Healthy subjects produce both anti-factor VIII and specific anti-idiotypic antibodies.

Gilles, Jean-Guy; Saint-Remy, Jean-Marie

doi:10.1172/jci117489

Cited by 109 publications

(111 citation statements)

References 21 publications

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“…In some patients, inhibitor recurrence has occurred, suggesting that clonal deletion of the responsible T-cell clones is not achieved; additional mechanisms including active T-regulatory cell suppression or anti-idiotype antibodies versus the inhibitor antibody have been suggested. [44][45][46] …”

Section: Discussionmentioning

confidence: 99%

“…It has been well documented that healthy non-hemophilic humans and hemophilia A patients without inhibitors have non-neutralizing anti-factor VIII antibodies as well as CD4+ FVIII-responsive T-cell clones. 45,47 The relevant investigations have not been performed to determine whether these clinically innocuous anti-factor VIII immune responses described in hemophilia A also occur against FIX in hemophilia B. In addition, wild-type nonhemophilic mice as well as FIXKO mice have been shown to have CD4+ T cells that recognize and proliferate in response to murine FIX epitopes, confirming that cells that respond to mouse FIX are neither deleted nor maintained in a state of anergy.…”

Section: Anti-factor IX Antibodies After Aav1 and Aav2 Fix T-p Zhang mentioning

confidence: 99%

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Transgene expression levels and kinetics determine risk of humoral immune response modeled in factor IX knockout and missense mutant mice

et al. 2006

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Immune responses leading to antibody-mediated elimination of the transgenic protein are a concern in gene replacement for congenital protein deficiencies, for which hemophilia is an important model. Although most hemophilia B patients have circulating non-functional but immunologically crossreactive factor IX (FIX) protein (CRM+ phenotype), inciting factors for FIX neutralizing antibody (inhibitor) development have been studied in crossreactive material-negative (CRMÀ) animal models. For this study, determinants of FIX inhibitor development were compared in hemophilia B mice, in which circulating FIX protein is absent (CRMÀ factor IX knockout (FIXKO) model) or present (CRM+ missense R333Q-hFIX model) modeling multiple potential therapies. The investigations compare for the first time different serotypes of adenoassociated virus (AAV) vectors (AAV2 and AAV1), each at multiple doses, in the setting of two different FIX mutations. The comparisons demonstrate in the FIXKO background (CRMÀ phenotype) that neither vector serotype nor vector particle number independently determine the inhibitor trigger, which is influenced primarily by the level and kinetics of transgene expression. In the CRM+ missense background, inhibitor development was never stimulated by AAV gene therapy or protein therapy, despite the persistence of lymphocytes capable of responding to FIX with non-inhibitory antibodies. This genotype/phenotype is strongly protective against antibody formation in response to FIX therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Anti-factor IX Antibodies After Aav1 and Aav2 Fix T-p Zhang mentioning

confidence: 99%

Transgene expression levels and kinetics determine risk of humoral immune response modeled in factor IX knockout and missense mutant mice

et al. 2006

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“…In plasma, FVIII is non-covalently bound to von Willebrand factor (VWF) which protects it from inactivation by activated protein C (APC). IgG2 classes, are mostly directed against the C2 domain of the factor VIII protein, and, in in-vitro mixing studies with normal plasma, display inhibitory activity against FVIII [15,16]. Some authors have postulated that this in-vitro activity does not correspond fully to the real in-vivo situation because these healthy subjects produce anti-idiotypic antibodies that neutralize circulating autoantibodies to factor VIII [14].…”

Section: Laboratory Investigationsmentioning

confidence: 99%

Acquired hemophilia A: A concise review

et al. 2005

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Acquired hemophilia A is a rare but severe autoimmune bleeding disorder. It is more frequent in the elderly and results from the presence of autoantibodies directed against clotting factor VIII. In this review, we briefly report on the present state of knowledge regarding acquired hemophilia A, analyzing its epidemiology, pathogenesis, diagnostic, and clinical features. We also describe the main characteristics of this disorder according to its association with different conditions and the most important advances in the treatment of bleeding episodes and the eradication of the autoantibody. Am.

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“…Moreover, anti-idiotypic antibodies have been described that can neutralize FVIII inhibitors [6,7]. To circumvent difficulties inherent to the use of polyclonal antibodies, we produced human monoclonal antibodies directed towards FVIII and representative of patients' pathogenic antibodies by immortalizing memory B cells from haemophilia A patients with inhibitor [8].…”

Section: Introductionmentioning

confidence: 99%

Variable region heavy chain glycosylation determines the anticoagulant activity of a factor VIII antibody

Jacquemin

2010

Haemophilia

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Summary. The mechanism of action of antibodies inhibiting partially factor VIII (FVIII) activity (type II inhibitor) is still poorly understood. We produced an unusual type II monoclonal antibody, called LE2E9, derived from a patient with mild haemophilia A. The antibody displayed several unexpected structural and functional properties such as glycosylation in the variable region, binding to the FVIII C1 domain, inhibition of maximum 80-90% FVIII activity when in excess over FVIII, and prevention of FVIII binding to von Willebrand factor (VWF). Those unusual characteristics of the antibody prompted multidisciplinary studies to determine its mechanism of action and the role of the FVIII C1 domain. Enzymatic deglycosylation and site-directed mutagenesis indicated that the oligosaccharides do not determine the affinity of the antibody but enhanced its FVIII neutralizing activity. Modification of glycosylation in the variable region of antibodies therefore contributes to the diversity of FVIII type II inhibition and provides a novel strategy with which to modulate the functional activity of antibodies. Investigation of the FVIII C1 domain function led to identification of mutations located in that domain and impairing FVIII binding to VWF as a common cause of mild/moderate haemophilia A. Finally, the cloning of human monoclonal antibodies inhibiting partially FVIII activity opened the way to evaluate such antibodies as a novel type of anticoagulant drug. This concept was validated in animal models of thrombosis. Those studies are expected to have a significant impact on the optimization of treatments for patients with inhibitor as well as for patients with thrombophilia.

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Healthy subjects produce both anti-factor VIII and specific anti-idiotypic antibodies.

Abstract: Anti-Factor VIII (FVI) antibodies were prepared by a combination of salt precipitation, gel filtration chromatography, and specific adsorption over insolubilized FYVM from the serum of 10 healthy subjects with normal levels of FVM.

Cited by 109 publications

References 21 publications

Transgene expression levels and kinetics determine risk of humoral immune response modeled in factor IX knockout and missense mutant mice

Transgene expression levels and kinetics determine risk of humoral immune response modeled in factor IX knockout and missense mutant mice

Acquired hemophilia A: A concise review

Variable region heavy chain glycosylation determines the anticoagulant activity of a factor VIII antibody

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