Biologic Responses to IFN-α Administration in Humans

Corssmit, Eleonora P M; Metz, Jesse de; Sauerwein, H. P.; Romijn, Johannes A.

doi:10.1089/107999000750053690

Cited by 55 publications

(62 citation statements)

References 87 publications

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“…13 Over-expression of class I antigens is associated with activation of cytotoxic T cells. 85 IFN␣ receptor activation results in gene transcription by activation of Janus family kinases (JAK), and signal transducers and activators of transcription (STATs), 86 which subsequently convey intracellular signals from IFN␣ receptors to the nucleus. 85 IFN␣ stimulates the transcription of various genes which include cytokine and adhesion molecule genes.…”

Section: Immune Mediated Efects Of Ifn␣mentioning

confidence: 99%

“…87 IFN␣ also has the ability to affect leukocyte function. It has been shown to enhance the activity of lymphocytes, macrophages, and NK cells, 2,85,88,89 and to stimulate neutrophil and monocyte activation. 85 IFN␣ can induce the release of other cytokines.…”

Section: Immune Mediated Efects Of Ifn␣mentioning

confidence: 99%

“…It has been shown to enhance the activity of lymphocytes, macrophages, and NK cells, 2,85,88,89 and to stimulate neutrophil and monocyte activation. 85 IFN␣ can induce the release of other cytokines. For example, IFN␣ has been shown to stimulate IL-6 release, 85 a cytokine that has been associated with autoimmune thyroiditis.…”

Section: Immune Mediated Efects Of Ifn␣mentioning

confidence: 99%

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The clinical and physiological spectrum of interferon‐alpha induced thyroiditis

et al. 2006

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Interferon-alpha (IFN␣) is a major treatment modality for several malignant and nonmalignant diseases, especially hepatitis C. Prospective studies have shown that up to 15% of patients with hepatitis C receiving IFN␣ develop clinical thyroid disease, and up to 40% were reported to develop thyroid antibodies. Some of these complications may result in discontinuation of interferon therapy. Thus, interferon induced thyroiditis (IIT) is a major clinical problem for patients receiving interferon therapy. IIT can be classified as autoimmune type and non-autoimmune type. I nterferons were discovered in the 1950Јs and were immediately recognized for their ability to render cells resistant to virus infection. 1 Interferons have been classified into two major groups, type I interferons and type II interferons, based on their capacity to bind to common receptor types. Type I interferons bind to a type I interferon receptor and include interferon-␣, interferon-␤, interferon-, and interferon-. 2 Type II interferons bind to a distinct type II receptor and include interferon-␥. 2 In addition to their antiviral properties, interferons have immunomodulatory, antiangiogenic, antiproliferative and antitumor activity, and act as important regulators of growth and differentiation. 3 Interferons work by directly binding to either type I or type II receptors. The cytoplasmic domains of the transmembrane glycoproteins are associated with members of the JAK family of kinases. They activate various signaling pathways, including the JAK-STAT pathway, the Crk-pathway, the IRS signaling pathway, and the MAP kinase pathway, which leads to signal transduction and subsequent activation or repression of specific genes. 3,4 More than twenty interferon-induced proteins have been identified. 5 Interferon-alpha (IFN␣) was the first cytokine to be reproduced by recombinant DNA technology and has emerged as a major therapeutic modality for several malignant and nonmalignant diseases. Among the diseases treated by IFN␣ are melanoma, renal cell carcinoma, hairy cell leukemia, Kaposi's sarcoma, and hepatitis B and C. 5 However, the most common prescription for IFN␣

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Section: Immune Mediated Efects Of Ifn␣mentioning

confidence: 99%

Section: Immune Mediated Efects Of Ifn␣mentioning

confidence: 99%

Section: Immune Mediated Efects Of Ifn␣mentioning

confidence: 99%

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The clinical and physiological spectrum of interferon‐alpha induced thyroiditis

et al. 2006

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“…[19][20][21][22] This receptor, on binding these type I IFNs, activates the Jak-STAT signaling cascade, to upregulate transcription of an array of cellular genes. [23][24][25] These IFNs have important effects on the immune system: they alter expression, activation, and localization of many cellular proteins, including MHC-I and -II, and TNFa, that activate and execute antiviral T and NK cell responses.…”

Section: Discussionmentioning

confidence: 99%

“…These include the need to maintain high blood concentrations of the recombinant protein in order to provide adequate therapeutic levels at disease sites, and uneven distribution of the proteins outside of the circulatory system. 20 Gene delivery could conceivably address these limitations, including the toxic side effects (especially of IFNg) by allowing localized gene delivery to the liver, and by making IFN expression responsive to the presence of the offending virus. Thus we sought to provide the potential for permanent, HCV-responsive IFN expression at the site where the IFN is needed, without having to maintain comparable levels throughout the body.…”

Section: Discussionmentioning

confidence: 99%

Exploiting hepatitis C virus activation of NFκB to deliver HCV-responsive expression of interferons α and γ

Matskevich

Strayer

2003

Gene Ther

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hronic infection with hepatitis C virus (HCV) may lead to liver failure and hepatocellular carcinoma. Current treatment for HCV includes high systemic doses of interferona (IFNa), which is effective in less than half of patients and may have severe side effects. We designed conditional IFNa and IFNg expression constructs to be triggered by HCV-induced activation of NFkB, and delivered these using highly efficient recombinant Tag-deleted SV40-derived vectors. NFkB activates the HIV-1NL4-3 long terminal repeat (HIVLTR) as a promoter, which accounts for the conditional transgene expression. Human hepatocyte lines and primary rat hepatocytes (PRH) were transduced with SV[HIVLTR](IFN) vectors, and transfected with HCV cDNA. Production of human and murine IFNa and IFNg in cytosol and culture supernatants was measured. HCV activated the HIVLTR to produce and secrete IFNs, and did so largely through the NFkB binding sites of the HIVLTR. Levels of IFNs secreted, and the magnitude of induction in response to HCV, were greater in hepatocyte lines than in primary cultured hepatocytes. However, even in the latter, supernatant IFNa concentrations achieved by this approach were similar to therapeutic serum concentrations sought in systemic IFNatreated patients. In coculture studies, secreted IFNa activated its cognate response elements in untransduced cells, suggesting that its potential inhibitory effects on HCV may not be limited to transduced cells. Although HCV replication in culture is difficult to assess, HCV-induced IFNa production demonstrably reduced HCV transcription. Conditional expression of IFNs within the liver may represent an attractive approach to therapy of severe chronic HCV infection that could avoid the side effects of systemic treatment regimens.

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Viral Inhibitors and Immune Response Mediators: The Interferons

Meager

2006

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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Biologic Responses to IFN-α Administration in Humans

Cited by 55 publications

References 87 publications

The clinical and physiological spectrum of interferon‐alpha induced thyroiditis

The clinical and physiological spectrum of interferon‐alpha induced thyroiditis

Exploiting hepatitis C virus activation of NFκB to deliver HCV-responsive expression of interferons α and γ

Viral Inhibitors and Immune Response Mediators: The Interferons

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