Functional studies of cell‐mediated immunity in haemophilia and other bleeding disorders

Mahir, Walla S.; Millard, Rosemary E.; Booth, J. C.; Flute, P.T.

doi:10.1111/j.1365-2141.1988.tb02375.x

Cited by 28 publications

(15 citation statements)

References 11 publications

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“…The anti‐proliferative effect of pdFVIII was shown by the pdFVIII dose‐dependent inhibition of upregulation of combined S and G 2 M phases of DNA after PHA stimulation. These results are consistent with those of previous reports of reduced tritiated thymidine uptake by purified lymphocytes after stimulation in the presence of pdFVIII (Sullivan et al , 1986; Mahir et al , 1988). However the apoptosis promoting effects of pdFVIII on T lymphocytes after stimulation are novel findings.…”

Section: Discussionsupporting

confidence: 93%

“…Factor concentrates have been shown to have a variety of in vitro immunomodulatory effects . The proliferative response of lymphocytes from normal individuals incubated in vitro with phytohaemagglutinin (PHA) has been shown previously to be diminished in the presence of plasma‐derived factor VIII concentrate (pdFVIII) (Sullivan et al , 1986; Mahir et al , 1988).…”

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confidence: 99%

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Effect of intermediate‐purity factor VIII (FVIII) concentrate on lymphocyte proliferation and apoptosis: transforming growth factor‐β is a significant immunomodulatory component of FVIII

Hodge

Han

2001

Br J Haematol

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Summary. Factor concentrates have been shown to have a variety of immunomodulatory effects in vitro. The presence of plasma-derived factor VIII (pdFVIII) has been shown to diminish lymphocyte proliferative response to mitogens. Recently, we have shown the presence of transforming growth factor-b (TGF-b) as an immunomodulatory component present in plasma-derived FVIII concentrate. However, the addition of neutralizing antibody to TGF-b did not abrogate the inhibitory effect of pdFVIII on monocyte cytokine production, suggesting the presence of other, as yet undetermined, immunomodulatory agent/s in pdFVIII. To further characterize the immunomodulatory effects of pdFVIII, the in vitro effect of pdFVIII concentrate on proliferation and apoptosis of mitogen-stimulated T cells was studied using whole blood and purified T cells. The presence of pdFVIII increased the apoptosis of phytohaemagglutinn (PHA) -stimulated CD4 and CD8 T-cell subsets as determined by Annexin V binding and DNA fragmentation. T-cell subsets showed a pdFVIII dosedependent inhibition of entry into S-phase and G 1 arrest. Addition of neutralizing anti-TGF-b reduced some of these changes. To determine the physiological relevance of these findings, blood samples from five patients receiving FVIII prophylaxis were similarly studied ex vivo and showed significantly increased apoptosis of T-cell subsets as determined by Annexin V staining. TGF-b has been reported to be a potent inhibitor of T-cell proliferation, arresting the cell cycle in G 1 phase and causing apoptosis. Together, these findings suggest that TGF-b is a significant immunomodulatory component of pdFVIII concentrates.

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Effect of intermediate‐purity factor VIII (FVIII) concentrate on lymphocyte proliferation and apoptosis: transforming growth factor‐β is a significant immunomodulatory component of FVIII

Hodge

Han

2001

Br J Haematol

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“…Our observation of impaired mitogen-induced proliferation of PBMC isolated from haemophilia A patients is not inconsistent with previous reports of significantly lower proliferative responses to PHA of PBMC isolated from haemophilia patients treated with cryoprecipitate and/or FVIII concentrates (Pollack et al, 1985;Mahir et al, 1988). In these previous studies, infection with HIV was excluded or considered unlikely, whereas infection with other viruses, such as cytomegalovirus or herpes simplex virus, was either documented or not excluded as a possibility (Pollack et al, 1985;Mahir et al, 1988). Our results differ, however, from a more recent report demonstrating that PBMC isolated from patients not infected with either HIV or hepatitis C virus had mitogen-induced proliferative responses comparable to controls (Evans et al, 1995).…”

Section: Discussionsupporting

confidence: 85%

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

et al. 1996

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The outcome of developing immune responses is influenced by interactions among a large and complex network of secreted cytokines. T-cell secretion of interferon-gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha) and TNF-beta, or lymphotoxin contributes to the development of cell-mediated immunity, whereas secretion of interleukin (IL)-4, IL-5 and IL-6 contributes to development of humoral immunity. Humoral immunity to factor VIII (FVIII) develops in approximately 25% of severe haemophilia A patients. The aim of our research was to understand the underlying immune response to FVIII in patients with FVIII inhibitors. We report a defect in IFN-gamma secretion by peripheral blood mononuclear cells (PBMC) derived from haemophilia A patients, which was accompanied by a low level of mitogen-induced proliferation and a significant decrease in the percentage of natural killer (NK) cells. All of the observed defects were found in haemophilia A patients, both with and without FVIII inhibitors, who were free of viral infection and had been treated predominantly or exclusively with monoclonal antibody-purified or recombinant FVIII.

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“…It is widely reported that clotting factor concentrate may be a cause of immunological abnormalities seen in haemophiliacs as it can inhibit T cell and monocyte function in vitro [Lederman et al, 1986;Ebil et al, 1987;Mahir et al, 1988;Thorpe et al, 19891. Our study found no such correlation, however, between the amount or type of concentrate used and the anti-HBs response in the patients.…”

Section: Discussionmentioning

confidence: 99%

Protective antibodies to hepatitis B virus in haemophiliacs

Oon

King

Higgins

et al. 1991

Journal of Medical Virology

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Haemophilic patients are at increased risk from hepatitis B virus infection because of their need for blood product therapy. They are potentially poor responders to hepatitis B vaccine due to immunological abnormalities resulting from two causes: infection with the human immunodeficiency virus and treatment with clotting factor concentrates. The protective antibody response to hepatitis B virus in vaccinated haemophiliacs was investigated using a competitive enzyme-linked immunosorbent assay which employs a monoclonal antibody, RF-HBs-1, that recognises a virus-neutralising epitope on HBsAg. Serum samples from 55 haemophilic patients were studied at 7, 12, and 24 months after the first injection with HB vaccine. Twenty-four vaccinated normal subjects were used as controls. The level of neutralising antibody was found to correlate with the polyclonal anti-HBs response in the majority of subjects in both the control and patient groups. There was a small but statistically significant reduction in both antibody responses in the patients compared with the normal controls. Treatment with FVIII or FIX concentrate did not influence the antibody response in the patients. Eleven of the haemophilic patients were anti-HIV seropositive. This group had a significantly lower antibody response than anti-HIV negative patients, and this correlated with the duration of anti-HIV seropositivity, rather than with their T4 counts. We conclude that, following vaccination, the majority of haemophiliacs are able to mount a protective antibody response to hepatitis B virus. HIV infection was found to be the sole cause of immunological suppression of this response.

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Functional studies of cell‐mediated immunity in haemophilia and other bleeding disorders

Cited by 28 publications

References 11 publications

Effect of intermediate‐purity factor VIII (FVIII) concentrate on lymphocyte proliferation and apoptosis: transforming growth factor‐β is a significant immunomodulatory component of FVIII

Effect of intermediate‐purity factor VIII (FVIII) concentrate on lymphocyte proliferation and apoptosis: transforming growth factor‐β is a significant immunomodulatory component of FVIII

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

Protective antibodies to hepatitis B virus in haemophiliacs

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