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Article ; Online: Imlifidase, a new option to optimize the management of patients with hemophilia A on emicizumab.

Bou-Jaoudeh, Melissa / Mimoun, Angelina / Delignat, Sandrine / Peyron, Ivan / Capdevila, Ladislas / Daventure, Victoria / Deligne, Claire / Dimitrov, Jordan D / Christophe, Olivier D / Denis, Cécile V / Lenting, Peter J / Proulle, Valérie / Lacroix-Desmazes, Sébastien

Journal of thrombosis and haemostasis : JTH

2023 Volume 21, Issue 10, Page(s) 2776–2783

Abstract: Background: Emicizumab is a bispecific, chimeric, humanized immunoglobulin G (IgG)4 that mimics the procoagulant activity of factor (F) VIII (FVIII). Its long half-life and subcutaneous route of administration have been life-changing in treating ... ...

Abstract	Background: Emicizumab is a bispecific, chimeric, humanized immunoglobulin G (IgG)4 that mimics the procoagulant activity of factor (F) VIII (FVIII). Its long half-life and subcutaneous route of administration have been life-changing in treating patients with hemophilia A (HA) with or without FVIII inhibitors. However, emicizumab only partially mimics FVIII activity; it prevents but does not treat acute bleeds. Emergency management is particularly complicated in patients with FVIII inhibitors receiving emicizumab prophylaxis in whom exogenous FVIII is inefficient. We have shown recently that Imlifidase (IdeS), a bacterial IgG-degrading enzyme, efficiently eliminates human anti-FVIII IgG in a mouse model of severe HA with inhibitors and opens a therapeutic window for the administration of exogenous FVIII. Objectives: To investigate the impact of IdeS treatment in inhibitor-positive HA mice injected with emicizumab. Methods: IdeS was injected to HA mice reconstituted with human neutralizing anti-FVIII IgG and treated with emicizumab. Results: IdeS hydrolyzed emicizumab in vitro and in vivo, albeit, at slower rates than another recombinant human monoclonal IgG4. While F(ab') Conclusion: Our results suggest that IdeS could be administered to inhibitor-positive patients with HA receiving emicizumab prophylaxis to improve and ease the management of breakthrough bleeds or programmed major surgeries.
MeSH term(s)	Humans ; Animals ; Mice ; Hemophilia A/drug therapy ; Factor VIII/therapeutic use ; Antibodies, Bispecific/therapeutic use ; Hemorrhage/drug therapy ; Immunosuppressive Agents/therapeutic use ; Immunoglobulin G
Chemical Substances	Factor VIII (9001-27-8) ; emicizumab (7NL2E3F6K3) ; Antibodies, Bispecific ; Immunosuppressive Agents ; Immunoglobulin G
Language	English
Publishing date	2023-07-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2023.06.038
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Zs.A 5805: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 295: Show issues

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Article ; Online: Hunting down factor VIII in the immunopeptidome.

Hartholt, Robin B / Peyron, Ivan / Voorberg, Jan

Cellular immunology

2016 Volume 301, Page(s) 59–64

Abstract: Major histocompatibility complex class II (MHCII)-restricted peptide presentation is crucial for the selection and subsequent proliferation of antigen specific CD4+ T cells. While selection of antigen-specific CD4+ T cells is beneficial in the context of ...

Abstract	Major histocompatibility complex class II (MHCII)-restricted peptide presentation is crucial for the selection and subsequent proliferation of antigen specific CD4+ T cells. While selection of antigen-specific CD4+ T cells is beneficial in the context of vaccination, emergence of antigen CD4+ T cells following administration of therapeutic proteins like factor VIII (FVIII) is not desirable. The mechanism of uptake, processing and presentation of FVIII by antigen-presenting cells (APCs) has been the subject of intense study over the past 10 years. Multiple receptors have been implicated in the uptake of FVIII by APCs. A crucial determinant directing its entry in APCs resides in the C1 domain of FVIII. Until recently, our knowledge on the repertoire of FVIII derived presented on MHCII was limited. Peptide sequences on FVIII recognized by CD4+ T cells have been identified using MHCII tetramers as well as by directly monitoring peptide-induced proliferation of CD4+ T cells. More recently, the repertoire of naturally presented peptides derived from FVIII has been identified by pulsing of immature dendritic cells with FVIII. In a complementary approach HLA-DRB1(∗)15 transgenic mice were used to identify HLA-DRB1(∗)15 restricted CD4+ T cells reactive towards human FVIII. In this review we summarize our current knowledge on FVIII derived peptides that are presented on MHCII and discuss the relevance of these findings for the etiology of inhibitor development in patients with hemophilia A.
MeSH term(s)	Animals ; Antigen Presentation/immunology ; CD4-Positive T-Lymphocytes/immunology ; Epitopes, T-Lymphocyte/immunology ; Factor VIII/immunology ; Hemophilia A/immunology ; Histocompatibility Antigens Class II/immunology ; Humans ; Lymphocyte Activation/immunology ; Peptides/immunology ; Proteome/immunology
Chemical Substances	Epitopes, T-Lymphocyte ; Histocompatibility Antigens Class II ; Peptides ; Proteome ; Factor VIII (9001-27-8)
Language	English
Publishing date	2016-03
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	80094-6
ISSN	1090-2163 ; 0008-8749
ISSN (online)	1090-2163
ISSN	0008-8749
DOI	10.1016/j.cellimm.2015.11.001
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Zs.A 417: Show issues

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Article ; Online: Transplacental delivery of therapeutic proteins by engineered immunoglobulin G: a step toward perinatal replacement therapy.

Mimoun, Angelina / Bou-Jaoudeh, Melissa / Delignat, Sandrine / Daventure, Victoria / Reyes Ruiz, Alejandra / Lecerf, Maxime / Azam, Aurélien / Noe, Remi / Peyron, Ivan / Christophe, Olivier D / Lenting, Peter J / Proulle, Valérie / McIntosh, Jenny / Nathwani, Amit C / Dimitrov, Jordan D / Denis, Cécile V / Lacroix-Desmazes, Sébastien

Journal of thrombosis and haemostasis : JTH

2023 Volume 21, Issue 9, Page(s) 2405–2417

Abstract: Background: Transplacental delivery of maternal immunoglobulin G (IgG) provides humoral protection during the first months of life until the newborn's immune system reaches maturity. The maternofetal interface has been exploited therapeutically to ... ...

Abstract	Background: Transplacental delivery of maternal immunoglobulin G (IgG) provides humoral protection during the first months of life until the newborn's immune system reaches maturity. The maternofetal interface has been exploited therapeutically to replace missing enzymes in the fetus, as shown in experimental mucopolysaccharidoses, or to shape adaptive immune repertoires during fetal development and induce tolerance to self-antigens or immunogenic therapeutic molecules. Objectives: To investigate whether proteins that are administered to pregnant mice or endogenously present in their circulation may be delivered through the placenta. Methods: We engineered monovalent immunoglobulin G (FabFc) specific for different domains of human factor VIII (FVIII), a therapeutically relevant model antigen. FabFc was injected with exogenous FVIII into pregnant severe hemophilia A mice or pregnant mice expressing human FVIII following AAV8-mediated gene therapy. FabFc and FVIII were detected in the pregnant mice and/or fetuses by enzyme-linked immunosorbent assay and immunohistochemistry. Results: Administration of FabFc to pregnant mice allowed the maternofetal delivery of FVIII in a FcRn-dependent manner. FVIII antigen levels achieved in the fetuses represented 10% of normal plasma levels in the human. We identified antigen/FabFc complex stability, antigen size, and shielding of promiscuous protein patches as key parameters to foster optimal antigen delivery. Conclusion: Our results pave the way toward the development of novel strategies for the in utero delivery of endogenous maternal proteins to replace genetically deficient fetal proteins or to educate the immune system and favor active immune tolerance upon protein encounter later in life.
MeSH term(s)	Pregnancy ; Female ; Mice ; Humans ; Animals ; Immunoglobulin G ; Factor VIII ; Hemophilia A/genetics ; Hemophilia A/therapy ; Placenta ; Genetic Therapy ; Immune Tolerance
Chemical Substances	Immunoglobulin G ; Factor VIII (9001-27-8)
Language	English
Publishing date	2023-06-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2023.05.021
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Zs.A 5805: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Relevance of the Materno-Fetal Interface for the Induction of Antigen-Specific Immune Tolerance.

Mimoun, Angelina / Delignat, Sandrine / Peyron, Ivan / Daventure, Victoria / Lecerf, Maxime / Dimitrov, Jordan D / Kaveri, Srinivas V / Bayry, Jagadeesh / Lacroix-Desmazes, Sébastien

Frontiers in immunology

2020 Volume 11, Page(s) 810

Abstract: In humans, maternal IgGs are transferred to the fetus from the second trimester of pregnancy onwards. The transplacental delivery of maternal IgG is mediated by its binding to the neonatal Fc receptor (FcRn) after endocytosis by the syncytiotrophoblast. ... ...

Abstract	In humans, maternal IgGs are transferred to the fetus from the second trimester of pregnancy onwards. The transplacental delivery of maternal IgG is mediated by its binding to the neonatal Fc receptor (FcRn) after endocytosis by the syncytiotrophoblast. IgGs present in the maternal milk are also transferred to the newborn through the digestive epithelium upon binding to the FcRn. Importantly, the binding of IgGs to the FcRn is also responsible for the recycling of circulating IgGs that confers them with a long half-life. Maternally delivered IgG provides passive immunity to the newborn, for instance by conferring protective anti-flu or anti-pertussis toxin IgGs. It may, however, lead to the development of autoimmune manifestations when pathological autoantibodies from the mother cross the placenta and reach the circulation of the fetus. In recent years, strategies that exploit the transplacental delivery of antigen/IgG complexes or of Fc-fused proteins have been validated in mouse models of human diseases to impose antigen-specific tolerance, particularly in the case of Fc-fused factor VIII (FVIII) domains in hemophilia A mice or pre-pro-insulin (PPI) in the case of preclinical models of type 1 diabetes (T1D). The present review summarizes the mechanisms underlying the FcRn-mediated transcytosis of IgGs, the physiopathological relevance of this phenomenon, and the repercussion for drug delivery and shaping of the immune system during its ontogeny.
MeSH term(s)	Animals ; Antigens/immunology ; Autoantibodies/metabolism ; Female ; Fetus/immunology ; Histocompatibility Antigens Class I/metabolism ; Humans ; Immune System/embryology ; Immune System/metabolism ; Immune Tolerance ; Immunoglobulin G/metabolism ; Maternal-Fetal Exchange/immunology ; Mice ; Placenta/immunology ; Pregnancy ; Protein Transport/immunology ; Receptors, Fc/metabolism ; Transcytosis/immunology
Chemical Substances	Antigens ; Autoantibodies ; Histocompatibility Antigens Class I ; Immunoglobulin G ; Receptors, Fc ; Fc receptor, neonatal (TW3XAW0RCY)
Language	English
Publishing date	2020-05-14
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.00810
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Article ; Online: Identification of von Willebrand factor D4 domain mutations in patients of Afro-Caribbean descent: In vitro characterization.

Dubois, Marie-Daniéla / Peyron, Ivan / Pierre-Louis, Olivier-Nicolas / Pierre-Louis, Serge / Rabout, Johalène / Boisseau, Pierre / de Jong, Annika / Susen, Sophie / Goudemand, Jenny / Neviere, Rémi / Fuseau, Pascal / Christophe, Olivier D / Lenting, Peter J / Denis, Cécile V / Casari, Caterina

Research and practice in thrombosis and haemostasis

2022 Volume 6, Issue 4, Page(s) e12737

Abstract: Background: Von Willebrand disease was diagnosed in two Afro-Caribbean patients and sequencing of the VWF gene (: Objectives: Our goal was to characterize how the D4 variants p.(Pro2145Thrfs*5) and p.(Cys2216Phefs*9) influenced VWF biosynthesis/ ... ...

Abstract	Background: Von Willebrand disease was diagnosed in two Afro-Caribbean patients and sequencing of the VWF gene ( Objectives: Our goal was to characterize how the D4 variants p.(Pro2145Thrfs5) and p.(Cys2216Phefs9) influenced VWF biosynthesis/secretion and functions using in vitro assays. Methods: Recombinant VWF (rVWF), mutant or wild-type, was produced via transient transfection of the human embryonic kidney cell line 293T. The use of different tags for the wild-type and the mutant allele allowed us to distinguish between the two forms when measuring VWF antigen in medium and cell lysates. Binding of rVWF to its ligands, collagen, factor VIII, ADAMTS13, and platelet receptors was also investigated. Results: Homozygous expression of the p.(Cys2216Phefs9)-rVWF mutation resulted in an almost complete intracellular retention of the protein. Heterozygous expression led to secretion of almost exclusively wild-type-rVWF, logically capable of normal interaction with the different ligands. In contrast, the p.(Pro2145Thrfs5)-rVWF exhibited reduced binding to type III collagen and αIIbβ3 integrin compared to wild-type-rVWF. Conclusions: We report two mutations of the D4 domains that induced combined qualitative and quantitative defects.
Language	English
Publishing date	2022-06-15
Publishing country	United States
Document type	Journal Article
ISSN	2475-0379
ISSN (online)	2475-0379
DOI	10.1002/rth2.12737
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Article ; Online: Antithrombotic potential of a single-domain antibody enhancing the activated protein C-cofactor activity of protein S.

Sedzro, Josepha C / Adam, Frédéric / Auditeau, Claire / Bianchini, Elsa / De Carvalho, Allan / Peyron, Ivan / Daramé, Sadyo / Gandrille, Sophie / Thomassen, Stella / Hackeng, Tilman M / Christophe, Olivier D / Lenting, Peter J / Denis, Cécile V / Borgel, Delphine / Saller, François

Journal of thrombosis and haemostasis : JTH

2022 Volume 20, Issue 7, Page(s) 1653–1664

Abstract: Background: Protein S (PS) is a natural anticoagulant acting as a cofactor for activated protein C (APC) in the proteolytic inactivation of activated factors V (FVa) and VIII (FVIIIa), but also for tissue factor pathway inhibitor α (TFPIα) in the ... ...

Abstract	Background: Protein S (PS) is a natural anticoagulant acting as a cofactor for activated protein C (APC) in the proteolytic inactivation of activated factors V (FVa) and VIII (FVIIIa), but also for tissue factor pathway inhibitor α (TFPIα) in the inhibition of activated factor X (FXa). Objective: For therapeutic purposes, we aimed at generating single-domain antibodies (sdAbs) that could specifically modulate the APC-cofactor activity of PS in vivo. Methods: A llama-derived immune library of sdAbs was generated and screened on recombinant human PS by phage display. PS binders were tested in a global activated partial thromboplastin time (APTT)-based APC-cofactor activity assay. Results: A PS-specific sdAb (PS003) was found to enhance the APC-cofactor activity of PS in our APTT-based assay, and this enhancing effect was greater for a bivalent form of PS003 (PS003biv). Further characterization of PS003biv demonstrated that PS003biv also enhanced the APC-cofactor activity of PS in a tissue factor (TF)-induced thrombin generation assay and stimulated APC in the inactivation of FVa, but not FVIIIa, in plasma-based assays. Furthermore, PS003biv was directed against the sex hormone-binding globulin (SHBG)-like domain but did not inhibit the binding of PS to C4b-binding protein (C4BP) and did not interfere with the TFPIα-cofactor activity of PS. In mice, PS003biv exerted an antithrombotic effect in a FeCl Discussion: Altogether, these results showed that pharmacological enhancement of the APC-cofactor activity of PS through an original anti-PS sdAb might constitute a promising and safe antithrombotic strategy.
MeSH term(s)	Animals ; Factor VIIIa/chemistry ; Fibrinolytic Agents/pharmacology ; Humans ; Mice ; Protein C/metabolism ; Protein S/metabolism ; Single-Domain Antibodies
Chemical Substances	Fibrinolytic Agents ; Protein C ; Protein S ; Single-Domain Antibodies ; Factor VIIIa (72175-66-7)
Language	English
Publishing date	2022-05-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1111/jth.15736
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Article ; Online: Non-inhibitory antibodies inducing increased emicizumab clearance in a severe haemophilia A inhibitor patient.

Harroche, Annie / Sefiane, Thibaud / Desvages, Maximilien / Borgel, Delphine / Lasne, Dominique / Casari, Caterina / Peyron, Ivan / Frenzel, Laurent / Chhun, Stéphanie / Lenting, Peter J / Bally, Cécile

Haematologica

2021 Volume 106, Issue 8, Page(s) 2287–2290

MeSH term(s)	Antibodies, Bispecific/therapeutic use ; Antibodies, Monoclonal, Humanized ; Factor VIII ; Hemophilia A/drug therapy ; Humans ; Kinetics
Chemical Substances	Antibodies, Bispecific ; Antibodies, Monoclonal, Humanized ; emicizumab (7NL2E3F6K3) ; Factor VIII (9001-27-8)
Language	English
Publishing date	2021-08-01
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2021.278579
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Article: Storage-Induced Platelet Apoptosis Is a Potential Risk Factor for Alloimmunization Upon Platelet Transfusion.

Saris, Anno / Peyron, Ivan / van der Meer, Pieter F / Stuge, Tor B / Zwaginga, Jaap Jan / van Ham, S Marieke / Ten Brinke, Anja

Frontiers in immunology

2018 Volume 9, Page(s) 1251

Abstract: Platelet transfusion can elicit alloimmune responses leading to alloantibody formation against donor-specific polymorphic residues, ultimately resulting in platelet transfusion refractoriness. Universal leukoreduction significantly reduced the frequency ... ...

Abstract	Platelet transfusion can elicit alloimmune responses leading to alloantibody formation against donor-specific polymorphic residues, ultimately resulting in platelet transfusion refractoriness. Universal leukoreduction significantly reduced the frequency of alloimmunization after platelet transfusion, thereby showing the importance of white blood cells (WBCs) in inducing this alloresponse. It is, however, unknown if the residual risk for alloimmunization is caused by WBCs remaining after leukoreduction or if alloimmunization can be induced by platelets themselves. This study investigated the capacity of platelets to induce alloimmunization and identified potential product-related risk factors for alloimmunization. First, internalization of allogeneic platelets by dendritic cells (DCs) was demonstrated by confocal microscopy. Second, after internalization, presentation of platelet-derived peptides was shown by mass spectrometry analysis of human leukocytes antigen (HLA)-DR eluted peptides. Third, platelet-loaded DCs induced platelet-specific CD4 T cell responses. Altogether, this indicates a platelet-specific ability to induce alloimmunization. Therefore, factors enhancing platelet internalization may be identified as risk factor for alloimmunization by platelet concentrates. To investigate if storage of platelets is such a risk factor, internalization of stored platelets was compared with fresh platelets and showed enhanced internalization of stored platelets. Storage-induced apoptosis and accompanied phosphatidylserine exposure seemed to be instrumental for this. Indeed, DCs pre-incubated with apoptotic platelets induced the strongest IFN-γ production by CD4 T cells compared with pre-incubation with untreated or activated platelets. In conclusion, this study shows the capacity of platelets to induce platelet-specific alloimmune responses. Furthermore, storage-induced apoptosis of platelets is identified as potential risk factor for alloimmunization after platelet transfusions.
MeSH term(s)	Antigen Presentation/immunology ; Apoptosis ; Blood Platelets/immunology ; Blood Platelets/metabolism ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Histocompatibility Antigens Class II/immunology ; Humans ; Immunization ; Isoantibodies/immunology ; Phagocytosis/immunology ; Platelet Transfusion/adverse effects ; Risk Factors ; T-Cell Antigen Receptor Specificity ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	Histocompatibility Antigens Class II ; Isoantibodies
Language	English
Publishing date	2018-06-05
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2018.01251
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Article ; Online: Biochemical characterization and immunogenicity of Neureight, a recombinant full-length factor VIII produced by fed-batch process in disposable bioreactors.

Delignat, Sandrine / Peyron, Ivan / El Ghazaly, Maria / V Kaveri, Srinivas / Rohde, Jan / Mueller, Frank / Lacroix-Desmazes, Sebastien

Cellular immunology

2018 Volume 331, Page(s) 22–29

Abstract: Hemophilia A is a X-linked recessive bleeding disorder consecutive to the lack of circulating pro-coagulant factor VIII (FVIII). The most efficient strategy to treat or prevent bleeding in patients with hemophilia A relies on replacement therapy using ... ...

Abstract	Hemophilia A is a X-linked recessive bleeding disorder consecutive to the lack of circulating pro-coagulant factor VIII (FVIII). The most efficient strategy to treat or prevent bleeding in patients with hemophilia A relies on replacement therapy using exogenous FVIII. Commercially available recombinant FVIII are produced using an expensive perfusion technology in stainless steel fermenters. A fed-batch fermentation technology was recently developed to produce 'Neureight', a full-length recombinant human FVIII, in Chinese hamster ovary (CHO) cells. Here, we investigated the structural and functional integrity and lack of increased immunogenicity of Neureight, as compared to two commercially available full-length FVIII products, Helixate and Advate, produced in baby hamster kidney or CHO cells, respectively. Our results demonstrate the purity, stability and functional integrity of Neureight with a standard specific activity of 4235 ± 556 IU/mg. The glycosylation and sulfation profiles of Neureight were similar to that of Advate, with the absence of the antigenic carbohydrate epitopes α-Gal and Neu5Gc, and with sulfation of Y1680, that is critical for FVIII binding to von Willebrand factor (VWF). The endocytosis of Neureight by human immature dendritic cells was inhibited by VWF, and its half-life in FVIII-deficient mice was similar to that of Advate, confirming unaltered binding to VWF. In vitro and in vivo assays indicated a similar immunogenicity for Neureight, Advate and Helixate. In conclusion, the production of full-length FVIII in a fed-batch fermentation mode generates a product that presents similar biochemical, functional and immunogenic properties as products developed using the classical perfusion technology.
MeSH term(s)	Animals ; Bioreactors ; CHO Cells ; Cricetinae ; Cricetulus ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Endocytosis/immunology ; Factor VIII/genetics ; Factor VIII/immunology ; Factor VIII/metabolism ; Fermentation ; Hemophilia A/drug therapy ; Hemophilia A/immunology ; Humans ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Recombinant Proteins/immunology ; Recombinant Proteins/metabolism ; Recombinant Proteins/therapeutic use
Chemical Substances	Recombinant Proteins ; F8 protein, human (839MOZ74GK) ; Factor VIII (9001-27-8)
Language	English
Publishing date	2018-05-05
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80094-6
ISSN	1090-2163 ; 0008-8749
ISSN (online)	1090-2163
ISSN	0008-8749
DOI	10.1016/j.cellimm.2018.05.002
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Article ; Online: Oxidation of factor VIII increases its immunogenicity in mice with severe hemophilia A.

Peyron, Ivan / Dimitrov, Jordan D / Delignat, Sandrine / Gangadharan, Bagirath / Srivastava, Alok / Kaveri, Srinivas V / Lacroix-Desmazes, Sébastien

Cellular immunology

2018 Volume 325, Page(s) 64–68

Abstract: The development of antibodies against therapeutic factor VIII (FVIII) represents the major complication of replacement therapy in patients with severe hemophilia A. Amongst the environmental risk factors that influence the anti-FVIII immune response, the ...

Abstract	The development of antibodies against therapeutic factor VIII (FVIII) represents the major complication of replacement therapy in patients with severe hemophilia A. Amongst the environmental risk factors that influence the anti-FVIII immune response, the presence of active bleeding or hemarthrosis has been evoked. Endothelium damage is typically associated with the release of oxidative compounds. Here, we addressed whether oxidation contributes to FVIII immunogenicity. The control with N-acetyl cysteine of the oxidative status in FVIII-deficient mice, a model of severe hemophilia A, reduced the immune response to exogenous FVIII. Ex vivo exposure of therapeutic FVIII to HOCl induced a mild oxidation of the molecule as evidenced by the loss of free amines and resulted in increased FVIII immunogenicity in vivo when compared to native FVIII. The increased immunogenicity of oxidized FVIII was not reverted by treatment of mice with N-acetyl cysteine, and did not implicate an increased maturation of professional antigen-presenting cells. Our data document that oxidation influences the immunogenicity of therapeutic FVIII.
MeSH term(s)	Acetylcysteine/pharmacology ; Animals ; Antibodies/immunology ; Antigen-Presenting Cells/immunology ; Antigen-Presenting Cells/metabolism ; Disease Models, Animal ; Factor VIII/immunology ; Factor VIII/metabolism ; Factor VIII/pharmacology ; Hemophilia A/drug therapy ; Hemophilia A/immunology ; Hemophilia A/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oxidation-Reduction ; Oxidative Stress/immunology
Chemical Substances	Antibodies ; Factor VIII (9001-27-8) ; Acetylcysteine (WYQ7N0BPYC)
Language	English
Publishing date	2018-01-31
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80094-6
ISSN	1090-2163 ; 0008-8749
ISSN (online)	1090-2163
ISSN	0008-8749
DOI	10.1016/j.cellimm.2018.01.008
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