. et al. Immunoprotective effect of von Wille-brand factor towards therapeutic factor VIII in experimental haemophilia A. Haemophilia 2012; 18: 248-254.
    CrossrefPubMedGoogle Scholar
  • 26 Franchini M, Lippi G. Von Willebrand factor-containing factor VIII concentrates and inhibitors in haemophilia A. A critical literature review. Thromb Hae-most 2010; 104: 931-940.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Steinitz KN, van Helden, Pauline M. et al. CD4+ T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVIII in humanized hemophilic E17 HLA-DRB1*1501 mice. Blood 2012; 119: 4073-4082.
    CrossrefPubMedGoogle Scholar
  • 28 Herczenik E, van Haren, Simon D. et al. Uptake of blood coagulation factor VIII by dendritic cells is mediated via its C1 domain. J Allergy Clin Immunol 2012; 129: 501-509 509.e1–5.
    CrossrefPubMedGoogle Scholar
  • 29 van Schooten CJ, Shahbazi S, Groot E. et al. Macrophages contribute to the cellular uptake of von Willebrand factor and factor VIII in vivo. Blood 2008; 112: 1704-1712.
    CrossrefPubMedGoogle Scholar
  • 30 Akira S. Mammalian Toll-like receptors. Curr Opin Immunol 2003; 15: 5-11.
    CrossrefPubMedGoogle Scholar
  • 31 Hemmi H, Kaisho T, Takeuchi O. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 2002; 03: 196-200.
    CrossrefPubMedGoogle Scholar
  • 32 Takeuchi O, Sato S, Horiuchi T. et al. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol 2002; 169: 10-14.
    CrossrefPubMedGoogle Scholar
  • 33 Coyle AJ, Gutierrez-Ramos JC. The expanding B7 superfamily: increasing complexity in costimulatory signals regulating T cell function. Nat Immunol 2001; 02: 203-209.
    CrossrefPubMedGoogle Scholar
  • 34 Abdallah AM, Renzoni EA, Anevlavis S. et al. A polymorphism in the promoter region of the CD86 (B7.2) gene is associated with systemic sclerosis. Int J Immunogenet 2006; 33: 155-161.
    CrossrefPubMedGoogle Scholar
  • 35 Qian J, Collins M, Sharpe AH. et al. Prevention and treatment of factor VIII inhibitors in murine hemophilia A. Blood 2000; 95: 1324-1329.
    PubMedGoogle Scholar
  • 36 Astermark J, Wang X, Oldenburg J. et al. Polymorphisms in the CTLA-4 gene and inhibitor development in patients with severe hemophilia A. J Thromb Hae-most 2007; 05: 263-265.
    CrossrefPubMedGoogle Scholar