Epitope repertoire of human CD4  T cells on the A3 domain of coagulation factor VIII

Reding, Mark T.; Okita, David K.; Diethelm‐Okita, Brenda; Anderson, T. A.; Conti‐Fine, Bianca M.

doi:10.1111/j.1538-7836.2004.00850.x

Cited by 57 publications

(64 citation statements)

References 48 publications

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“…However, we speculate that the PI reduces FVIII immunogenicity by multiple mechanisms. Anti-FVIII antibodies targeted against epitopes in A2, A3, and C2 domains of FVIII (24)(25)(26). As the lipid binding involve these domains, these immunogenic epitopes were shielded resulting in reduction of antibody titer levels by immune ignorance.…”

Section: Discussionmentioning

confidence: 99%

“…The A2, A3, and C2 domains of FVIII participate in vWF (9-13), LRP (14,15), and phospholipid binding (16)(17)(18)(19)(20) that contributes to catabolism of FVIII, and these domains also contain epitopes that can lead to inhibitor development (24)(25)(26). Therefore, it will be of interest to investigate the influence of macromolecular interactions on catabolism and immunogenicity.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, 15-35% of patients develop FVIII neutralizing antibodies that abrogate the activity of the protein, thus complicating FVIII replacement therapy and clinical manage-ment of the disease (22,23). Based on systematic epitope mapping experiments, the anti-FVIII antibodies have been found to mainly target defined regions in the A2 (heavy chain) and A3 and C2 domains (light chain) of FVIII (24)(25)(26). Thus, macromolecular interactions of FVIII involve A2, A3, and C2 domains, and these domains also contain epitope regions that can lead to inhibitor development in FVIII replacement therapy.…”

Section: Introductionmentioning

confidence: 99%

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Phosphatidylinositol Containing Lipidic Particles Reduces Immunogenicity and Catabolism of Factor VIII in Hemophilia A Mice

Peng

Straubinger

Balu‐Iyer

2010

AAPS J

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Abstract. Factor VIII (FVIII) is an important cofactor in blood coagulation cascade. It is a multidomain protein that consists of six domains, NH 2 -A1-A2-B-A3-C1-C2-COOH. The deficiency or dysfunction of FVIII causes hemophilia A, a life-threatening bleeding disorder. Replacement therapy using recombinant FVIII (rFVIII) is the first line of therapy, but a major clinical complication is the development of inhibitory antibodies that abrogate the pharmacological activity of the administered protein. FVIII binds to anionic phospholipids (PL), such as phosphatidylinositol (PI), via lipid binding region within the C2 domain of FVIII. This lipid binding site not only consists of immunodominant epitopes but is also involved in von Willebrand factor binding that protects FVIII from degradation in vivo. Thus, we hypothesize that FVIII-PL complex will influence immunogenicity and catabolism of FVIII. The biophysical studies showed that PI binding did not alter conformation of the protein but improved intrinsic stability as measured by thermal denaturation studies. ELISA studies confirmed the involvement of the C2 domain in binding to PI containing lipid particles. PI binding prolonged the in vivo circulation time and reduced catabolism of FVIII in hemophilia A mice. FVIII-PI complex reduced inhibitor development in hemophilia A mice following intravenous and subcutaneous administration. The data suggest that PI binding reduces catabolism and immunogenicity of FVIII and has potential to be a useful therapeutic approach for hemophilia A.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phosphatidylinositol Containing Lipidic Particles Reduces Immunogenicity and Catabolism of Factor VIII in Hemophilia A Mice

Peng

Straubinger

Balu‐Iyer

2010

AAPS J

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“…Inhibition of FVIII activity results from antibodies against the A2 and A3 domains blocking interaction with factor IXa (7,10) while antibodies against the C2 domain interfere with binding to platelet membranes (9,11). Shielding or modification of these epitopes could potentially reduce the immunogenicity of the protein (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

PEGylation of a Factor VIII–Phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice

Peng

Kosloski

Nakamura

et al. 2011

AAPS J

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Abstract. Hemophilia A is an X-linked bleeding disorder caused by the deficiency of factor VIII (FVIII). Exogenous FVIII is administered therapeutically, and due to a short half-life, frequent infusions are often required. Fifteen to thirty-five percent of severe hemophilia A patients develop inhibitory antibodies toward FVIII that complicate clinical management of the disease. Previously, we used phosphatidylinositol (PI) containing lipidic nanoparticles to improve the therapeutic efficacy of recombinant FVIII by reducing immunogenicity and prolonging the circulating half-life. The objective of this study is to investigate further improvements in the FVIII-PI formulation resulting from the addition of polyethylene glycol (PEG) to the particle. PEGylation was achieved by passive transfer of PEG conjugated lipid into the FVIII-PI complex. PEGylated FVIII-PI (FVIII-PI/PEG) was generated with high association efficiency. Reduced activity in vitro and improved retention of activity in the presence of antibodies suggested strong shielding of FVIII by the particle; thus, in vivo studies were conducted in hemophilia A mice. Following intravenous administration, the apparent terminal half-life was improved versus both free FVIII and FVIII-PI, but exposure determined by area under the curve was reduced. The formation of inhibitory antibodies after subcutaneous immunization with FVIII-PI/PEG was lower than free FVIII but resulted in a significant increase in inhibitors following intravenous administration. Passive transfer of PEG onto the FVIII-PI complex does not provide any therapeutic benefit.

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“…Depending on the reports, circulating CD4 ϩ T cells from 52% to 78% of the donors proliferated when incubated with FVIII in vitro. 45,46 Conti-Fine and coworkers demonstrated transient proliferative responses toward pools of peptides spanning the C2 domain (Reding et al 47 ), the A3 domain (Reding et al 48 ), and the A2 domain (Hu et al 49 ) of FVIII. The detection of FVIII-reactive CD4 ϩ T cells in these experiments may have been underestimated, however; indeed, naturally occurring self-reactive T lymphocytes may be controlled by regulatory T cells.…”

Section: Fviii As Seen By the Immune System Under Physiologic Conditionsmentioning

confidence: 99%

Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A

Lacroix‐Desmazes

Navarrete

André

et al. 2008

Blood

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Procoagulant factor VIII (FVIII) is either produced endogenously under physiologic conditions, or administered exogenously as a therapeutic hemostatic drug in patients with hemophilia A. In the circulation, FVIII interacts with a multitude of glycoproteins, and may be used for coagulation at the sites of bleeding, eliminated by scavenger cells, or processed by the immune system, either as a self-constituent or as a foreign antigen. The fate of FVIII is dictated by the immune status of the individual, the location of FVIII in the body at a given time point, and the inflammatory microenvironment. It also depends on the local concentration of FVIII and of each interacting partner, and on the affinity of the respective interactions. FVIII, by virtue of its promiscuity, thus constitutes the core of a dynamic network that links the coagulation cascade, cells of the immune system, and, presumably, the inflammatory compartment. We describe the different interactions that FVIII is prone to establish during its life cycle, with a special focus on players of the innate and adaptive immune response. Lessons The life cycle of FVIII has been described in great detail previously. 1 Here we recapitulate the key steps of the FVIII life cycle, and highlight the different molecules that FVIII may interact with at different stages of its life. In the circulation, FVIII binds to at least 10 different identified proteins, some of them behaving as physiologic chaperones, some that participate in the coagulation cascade, and others being involved in removal of biologic wastes ( Figure 1). While binding to different proteins may involve the same structures on the FVIII molecule, the sequence of FVIII interactions with its physiologic partners is ordered temporally and spatially, depending on the quiescent, activated, or inactivated state of the molecule. Three phases in the life cycle of FVIII may thus be distinguished: transport of FVIII from the site of secretion to the bleeding site; participation of FVIII in the coagulation cascade; and clearance of FVIII from the circulation. Because it is not pertinent for the present discussions, we leave aside the intramolecular interactions of FVIII within the cells that produce it. 2 Transport of FVIII from the site of secretion to the bleeding site. FVIII is synthesized mainly in the liver by sinusoidal endothelial cells 3,4 and possibly by hepatocytes. 5,6 Production of FVIII by human microvascular lung endothelial cells has also been reported. 7 Indeed, transplantation experiments in dogs have indicated that extrahepatic FVIII synthesis suffices for hemostasis. [8][9][10] The mature FVIII is released in the circulation as a heterodimeric glycoprotein that consists of 2332 amino acids and encompasses a heavy chain (HC; domains A1-a1-A2-a2-B, residues 1-1648) and a light chain (LC; domains a3-A3-C1-C2, residues 1649-2332). 1 The molecule contains 25 consensus sequences (Asn-Xxx-Thr/Ser) that allow N-linked glycosylation, of which 19 have been shown to be glycosylated. The overall sugar cont...

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Epitope repertoire of human CD4 T cells on the A3 domain of coagulation factor VIII

Cited by 57 publications

References 48 publications

Phosphatidylinositol Containing Lipidic Particles Reduces Immunogenicity and Catabolism of Factor VIII in Hemophilia A Mice

Phosphatidylinositol Containing Lipidic Particles Reduces Immunogenicity and Catabolism of Factor VIII in Hemophilia A Mice

PEGylation of a Factor VIII–Phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice

Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A

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