Immunogenicity of long-lasting recombinant factor VIII products

International audienceReplacement therapy for patients with hemophilia A using plasma-derived or recombinant factor VIII (FVIII) is complicated by the short half-life of the FVIII products and by the occurrence of neutralizing antibodies in a substantial number of patients. In the recent years, enormous efforts have been invested to develop new generations of coagulation factors with extended half-lives. Presumably, the use of long-lasting FVIII products should reduce the frequency of administration to the patients and drastically improve their quality of life. The question of their immunogenicity remains however unanswered as yet. The present review proposes a summary of the different strategies developed to enhance the half-life of FVIII, including fusion of FVIII to the Fc fragment of the human IgG1 or to human serum albumin, or attachment of polyethylene glycol. Based on the available literature, we hypothesize on the potential benefits or risks associated with each of the latter strategies in terms of immunogenicity of the newly derived hemostatic drugs

Les signaux de danger dans l'initiation de la réponse immunitaire contre le facteur VIII thérapeutique

Hemophilia A (HA) is a rare congenital hemorrhagic disorder resulting from a defective production of coagulation factor VIII (FVIII). Treatment of HA patients with therapeutic FVIII results, in up to 30% of the cases, in the emergence of anti-FVIII antibodies that inhibit the pro-coagulant activity of the therapeutically administered FVIII. FVIII endocytosis by dendritic cells (DCs) and its presentation to T cells have been well established. However, the nature of the danger signals responsible for the maturation of DCs that is mandatory to the initiation of anti-FVIII immune response, remains poorly understood. During my thesis, I investigated the origin of these danger signals, and explored 3 possibilities: an origin linked to the intrinsic structure of FVIII, to the inflammatory environment that prevails before FVIII administration, or to the inflammatory environment generated upon injection of exogenous FVIII. My work demonstrates that FVIII is not able to trigger macrophages maturation or to induce direct TLR2 activation. I also rejected the hypothesis of a role of a compensatory activation state of HA patients' platelets (PLT) in the initiation of the immune response against FVIII in a murine model of HA. My results suggest that PLT involvement depends on their activation by thrombin which is generated by FVIII administration. The identification of the inflammatory mediators released by activated PLT should open attractive therapeutic perspectives in the control of inflammation at the time of FVIII administration, in order to reduce FVIII immunogenicity.L'hémophilie A (HA) est une maladie hémorragique congénitale qui se traduit par un défaut en facteur VIII (FVIII) de la coagulation. Le traitement privilégié des saignements est l'administration de FVIII exogène cependant, 30% des patients développent une réponse anticorps alloimmune contre le FVIII thérapeutique qui inhibe son activité pro-coagulante. L'endocytose du FVIII par les cellules dendritiques (DC) et sa présentation aux lymphocytes T ont été documentées. Cependant, la nature des signaux de danger (SD) responsables de la maturation des DC indispensable à l'initiation de la réponse immunitaire anti-FVIII, est inconnue. Au cours de ma thèse, j'ai cherché à identifier l'origine de ces SD et envisagé 3 possibilités: Une origine liée à la structure intrinsèque du FVIII, au contexte inflammatoire avant l'administration de FVIII, ou au contexte inflammatoire généré par l'injection de FVIII. Mes résultats ont montré que le FVIII n'était pas capable d'induire la maturation de macrophages ou d'activer directement le TLR2. J'ai également écarté l'hypothèse d'un état d'activation compensatoire des plaquettes (PLT) dans un organisme privé de FVIII. En revanche, mes travaux ont mis en évidence un rôle des PLT dans l'initiation de la réponse immunitaire anti-FVIII dans le modèle murin d'HA. Mes résultats suggèrent que l'implication des PLT passe par leur activation par la thrombine générée lors de l'administration de FVIII. L'identification des médiateurs de l'inflammation issus de l'activation plaquettaire devrait ouvrir des perspectives thérapeutiques intéressantes dans le contrôle de l'inflammation au moment de l'administration de FVIII, afin de réduire son immunogénicité

Les signaux de danger dans l'initiation de la réponse immunitaire contre le facteur VIII thérapeutique

L hémophilie A (HA) est une maladie hémorragique congénitale qui se traduit par un défaut en facteur VIII (FVIII) de la coagulation. Le traitement privilégié des saignements est l administration de FVIII exogène cependant, 30% des patients développent une réponse anticorps alloimmune contre le FVIII thérapeutique qui inhibe son activité pro-coagulante. L'endocytose du FVIII par les cellules dendritiques (DC) et sa présentation aux lymphocytes T ont été documentées. Cependant, la nature des signaux de danger (SD) responsables de la maturation des DC indispensable à l initiation de la réponse immunitaire anti-FVIII, est inconnue. Au cours de ma thèse, j ai cherché à identifier l origine de ces SD et envisagé 3 possibilités: Une origine liée à la structure intrinsèque du FVIII, au contexte inflammatoire avant l administration de FVIII, ou au contexte inflammatoire généré par l injection de FVIII. Mes résultats ont montré que le FVIII n était pas capable d induire la maturation de macrophages ou d activer directement le TLR2. J ai également écarté l hypothèse d un état d activation compensatoire des plaquettes (PLT) dans un organisme privé de FVIII. En revanche, mes travaux ont mis en évidence un rôle des PLT dans l initiation de la réponse immunitaire anti-FVIII dans le modèle murin d HA. Mes résultats suggèrent que l implication des PLT passe par leur activation par la thrombine générée lors de l administration de FVIII. L identification des médiateurs de l inflammation issus de l activation plaquettaire devrait ouvrir des perspectives thérapeutiques intéressantes dans le contrôle de l inflammation au moment de l administration de FVIII, afin de réduire son immunogénicitéHemophilia A (HA) is a rare congenital hemorrhagic disorder resulting from a defective production of coagulation factor VIII (FVIII). Treatment of HA patients with therapeutic FVIII results, in up to 30% of the cases, in the emergence of anti-FVIII antibodies that inhibit the pro-coagulant activity of the therapeutically administered FVIII. FVIII endocytosis by dendritic cells (DCs) and its presentation to T cells have been well established. However, the nature of the danger signals responsible for the maturation of DCs that is mandatory to the initiation of anti-FVIII immune response, remains poorly understood. During my thesis, I investigated the origin of these danger signals, and explored 3 possibilities: an origin linked to the intrinsic structure of FVIII, to the inflammatory environment that prevails before FVIII administration, or to the inflammatory environment generated upon injection of exogenous FVIII. My work demonstrates that FVIII is not able to trigger macrophages maturation or to induce direct TLR2 activation. I also rejected the hypothesis of a role of a compensatory activation state of HA patients platelets (PLT) in the initiation of the immune response against FVIII in a murine model of HA. My results suggest that PLT involvement depends on their activation by thrombin which is generated by FVIII administration. The identification of the inflammatory mediators released by activated PLT should open attractive therapeutic perspectives in the control of inflammation at the time of FVIII administration, in order to reduce FVIII immunogenicityPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

The C1 and C2 domains of blood coagulation factor VIII mediate its endocytosis by dendritic cells

The development of inhibitory antibodies to therapeutic factor VIII is the major complication of replacement therapy in patients with hemophilia A. The first step in the initiation of the anti-factor VIII immune response is factor VIII interaction with receptor(s) on antigen-presenting cells, followed by endocytosis and presentation to naïve CD4(+) T cells. Recent studies indicate a role for the C1 domain in factor VIII uptake. We investigated whether charged residues in the C2 domain participate in immunogenic factor VIII uptake. Co-incubation of factor VIII with BO2C11, a monoclonal C2-specific immunoglobulin G, reduced factor VIII endocytosis by dendritic cells and presentation to CD4(+) T cells, and diminished factor VIII immunogenicity in factor VIII-deficient mice. The mutation of basic residues within the BO2C11 epitope of C2 replicated reduced in vitro immunogenic uptake, but failed to prevent factor VIII immunogenicity in mice. BO2C11 prevents factor VIII binding to von Willebrand factor, thus potentially biasing factor VIII immunogenicity by perturbing its half-life. Interestingly, a factor VIII(Y1680C) mutant, that does not bind von Willebrand factor, demonstrated unaltered endocytosis by dendritic cells as well as immunogenicity in factor VIII-deficient mice. Co-incubation of factor VIII(Y1680C) with BO2C11, however, resulted in decreased factor VIII immunogenicity in vivo. In addition, a previously described triple C1 mutant showed decreased uptake in vitro, and reduced immunogenicity in vivo, but only in the absence of endogenous von Willebrand factor. Taken together, the results indicate that residues in the C1 and/or C2 domains of factor VIII are implicated in immunogenic factor VIII uptake, at least in vitro. Conversely, in vivo, the binding to endogenous von Willebrand factor masks the reducing effect of mutations in the C domains on factor VIII immunogenicity

Endocytic receptor for pro-coagulant factor VIII: Relevance to inhibitor formation

International audienc

Induction of heme oxygenase-1 in factor VIII–deficient mice reduces the immune response to therapeutic factor VIII

International audienc

Workshop Summary:Exoplanet Orbits and Dynamics

Exoplanetary systems show a wide variety of architectures, which can be explained by different formation and dynamical evolution processes. Precise orbital monitoring is mandatory to accurately constrain their orbital and dynamical parameters. Although major observational and theoretical advances have been made in understanding the architecture and dynamical properties of exoplanetary systems, many outstanding questions remain. This paper aims to give a brief review of a few current challenges in orbital and dynamical studies of exoplanetary systems and a few future prospects for improving our knowledge. Joint data analyses from several techniques are providing precise measurements of orbits and masses for a growing sample of exoplanetary systems, both with close-in orbits and with wide orbits, as well as different evolutionary stages. The sample of young planets detected around stars with circumstellar disks is also growing, allowing for simultaneous studies of planets and their birthplace environments. These analyses will expand with ongoing and future facilities from both ground and space, allowing for detailed tests of formation, evolution, and atmospheric models of exoplanets. Moreover, these detailed analyses may offer the possibility of finding missing components of exoplanetary systems, such as exomoons, or even finding new exotic configurations such as co-orbital planets. In addition to unveiling the architecture of planetary systems, precise measurements of orbital parameters and stellar properties—in combination with more realistic models for tidal interactions and the integration of such models in N-body codes—will improve the inference of the past history of mature exoplanetary systems in close-in orbits. These improvements will allow a better understanding of planetary formation and evolution, placing the solar system in context.</p