Coimmunisation with type I IFN genes enhances protective immunity against cytomegalovirus and myocarditis in gB DNA-vaccinated mice

Cull, Vanessa S.; Broomfield, Steve; Bartlett, Emmalene J.; Brekalo, Natalie L; James, Cassandra M.

doi:10.1038/sj.gt.3301809

Cited by 41 publications

(33 citation statements)

References 40 publications

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“…IFN DNA therapy has clearly demonstrated that type I IFNs differ in their antiviral capacity and modulation of the immune response. 51,[57][58][59]93 Other investigators have found that type I IFN is a clinical target with promising antileukemic potential. In cancer treatment, IFN-␣ electroporation gene therapy results in tumor regression.…”

Section: Discussionmentioning

confidence: 99%

Type I interferon differential therapy for erythroleukemia: specificity of STAT activation

Cull

Tilbrook

Bartlett

et al. 2003

Blood

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IntroductionErythroleukemias represent the highly malignant M6 subtype of acute myeloid leukemia. 1 The J2E cell line, immortalized at the proerythroblast/basophilic erythroblast stage of erythroid development, 2 induces a rapid and fatal erythroleukemia in mice. 3 However, while these cells are immortalized, they are still capable of normal signaling in response to erythropoietin (Epo) stimulation. They maintain all biologic responses to Epo by differentiating biochemically with hemoglobin production and undergoing cellular alterations with a percentage of cells enucleating to form mature reticulocytes. 2,4-7 J2E cells also display increased proliferation and enhanced viability in the absence of serum as a result of Epo stimulation. 2,4,5 Type I interferon (IFN) subtypes are clinically effective in the treatment of disease conditions such as hepatitis, hairy cell leukemia, condyloma acuminatum, multiple sclerosis, and Kaposi sarcoma. [8][9][10][11] These IFNs have also proven effective in the treatment of both myelogenous and metastatic tumors, 12,13 and IFN-␣ has the ability to normalize hemoglobin levels in anemic patients. 14 Subtype diversity for treatment is limited however to human IFN-␣2 (huIFN-␣2) 15 and huIFN-␤ (IFN-␤-1b; IFN-␤-1a).The type I IFNs have been attributed to multiple and diverse functions in the immune response. This multigene family has over 14 IFN-␣ subtypes in humans and 10 IFN-␣ subtypes in mice, with a single IFN-␤ subtype for each. The murine and human IFN gene families are highly analogous. 16 Induced early in the immune response, IFNs stimulate antiviral, 17,18 antiproliferative, 19 and apoptotic activity, 20 as well as have numerous immunomodulatory effects. Type I IFNs regulate dendritic cell major histocompatibility complex (MHC) expression and maturation, 21-24 activate natural killer (NK) cells, 25 induce bystander T-cell proliferation, 26 selectively induce clonal CD8 ϩ T-cell expansion, 26 and skew the immune response to a Th1-like response. 27,28 At the cellular level, type I IFN binds the IFN-␣ receptor 2 (IFNAR2) subunit 29 instigating its association with the IFNAR1 subunit. 30 The preassociated Jak kinases, Jak1 and Tyk2, are subsequently cross-phosphorylated. 31,32 Phosphorylation of signal transducers and activators of transcription 2 (STAT2) occurs, which forms a heterodimer with STAT1 and phosphorylation of the latter. Phosphorylation of other STATs in response to 33 STAT4, 34 STAT5, and STAT6. 35,36 Phosphorylation of STAT4 however is not generally reported in the murine system and is believed to be due to a microsatellite insertion in Stat2. 37 44 Alternatively, IFN-␣ activation of p42 MAPK is essential for cell proliferation. 45 Previously, J2E cells stimulated with mixed murine IFN-␣ (muIFN-␣), IFN-␣1, and IFN-␣4 differed in their antiproliferative capacity, 46 while levels of Epo-induced differentiation were maintained. 47 In this report, we investigated the differential antileukemic properties of a panel of 7 type I IFN subtypes (-␣1, -␣2, -␣4, -␣5, -␣6, -␣9,...

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Section: Discussionmentioning

confidence: 99%

Type I interferon differential therapy for erythroleukemia: specificity of STAT activation

Cull

Tilbrook

Bartlett

et al. 2003

Blood

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“…Recent studies suggest that immunomodulation of both antiviral, antitumor and autoimmune responses by IFN DNA immunization may be an avenue for improved immunotherapy [9,29]. For example, delivery of type I IFN transgenes by naked DNA immunization can protect against cytomegalovirus infection and myocarditis [9,39,40,83]. The development of IFN-based gene therapy is currently being tested to stimulate the immune system of patients with various viral or tumor diseases [29,56,83].…”

Section: Summary and Perspectivesmentioning

confidence: 99%

Interferons: Mechanisms, Biological Activities and Survey of their Use in Human Diseases

Obeid¹,

Bauvois²

2006

CBC

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Human interferons (IFNs) form a family of cytokines produced by a large number of cells. On the basis of their physicochemical and biological properties, the IFN family can be subdivided into two subtypes: the Type I IFNs (α, β, ω) and the Type II IFN represented by IFN-γ. IFN binding to specific cell surface receptors activates the Jaks kinases which phosphorylate Stats leading to their dimerization, translocation to the nucleus, and activation of their transcription factor activity. In addition, IFNs activate several protein kinases including the MAP kinase family, and downstream transcription factors through Stat-independent pathways. IFNs could induce the expression of more than 300 genes. Through these Stat-dependent and Stat-independent pathways, IFNs exhibit antiviral, antitumor, and immune-enhancing properties. Recombinant DNA technology has allowed IFNs to be produced in sufficient quantity for large scale clinical studies. IFNs are effective in the treatment of viral diseases (hepatitis B and C, VIH, HPV), solid tumors (melanoma, Kaposi's sarcoma, renal and hepatocellular carcinomas), hematological disorders (hairy cell leukemia, multiple myeloma, chronic granulomatosis) and in other diseases such as multiple sclerosis and infancy hemangioma. The limitations to their clinical use include side effects such as induced toxicity and development of antibodies in patients. Pegylated IFNs (IFN covalently bound to polyethylene glycol polymers) with little inmunogenicity, longer plasma half-life, greater stability and efficacy, as single agents or in combination with other therapeutic agents, appear to improve IFN clinical efficacy. New options involve IFN gene therapy.

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“…Efficacious IFN treatment was associated with antiviral and immunomodulatory properties, cytokine expression, antibody class switching to IgG2a and homing of CD8+ T cells to the heart [116,121,122]. Moreover, IFN−α9 and IFN−β transgenes co-delivered with viral gB DNA vaccines to mice reduced virus replication in target organs and acute myocarditis [123]. IFN−α6 or IFN−α9 treatment alone prior to MCMV infection reduced CD8+ T-cell infiltrates in the heart during the acute phase, whereas IFN−β treatment reduced CD8+ T-cell numbers in the cardiac infiltrate, without affecting virus replication, and reduced chronic myocarditis.…”

Section: Ifns and Cytomegalovirusmentioning

confidence: 99%

Interferons as Biomarkers and Effectors: Lessons Learned from Animal Models

2012

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Interferons (IFNs) comprise type I, II and III families with multiple subtypes. Via transcription of IFNstimulated genes (ISGs), IFNs can exert multiple biological effects on the cell. In infectious and chronic inflammatory diseases, the IFNs and their ISG sets can be potentially utilized as biomarkers of disease outcome. Animal models allow investigations into disease pathogenesis and gene knockout models have proved cause and effect relationships of molecules related to the IFN response. Sets of IFN subtypes and their ISG products provide immunological signature patterns for different viral and other diseases. In this article, we give an overview of IFNs in several virus infection models and autoimmune diseases of medical relevance. Lessons learned from animal models inform us of IFN system parameters as indicators of disease outcome and whether clinical research is warranted. Moreover, validated IFN biomarkers for prognosis enhance our understanding of therapeutic and vaccine development.

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Coimmunisation with type I IFN genes enhances protective immunity against cytomegalovirus and myocarditis in gB DNA-vaccinated mice

Cited by 41 publications

References 40 publications

Type I interferon differential therapy for erythroleukemia: specificity of STAT activation

Type I interferon differential therapy for erythroleukemia: specificity of STAT activation

Interferons: Mechanisms, Biological Activities and Survey of their Use in Human Diseases

Interferons as Biomarkers and Effectors: Lessons Learned from Animal Models

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