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Special Issue "Interferons"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (30 November 2009)

Special Issue Editor

Guest Editor
Dr. Howard A. Young

Principal Investigator & Deputy Lab Chief, Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Bldg. 560/31-23, Chandler Street, Frederick, MD 21702-1201, USA
Website | E-Mail
Phone: 301-846-5743
Fax: +1 301 846 1673
Interests: interferon-gamma; cytokines, interferons, post transcriptional mRNA regulation; interleukins

Special Issue Information

Dear Colleagues,

This issue of Pharmaceuticals will focus on the pre-clinical and clinical biology of the interferons including how the interferons affect and alter the biological responses of the host in conditions of autoimmunity, infectious diseases and cancer.

Howard A. Young, Ph. D.
Guest Editor

Keywords

  • interferon
  • interleukins
  • pre-clinical models
  • clinical applications
  • STAT
  • receptors
  • gene induction
  • cancer
  • autoimmunity
  • infectious diseases

Published Papers (7 papers)

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Research

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Open AccessArticle Ingested Type I Interferon—State of the Art as Treatment for Autoimmunity Part 2
Pharmaceuticals 2010, 3(4), 1108-1121; doi:10.3390/ph3041108
Received: 25 January 2010 / Revised: 19 March 2010 / Accepted: 1 April 2010 / Published: 14 April 2010
Cited by 1 | PDF Full-text (244 KB) | HTML Full-text | XML Full-text
Abstract
We have proposed a unifying hypothesis of the etiopathogenesis of autoimmunity that defines autoimmunity as a type I interferon (IFN) immunodeficiency syndrome. We have examined toxicity and potential efficacy in two phase I (type 1 diabetes [T1D], multiple sclerosis [MS]) and phase II
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We have proposed a unifying hypothesis of the etiopathogenesis of autoimmunity that defines autoimmunity as a type I interferon (IFN) immunodeficiency syndrome. We have examined toxicity and potential efficacy in two phase I (type 1 diabetes [T1D], multiple sclerosis [MS]) and phase II clinical trials in T1D and MS. In a phase I open label trial in T1D, ingested IFN-alpha preserved residual beta-cell function in recent onset patients. In a second phase I trial in MS, there was a significant decrease in peripheral blood mononuclear cell IL-2 and IFN-gamma production after ingesting IFN-alpha. In a phase II randomized, placebo-controlled, double-blind trial in MS, 10,000 IU ingested IFN-alpha significantly decreased gadolinium enhancements compared to the placebo group at month 5. TNF-alpha and IFN-gamma cytokine secretion in the 10,000 IU group at month 5 showed a significant decrease that corresponded with the effect of ingested IFN-alpha on decreasing gadolinium enhancements. In a phase II randomized, placebo-controlled, double-blind trial in T1D, patients in the 5,000 unit hrIFN-alpha treatment group maintained more beta-cell function one year after study enrollment compared to individuals in the placebo group. Ingested IFN-alpha was not toxic in these clinical trials. These studies suggest that ingested IFN-alpha may have a potential role in the treatment of autoimmunity. Full article
(This article belongs to the Special Issue Interferons)

Review

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Open AccessReview Safety, Tolerability, and Immunogenicity of Interferons
Pharmaceuticals 2010, 3(4), 1162-1186; doi:10.3390/ph3041162
Received: 9 March 2010 / Revised: 3 April 2010 / Accepted: 12 April 2010 / Published: 20 April 2010
Cited by 5 | PDF Full-text (203 KB) | HTML Full-text | XML Full-text
Abstract
Interferons (IFNs) are class II cytokines that are key components of the innate immune response to virus infection. Three IFN sub-families, type I, II, and III IFNs have been identified in man, Recombinant analogues of type I IFNs, in particular IFNα2 and IFNβ1,
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Interferons (IFNs) are class II cytokines that are key components of the innate immune response to virus infection. Three IFN sub-families, type I, II, and III IFNs have been identified in man, Recombinant analogues of type I IFNs, in particular IFNα2 and IFNβ1, have found wide application for the treatment of chronic viral hepatitis and remitting relapsing multiple sclerosis respectively. Type II IFN, or IFN gamma, is used principally for the treatment of chronic granulomatous disease, while the recently discovered type III IFNs, also known as IFN lambda or IL-28/29, are currently being evaluated for the treatment of chronic viral hepatitis. IFNs are in general well tolerated and the most common adverse events observed with IFNα or IFNβ therapy are “flu-like” symptoms such as fever, headache, chills, and myalgia. Prolonged treatment is associated with more serious adverse events including leucopenia, thrombocytopenia, increased hepatic transaminases, and neuropsychiatric effects. Type I IFNs bind to high-affinity cell surface receptors, composed of two transmembrane polypeptides IFNAR1 and IFNAR2, resulting in activation of the Janus kinases Jak1 and Tyk2, phosphorylation and activation of the latent cytoplasmic signal transducers and activators of transcription (STAT1) and STAT2, formation of a transcription complex together with IRF9, and activation of a specific set of genes that encode the effector molecules responsible for mediating the biological activities of type I IFNs. Systemic administration of type I IFN results in activation of IFN receptors present on essentially all types of nucleated cells, including neurons and hematopoietic stem cells, in addition to target cells. This may well explain the wide spectrum of IFN associated toxicities. Recent reports suggest that certain polymorphisms in type I IFN signaling molecules are associated with IFN-induced neutropenia and thrombocytopenia in patients with chronic hepatitis C. IFNγ binds to a cell-surface receptor composed of two transmembrane polypeptides IFGR1 and IFGR2 resulting in activation of the Janus kinases Jak1 and Jak2, phosphorylation of STAT1, formation of STAT1 homodimers, and activation of a specific set of genes that encode the effector molecules responsible for mediating its biological activity. In common with type I IFNs, IFNγ receptors are ubiquitous and a number of the genes activated by IFNγ are also activated by type I IFNs that may well account for a spectrum of toxicities similar to that associated with type I IFNs including “flu-like” symptoms, neutropenia, thrombocytopenia, and increased hepatic transaminases. Although type III IFNs share the major components of the signal transduction pathway and activate a similar set of IFN-stimulated genes (ISGs) as type I IFNs, distribution of the IFNλ receptor is restricted to certain cell types suggesting that IFNλ therapy may be associated with a reduced spectrum of toxicities relative to type I or type II IFNs. Repeated administration of recombinant IFNs can cause in a break in immune tolerance to self-antigens in some patients resulting in the production of neutralizing antibodies (NABs) to the recombinant protein homologue. Appearance of NABs is associated with reduced pharmacokinetics, pharmacodynamics, and a reduced clinical response. The lack of cross-neutralization of IFNβ by anti-IFNα NABs and vice versa, undoubtedly accounts for the apparent lack of toxicity associated with the presence of anti-IFN NABs with the exception of relatively mild infusion/injection reactions. Full article
(This article belongs to the Special Issue Interferons)
Open AccessReview Antiproliferative Properties of Type I and Type II Interferon
Pharmaceuticals 2010, 3(4), 994-1015; doi:10.3390/ph3040994
Received: 2 March 2010 / Revised: 15 March 2010 / Accepted: 29 March 2010 / Published: 30 March 2010
Cited by 51 | PDF Full-text (588 KB) | HTML Full-text | XML Full-text
Abstract
The clinical possibilities of interferon (IFN) became apparent with early studies demonstrating that it was capable of inhibiting tumor cells in culture and in vivo using animal models. IFN gained the distinction of being the first recombinant cytokine to be licensed in the
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The clinical possibilities of interferon (IFN) became apparent with early studies demonstrating that it was capable of inhibiting tumor cells in culture and in vivo using animal models. IFN gained the distinction of being the first recombinant cytokine to be licensed in the USA for the treatment of a malignancy in 1986, with the approval of IFN-α2a (Hoffman-La Roche) and IFN-α2b (Schering-Plough) for the treatment of Hairy Cell Leukemia. In addition to this application, other approved antitumor applications for IFN-α2a are AIDS-related Kaposi’s Sarcoma and Chronic Myelogenous Leukemia (CML) and other approved antitumor applications for IFN-α2b are Malignant Melanoma, Follicular Lymphoma, and AIDS-related Kapoisi’s Sarcoma. In the ensuing years, a considerable number of studies have been conducted to establish the mechanisms of the induction and action of IFN’s anti-tumor activity. These include identifying the role of Interferon Regulatory Factor 9 (IRF9) as a key factor in eliciting the antiproliferative effects of IFN-α as well as identifying genes induced by IFN that are involved in recognition of tumor cells. Recent studies also show that IFN-activated human monocytes can be used to achieve >95% eradication of select tumor cells. The signaling pathways by which IFN induces apoptosis can vary. IFN treatment induces the tumor suppressor gene p53, which plays a role in apoptosis for some tumors, but it is not essential for the apoptotic response. IFN-α also activates phosphatidylinositol 3-kinase (PI3K), which is associated with cell survival. Downstream of PI3K is the mammalian target of rapamycin (mTOR) which, in conjunction with PI3K, may act in signaling induced by growth factors after IFN treatment. This paper will explore the mechanisms by which IFN acts to elicit its antiproliferative effects and more closely examine the clinical applications for the anti-tumor potential of IFN. Full article
(This article belongs to the Special Issue Interferons)
Open AccessReview Lambda Interferons: New Cytokines with Old Functions
Pharmaceuticals 2010, 3(4), 795-809; doi:10.3390/ph3040795
Received: 5 February 2010 / Revised: 24 March 2010 / Accepted: 24 March 2010 / Published: 25 March 2010
Cited by 7 | PDF Full-text (1337 KB) | HTML Full-text | XML Full-text
Abstract
Interferon lambda (IFN-λ) is a member of the class II cytokine family, and like the other members of this family, they are small helical proteins. Since their discovery significant efforts have been made to determine their role in innate and adaptive immunity. Their
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Interferon lambda (IFN-λ) is a member of the class II cytokine family, and like the other members of this family, they are small helical proteins. Since their discovery significant efforts have been made to determine their role in innate and adaptive immunity. Their strong antiviral activity, both in vitro and in vivo, has firmly established their interferon status. However, in contrast to type I interferon, only a very limited subset of cells/tissues responds to interferon lambda. In addition to inducing an antiviral state in responsive cells, recent data suggest that IFN-l plays a role in shaping the adaptive immune response. However, the data is not in complete agreement regarding the effect of IFN-λ on the adaptive immune system. Recently IFN-l has entered clinical trials against hepatitis C Virus and IFN-l is a promising future therapeutic, against different viruses replicating in responsive tissues, like that of the airway epithelia. In this review we describe the knowledge acquired during the past six years about the structure and function of interferon lambda. Full article
(This article belongs to the Special Issue Interferons)
Figures

Open AccessReview Deregulation of Interferon Signaling in Malignant Cells
Pharmaceuticals 2010, 3(2), 406-418; doi:10.3390/ph3020406
Received: 10 December 2009 / Revised: 28 January 2010 / Accepted: 1 February 2010 / Published: 4 February 2010
Cited by 3 | PDF Full-text (1015 KB) | HTML Full-text | XML Full-text
Abstract
Interferons (IFNs) are a family of cytokines with potent antiproliferative, antiviral, and immunomodulatory properties. Much has been learned about IFNs and IFN-activated signaling cascades over the last 50 years. Due to their potent antitumor effects in vitro and in vivo, recombinant IFNs
[...] Read more.
Interferons (IFNs) are a family of cytokines with potent antiproliferative, antiviral, and immunomodulatory properties. Much has been learned about IFNs and IFN-activated signaling cascades over the last 50 years. Due to their potent antitumor effects in vitro and in vivo, recombinant IFNs have been used extensively over the years, alone or in combination with other drugs, for the treatment of various malignancies. This review summarizes the current knowledge on IFN signaling components and pathways that are deregulated in human malignancies. The relevance of deregulation of IFN signaling pathways in defective innate immune surveillance and tumorigenesis are discussed. Full article
(This article belongs to the Special Issue Interferons)
Open AccessReview Oromucosal Administration of Interferon to Humans
Pharmaceuticals 2010, 3(2), 323-344; doi:10.3390/ph3020323
Received: 1 December 2009 / Revised: 20 January 2010 / Accepted: 25 January 2010 / Published: 28 January 2010
Cited by 5 | PDF Full-text (337 KB) | HTML Full-text | XML Full-text
Abstract
The prevailing dogma is that, to be systemically effective, interferon-alpha (IFNα) must be administered in sufficiently high doses to yield functional blood concentrations. Such an approach to IFNa therapy has proven effective in some instances, but high-dose parenteral IFNα therapy has the disadvantage
[...] Read more.
The prevailing dogma is that, to be systemically effective, interferon-alpha (IFNα) must be administered in sufficiently high doses to yield functional blood concentrations. Such an approach to IFNa therapy has proven effective in some instances, but high-dose parenteral IFNα therapy has the disadvantage of causing significant adverse events. Mounting evidence suggests that IFNα delivered into the oral cavity in low doses interacts with the oral mucosa in a unique manner to induce systemic host defense mechanisms without IFNα actually entering the circulation, thus reducing the potential for toxic side effects. A better understanding of the applications and potential benefits of this treatment modality are under active investigation. This paper provides a review of the relevant literature on the clinical use of the oromucosal route of administration of interferon, with an emphasis on the treatment of influenza. Full article
(This article belongs to the Special Issue Interferons)
Open AccessReview Interferons as Therapy for Viral and Neoplastic Diseases: From Panacea to Pariah to Paragon
Pharmaceuticals 2009, 2(3), 206-216; doi:10.3390/ph2030206
Received: 13 November 2009 / Revised: 2 December 2009 / Accepted: 7 December 2009 / Published: 15 December 2009
PDF Full-text (164 KB) | HTML Full-text | XML Full-text
Abstract
For more than 20 years after the excitement engendered by their discovery in 1957 as antiviral agents, there were no significant clinical uses of interferons; however, following their cloning they have been employed as effective treatment for several viral, autoimmune, and neoplastic diseases.
[...] Read more.
For more than 20 years after the excitement engendered by their discovery in 1957 as antiviral agents, there were no significant clinical uses of interferons; however, following their cloning they have been employed as effective treatment for several viral, autoimmune, and neoplastic diseases. Full article
(This article belongs to the Special Issue Interferons)

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