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Thromb Haemost 2018; 118(04): 688-699
DOI: 10.1055/s-0038-1637734
Coagulation and Fibrinolysis
Schattauer GmbH Stuttgart

Human Dendritic Cells Synergistically Activated by FVIII Plus LPS Induce Activation of Autologous CD4+ T Cells

Lilija Miller
1   Section 3/1 “Product Testing of Biomedicines,” Paul-Ehrlich-Institut, Langen, Germany
,
Eva Ringler
1   Section 3/1 “Product Testing of Biomedicines,” Paul-Ehrlich-Institut, Langen, Germany
,
Klaus Maximilian Kistner
1   Section 3/1 “Product Testing of Biomedicines,” Paul-Ehrlich-Institut, Langen, Germany
,
Zoe Waibler
1   Section 3/1 “Product Testing of Biomedicines,” Paul-Ehrlich-Institut, Langen, Germany
,
on behalf of the ABIRISK Consortium › Author Affiliations Funding Partially, the research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007–2013) and EFPIA companies' in kind contribution.
Further Information

Publication History

13 June 2017

30 January 2018

Publication Date:
19 March 2018 (online)

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Abstract

The most severe side effect in haemophilia A (HA) treatment is the development of anti-factor VIII antibodies, also called inhibitors. Why inhibitors develop in a proportion of treated HA patients and how this can be prevented remains largely unanswered. Among numerous theories, the presence of immunological danger signals, associated with events such as surgery or infection, has been proposed to play a role. In this study, we demonstrate that human dendritic cells (DC) synergistically activated by a combination of factor VIII (FVIII) concentrate plus the bacterial danger signal lipopolysaccharide (LPS) induce a significantly stronger activation of autologous CD4+ T cells than DC pretreated with FVIII or LPS alone. The observed T cell activation is dependent on antigen processing, presentation on MHC class II molecules and costimulation via CD86. Of note, FVIII plus LPS pretreated DC predominantly induce the activation of memory T cells and a minor proportion of naive T cells. Collectively, our data support a model in which immunological danger signals plus FVIII concentrates synergistically increase human CD4+ T cell responses to FVIII protein.

Keywords

anti-FVIII immune response - lipopolysaccharide - T cells - danger signal - inhibitors

Authors' Contributions

L.M. performed experiments, collected, analysed and interpreted the data, generated figures and wrote the article; E.R. and K.M.K. performed experiments; Z.W. designed experiments, interpreted the data and wrote the article.


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