Interferon‐γ secretion defects in haemophilia A patients receiving highly purified plasma‐derived or recombinant factor VIII

Newton-Nash, Debra K.; Tollerud, David J.; Guevarra, Lucille; Gill, Joan Cox

doi:10.1046/j.1365-2141.1996.d01-1924.x

Cited by 4 publications

(2 citation statements)

References 28 publications

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“…Several studies have examined the responses of T cells isolated from hemophilic patients to FVIII or to peptides corresponding to the FVIII sequence (23)(24)(25)(26)(27)(28). Proliferative responses to FVIII antigens could be detected in many hemophilia A patients, and even in healthy blood donors (29).…”

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confidence: 99%

Immunodominant T-cell epitopes in the factor VIII C2 domain are located within an inhibitory antibody binding site

Pratt¹,

Qian²,

Ellaban³

et al. 2004

Thromb Haemost

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Formation of inhibitor antibodies to factor VIII (FVIII) is a major complication of FVIII replacement therapy for hemophilia A patients, and it occurs through a T-cell dependent process. The C2 domain of FVIII contains epitopes that are recognized by antibody inhibitors. We have examined regions of the C2 domain that form epitopes for T cells in mice congenitally deficient in FVIII. We obtained CD4(+)T cells from mice immunized by intravenous infusion of therapeutic doses of recombinant human FVIII (rFVIII), or by subcutaneous injections of rFVIII or recombinant human C2 domain in adjuvant. In all cases, the T cells recognized most strongly and consistently two overlapping peptides that spanned residues 2191 to 2220 of the C2 domain. Analysis of the crystal structure of human factor VIII C2 bound to a human monoclonal antibody, BO2C11, showed these residues also constitute part of a human alloimmune B-cell epitope (Spiegel et al., Blood 2001; 98: 13-19). This region includes one of the "hydrophobic spike" protrusions, consisting of M2199 and F2200, as well as the basic residues R2215 and R2220. These residues contribute to membrane binding and to association with von Willebrand factor (vWF). These findings suggest that a major T-cell epitope in the C2 domain recognized by hemophilic mice is located within the same region that binds to inhibitors, vWF, and activated membranes.

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mentioning

confidence: 99%

Immunodominant T-cell epitopes in the factor VIII C2 domain are located within an inhibitory antibody binding site

Pratt¹,

Qian²,

Ellaban³

et al. 2004

Thromb Haemost

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“…Immunological disorders have been described in haemophilic patients even if they were HIV-negative. These include abnormalities in circulating lymphocyte subsets [3], decreased production of interleukin-2 [10] or of interferon-gamma [12], B-cell dysfunction [11], impaired monocyte chemotaxis and phagocytic function [17] or de®cient skin test responses [1]. Findings suggestive of immunosupression might be due to the action of transforming growth factor-b which has been found as a contaminant in many of the factor VIII concentrates [18,19].…”

Section: Discussionmentioning

confidence: 99%

Longitudinal growth in HIV-negative boys with haemophilia

Lebl

Falger

Zidek

et al. 2000

European Journal of Pediatrics

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Safety of coagulation factor concentrates

Lee¹,

Kessler²,

Varon³

et al. 1998

Haemophilia

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Many of the adverse effects of the early crude plasma-derived concentrates were ameliorated by increasing their purity. Ironically, this strategy may have increased the risks of inhibitor formation and pathogen transmission due to the addition of processing steps which can alter the immunogenicity of clotting factors and the use of very large plasma pools, as dictated by economic considerations. In the absence of extremely sensitive donor screening, these large pools have a high probability of contamination with pathogens, which may be only partially offset by their removal during protein purification. One approach to minimize the risk of viral transmission is to use recombinant clotting factors produced without the use of human or animal plasma proteins at any step in the manufacturing or formulation process. However, as these proteins are synthesized in mammalian cells, even they pose a theoretical risk of pathogen transmission. For plasma-derived concentrates, the initial viral burden is minimized by screening individual donations and plasma pools with tests which detect virus-specific antibodies, protein antigens, or nucleic acid. These techniques are supplemented by non-specific viral reduction steps based on physical partitioning and/or inactivation of pathogens which share chemical or physical characteristics. Prion proteins, the putative causative agents of transmissible spongiform encephalopathies, do not share these characteristics with viruses, and it remains to be determined whether they partition into clotting factor concentrates and whether the current strategies can efficiently remove or inactivate them. For all blood-borne pathogens, active immunization (currently available only for hepatitis B and A) and continued surveillance of susceptible recipients are critical approaches to achieving optimal safety of coagulation factor concentrates.

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Interferon‐γ secretion defects in haemophilia A patients receiving highly purified plasma‐derived or recombinant factor VIII

Cited by 4 publications

References 28 publications

Immunodominant T-cell epitopes in the factor VIII C2 domain are located within an inhibitory antibody binding site

Immunodominant T-cell epitopes in the factor VIII C2 domain are located within an inhibitory antibody binding site

Longitudinal growth in HIV-negative boys with haemophilia

Safety of coagulation factor concentrates

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