A component of factor VIII preparations which can be separated from factor VIII activity down modulates human monocyte functions

In HIV-seronegative haemophiliac patients abnormal immune parameters have been demonstrated. In this review data on these abnormalities, their aetiology and clinical consequences are summarized and discussed. The data reviewed show abnormalities at different levels of the adaptive immune system. Most of the reported abnormalities regard lymphocyte subsets and their function, both in vivo and in vitro testing. Strong evidence has not been found for a causal relation between abnormalities and the consumption of factor VIII concentrates nor the purity of the concentrates. It seems likely that certain contaminants in the factor VIII concentrates have an inhibiting effect on lymphocytes and monocytes. Two clinical consequences of the abnormalities have been suggested: a higher susceptibility for infections and a greater risk to develop malignancies. Data on these consequences, however, are contradicting and not in agreement with the good results of long-term treatment of HIV-seronegative haemophiliac patients with factor VIII concentrates. The studies reviewed give no convincing evidence that more pure concentrates are advantageous in HIV-negative haemophiliacs.

Section: The Aetiology Of the Immune Parameter Abnormalitiessupporting

confidence: 69%

Abnormal immune parameters in HIV‐seronegative haemophilic patients

Allersma

Smid²,

Briët

1996

“…Despite signi®cantly higher speci®c activity and purity, with elimination of foreign proteins and contaminating antigens, recombinant factor concentrates continue to have a degree of immunomodulatory eects similar to plasma-derived factor concentrates. Chronic exposure to hepatitis and foreign proteins or antigens in concentrates may also result in immunological defects in B-cell and T-cell function in individuals with haemophilia, including down-regulation of monocyte function [26,27] and depressed natural killer cell activity [29], CD4 + number [29], mitogen-induced B-cell responses [30±32], antibody response to vaccine [32,33], and IL-2 secretion and proliferation [34]. The signi®cance of this immunosuppression is not clear, although studies continue to show that, when compared with nonhaemophilic subjects, haemophilic children and adults have less-intense response to vaccines [32,33] and to antiretroviral therapy [35].…”

Section: Immunosuppressionmentioning

confidence: 99%

New‐generation recombinant factor concentrates: bridge to gene therapy

Ragni

2001

Despite our best efforts to deceive the immune system, outwit pathogens, and improve upon the design of nature, there continues to be a need to improve the margin of safety of treatment for those with bleeding disorders. The current approach includes: (1) recombinant factor concentrates free of added proteins; (2) 'designer' factor molecules that enhance function and reduce immunogenicity; and (3) modulation of the immune system to suppress immune response in those who develop inhibitors. The hope is that through advances in our understanding of the coagulation and immune systems, treatment of haemophilia in the new millennium will be safer and less immunogenic. Currently available recombinant clotting factor concentrates include those produced: (1) with pasteurized human serum albumin in the cell culture medium as a stabilizer; (2) with bovine serum proteins in the cell culture medium; and (3) free of plasma derivatives. To the extent that current recombinant clotting factor concentrates contain even trace amounts of human or animal protein, there is continuing potential for transmission of nonenveloped viruses, including hepatitis A and parvovirus, and the theoretical potential for transmission of relatively unknown agents, such as prions (Creutzfeldt-Jakob disease or its variant). Second-generation recombinant factor concentrates that do not use human albumin as a stabilizer are currently in clinical trials, and third-generation recombinant factor concentrates currently in development take advantage of new strategies to achieve a 'protein-free' cell culture, purification, and final formulation. It is likely that improvement in safety and reduction in immunogenicity will require modification not only of antigenic structure but also of the immune response to coagulation proteins.

“…Immunoglobulins have been shown to interact with macrophage Fc receptors, bind to T cells and bind to speci®c and nonspeci®c antigens, thus potentially stimulating complement-mediated immune responses [39]. Immune complexes of IgG and IgM classes and F VIII have been implicated in the down-regulation of monocyte/macrophage function seen in haemophiliac patients given CFCs (discussed below) [40,41]. Mannhalter et al [42] also showed that murine IgG-F VIII complexes were very potent inhibitors of Fc-receptor-bearing cells, underscoring the importance of removing even trace amounts of murine IgG from CFCs processed by murine MAb puri®cation.…”

Section: Protein Contaminantsmentioning

confidence: 99%

“…Thus, intermediate-purity products were associated with the greatest inhibition, high-purity products with less, and a very high-purity product with minimal change [47]. The impairment of monocyte function in vivo appears to be associated with immune complexes and immune globulin aggregates and down-regulation of macrophage Fc expression [40,41]. The down-regulation results in decreased phagocytosis, bacterial killing and oxygen radical generation.…”

Section: In Vitro and Ex Vivo Studiesmentioning

confidence: 99%

Clotting factor concentrates and immune function in haemophilic patients

Hoots¹,

Canty

1998

Patients with haemophilia often exhibit a variety of disturbances in immune function. Although infections with HIV, hepatitis and other viruses no doubt contribute to these abnormalities, chronic exposure to extraneous proteins in clotting factor concentrates (CFCs) may also play a role. Numerous in vitro and ex vivo studies show that protein contaminants--such as immunoglobulins, fibrinogen and fibronectin--can depress various immune function indicators. Generally, such studies show that intermediate-purity CFCs are more inhibitory than very high-purity (e.g. monoclonal-purified) CFCs. In many, but not all, studies, the degree of immunosuppression correlates with the amount of intermediate-purity CFC administered over time. Among various indicators of immune function, CD4+ lymphocyte number is a marker for the progression of HIV infection, and maintenance of CD4+ number is associated with delayed progression. A number of studies suggest that, compared with intermediate-purity CFCs, use of very high-purity CFCs is associated with longer preservation of this class of lymphocytes. However, it remains to be seen whether this translates to improved long-term clinical outcomes. Further research is needed on the impact of CFCs on the immune system. For the time being, however, evidence to date favours the use of very high-purity products because they appear to preserve immune function and reduce the risk of infection with hepatitis and other viruses.