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Wroblewska A.,Sanquin AMC Landsteiner Laboratory and Van Creveld Laboratory | Reipert B.M.,Baxter Bioscience | Pratt K.P.,University of Washington | Voorberg J.,Sanquin AMC Landsteiner Laboratory and Van Creveld Laboratory
Journal of Thrombosis and Haemostasis | Year: 2013

Only a fraction of patients with hemophilia A develop a neutralizing antibody (inhibitor) response to therapeutic infusions of factor VIII. Our present understanding of the underlying causes of the immunogenicity of this protein is limited. In the past few years, insights into the uptake and processing of FVIII by antigen-presenting cells (APCs) have expanded significantly. Although the mechanism of endocytosis remains unclear, current data indicate that FVIII enters APCs via its C1 domain. Its subsequent processing within endolysosomes allows for presentation of a heterogeneous collection of FVIII-derived peptides on major histocompatibility complex (MHC) class II, and this peptide-MHC class II complex may then be recognized by cognate effector CD4+ T cells, leading to anti-FVIII antibody production. Here we aim to summarize recent knowledge gained about FVIII processing and presentation by APCs, as well as the diversity of the FVIII-specific T-cell repertoire in mice and humans. Moreover, we discuss possible factors that can drive FVIII immunogenicity. We believe that increasing understanding of the immune recognition of FVIII and the cellular mechanisms of anti-FVIII antibody production will lead to novel therapeutic approaches to prevent inhibitor formation in patients with hemophilia A. © 2012 International Society on Thrombosis and Haemostasis. Source


Rabel P.O.,Baxter Bioscience
Euro surveillance : bulletin européen sur les maladies transmissibles = European communicable disease bulletin | Year: 2011

We analysed by neutralisation assay 55 intravenous immunoglobulin preparations produced from human plasma collected in three central European countries, specifically Austria, Germany and the Czech Republic, from 2006 to 2010. The preparations from 2009 and 2010 contained increasing titres of neutralising antibodies against West Nile virus (WNV) in the absence of reported human WNV cases in these countries. Source


Saint-Remy J.-M.,Catholic University of Leuven | Reipert B.M.,Baxter Bioscience | Monroe D.M.,University of North Carolina at Chapel Hill
Haemophilia | Year: 2012

Inhibitor development remains a challenge to appropriate haemophilia treatment. This challenge is being addressed, in part, by an expanding knowledge of the mechanisms that drive inhibitor development including how elements of the innate immune response play a role in inhibitor development. There are promising therapies that may suppress an active immune response. Models to assess the immune responses are becoming ever more sophisticated. Newer models can be used at the preclinical level to evaluate the role of MHC-class II presentation of antigens in both in vitro cell culture studies and in vivo in transgenic mice that express either the protein to be studied or that express human MHC-class II proteins. Parallel to work designed to reduce or reverse inhibitors is development of improved therapies including bypassing agents to treat patients with inhibitors. With these new treatment modalities comes the problem of assessing efficacy at the preclinical level. Models to evaluate bleeding are being developed that may give a more subtle assessment of bypassing agents. These models represent in part an attempt to incorporate the role of ongoing bleeding into the evaluation. Overall, these newer models have great potential in preclinical studies to evaluate the risk of inhibitor development of new therapeutics and to assess the functionality of these new therapeutics. © 2012 Blackwell Publishing Ltd. Source


Barrett P.N.,Biomedical Research Center | Portsmouth D.,Biomedical Research Center | Ehrlich H.J.,Baxter Bioscience
Current Opinion in Molecular Therapeutics | Year: 2010

The growing prospect of avian influenza viruses achieving sustained interhuman transmission, combined with the recent emergence of a novel swine-origin A/H1N1 influenza strain, has brought the issue of influenza vaccine production capacity into sharp focus. It is becoming increasingly clear that traditional egg-based manufacturing processes may be insufficient to meet global vaccine demands in a pandemic situation that is caused by a highly pathogenic influenza virus. This review introduces the concepts of modern, cell culture-derived influenza vaccines and their manufacture, and explains the advantages of these vaccines in terms of both speed and efficiency of production as well as immunogenic efficacy. Vaccine production technologies using the mammalian cell lines Vero, MDCK and PER.C6, as well as the baculovirus/insect cell platform, are described in detail. Clinical data are provided from cell culture-derived vaccines that are at an advanced stage of development, and insights are provided into recent developments in the preclinical evaluation of more experimental technologies. © Thomson Reuters (Scientific) Ltd. Source


The development of neutralizing antibodies against factor VIII (FVIII inhibitors) and factor IX (FIX inhibitors) is the major complication in hemophilia care today. The antibodies neutralize the biological activity of FVIII and FIX and render replacement therapies ineffective. Antibodies are generated as a result of a cascade of tightly regulated interactions between different cells of the innate and the adaptive immune system located in distinct compartments. Any event that modulates the repertoire of specific B or T cells, the activation state of the innate and adaptive immune system, or the migration pattern of immune cells will therefore potentially influence the risk for patients to develop inhibitors. This chapter reviews our current understanding of different pathways of antibody development that result in different qualities of antibodies. Potential differences in differentiation pathways leading to high-affinity neutralizing or low-affinity non-neutralizing antibodies and the potential influence of gene polymorphisms such as HLA haplotype, FVIII haplotype, and polymorphisms of immunoregulatory genes are discussed. Source

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