Use of Interferon-Alpha in Recurrent Respiratory Papillomatosis: 20-Year Follow-up

Gerein, V.; Rastorguev, E.; Gerein, Johann; Jecker, Peter; Pfister, Herbert

doi:10.1177/000348940511400608

Cited by 86 publications

(70 citation statements)

References 30 publications

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“…It will therefore be interesting to assess whether the events that we have reported here are also seen in patients, based on analysis of IRF-1 expression and function during both active viral replication and selection of integrants. This could in part explain the various clinical outcomes of IFN therapy of papillomatoses and the differential regulation of HPV expression observed in various cancer cell lines upon IFN treatment (9,19). Similarly, studies on the effect of E5 protein on IFN expression in the natural context of the complete viral genome during a de novo HPV infection would help to further elucidate its normal functions, as already reported for E5 activity on cell proliferation (40).…”

Section: Discussionmentioning

confidence: 71%

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Human Papillomavirus Type 16 E5 Protein Induces Expression of Beta Interferon through Interferon Regulatory Factor 1 in Human Keratinocytes

Muto

Stellacci

Lamberti

et al. 2011

J Virol

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Crucial steps in high-risk human papillomavirus (HR-HPVHuman papillomaviruses (HPVs) are small, doublestranded DNA viruses that infect cutaneous and mucosal epithelial tissues in several ano-genital and skin regions and the tracheo-bronchial and oral mucosa. Ninety-nine percent of cervical cancers are positive for HPV DNA, and a subset of HPVs, known as high-risk (HR) types, including HPV16 and HPV18, is primarily associated with cancer development (57).A critical step in cervical neoplastic progression is the integration of HPV DNA into the host genome (33, 57). Integration is associated with deletion of regions, including the El, E2, E4, and E5 open reading frames (ORFs), while E6 and E7 genes, together with the upstream regulatory region, are retained, and their deregulation, related to high-level expression throughout the epithelium, represents the main determinant of progression toward the malignant phenotype (47).The mechanisms that promote cervical neoplastic progression are not clearly understood. Recently, it has been reported that spontaneous loss of episomes in W12 cells, a unique model of progression of HPV16-related cervical neoplasia, is associated with increased expression of antiviral genes that are inducible by type I interferon (IFN) (37). Accordingly, the treatment of W12 cells with IFN-␤ can dramatically accelerate the progression from an ostensibly episomal population to one in which only integrants remain (21).

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Section: Discussionmentioning

confidence: 71%

“…There has been sustained interest in using IFNs and other immunomodulators to treat benign and premalignant HPVassociated lesions; however, inconsistent clinical outcomes have been observed (19,24), and the mechanistic bases for these inconsistencies are not yet understood.…”

Section: Discussionmentioning

confidence: 99%

Human Papillomavirus Type 16 E5 Protein Induces Expression of Beta Interferon through Interferon Regulatory Factor 1 in Human Keratinocytes

Muto

Stellacci

Lamberti

et al. 2011

J Virol

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“…Interferons (IFNs) have a critical role in the generation of an innate immune response against invading pathogens and, as a consequence, are an approved therapy for many diseases 1,2 including human papillomavirus (HPV)-associated diseases. 3,4 On infection, IFNs are synthesized and secreted to evoke anti-viral, 5 anti-tumor, 6 and immunoregulatory (reviewed in Stetson and Medzhitov 7 ) activity conferring protection to neighboring cells. Two main classes of IFNs exist.…”

mentioning

confidence: 99%

IFN-κ, a novel type I IFN, is undetectable in HPV-positive human cervical keratinocytes

DeCarlo

Severini

Edler

et al. 2010

Laboratory Investigation

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Interferons (IFNs) are expressed by many cell types and play a pivotal role in the generation of immune responses against viral infections. IFN-k, a novel type I IFN, displays a tight tropism for keratinocytes and specific lymphoid populations and exhibits functional similarities with other type I IFNs. The human papillomavirus (HPV), the etiological agent for cervical cancer, infects keratinocytes of the uterine cervix and has been shown to directly inhibit the IFN pathway. We evaluated IFN-k, -b, and -g gene expression in HPV-negative normal and HPV-positive pre-malignant and malignant ex vivo cervical tissue covering the entire spectrum of cervical disease. Quantitative real-time polymerase chain reaction and methods previously optimized for detecting low-expressing genes in cervical tissue were used. In contrast to IFN-b and -g, IFN-k mRNA prevalence and levels were unexpectedly higher in diseased compared with normal whole cervical tissue with highest levels observed in invasive carcinoma tissue. Strikingly, laser capture microdissection revealed an absence of IFN-k mRNA in diseased epithelium, whereas stromal IFN-k was found exclusively in diseased tissue. IFN-g and IFN-b were likewise found to be upregulated in diseased cervical stroma. Immunofluorescence supports the involvement of monocytes and dendritic cells in the stromal induction of IFNs in diseased tissue. Further, using three-dimensional raft cultures in which the viral life cycle can be mimicked, human keratinocytes transfected with full-length HPV16 displayed a significant decrease in IFN-k mRNA compared with non-transfected human keratinocytes. Altogether, these findings show that IFN-k is down-regulated in cervical keratinocytes harboring HPV, which may be a contributing factor in the progression of a cervical lesion. Interferons (IFNs) have a critical role in the generation of an innate immune response against invading pathogens and, as a consequence, are an approved therapy for many diseases 1,2 including human papillomavirus (HPV)-associated diseases. 3,4 On infection, IFNs are synthesized and secreted to evoke anti-viral, 5 anti-tumor, 6 and immunoregulatory (reviewed in Stetson and Medzhitov 7 ) activity conferring protection to neighboring cells. Two main classes of IFNs exist. The type I IFNs, consisting of IFN-a, -b, -k, -d, -e, -o, and -t, share a common receptor and downstream signaling pathways (reviewed in Pestka et al. 8 ) and are chiefly involved in generating anti-viral activity in response to pathogens. The sole member of the type II IFN subclass, IFN-g, uses a discrete type II IFN receptor, 9 distinct signaling pathways and is primarily involved in the regulation of immune and inflammatory responses. IFN-k, a newly identified type I IFN, has been shown to signal through the type I IFN pathway 10 and displays a tight tropism for keratinocytes, monocytes (MCs), and dendritic cells (DCs). 10 IFN-k has been shown to display similar anti-viral activity to other type I IFNs. 11 However, it is distinct from other type I IFNs, as it...

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“…However, debate is ongoing regarding the effectiveness of long-term IFN-α therapy, with even multicenter studies on the application of IFN-α as an adjuvant for RRP therapy providing contradictory results 13,15 . A recent study revealed the maximal effectiveness of INF-α therapy in patients having RRP with HPV 6 as compared to HPV 11 12 . In addition, these results suggest that long-term IFN-α therapy (mean 32.4±21.6 months) 12 was more effective in preventing relapse than the a short course (0.5 or 1 year) 13,15 of injection.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study revealed the maximal effectiveness of INF-α therapy in patients having RRP with HPV 6 as compared to HPV 11 12 . In addition, these results suggest that long-term IFN-α therapy (mean 32.4±21.6 months) 12 was more effective in preventing relapse than the a short course (0.5 or 1 year) 13,15 of injection. Accumulation of additional evidence, however, is required to determine the dosage and duration of IFN-α treatment suitable for patients with RRP.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Long-term Interferon-alpha Therapy in Adult Patients with Recurrent Respiratory Papillomatosis

et al. 2008

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Use of Interferon-Alpha in Recurrent Respiratory Papillomatosis: 20-Year Follow-up

Cited by 86 publications

References 30 publications

Human Papillomavirus Type 16 E5 Protein Induces Expression of Beta Interferon through Interferon Regulatory Factor 1 in Human Keratinocytes

Human Papillomavirus Type 16 E5 Protein Induces Expression of Beta Interferon through Interferon Regulatory Factor 1 in Human Keratinocytes

IFN-κ, a novel type I IFN, is undetectable in HPV-positive human cervical keratinocytes

Efficacy of Long-term Interferon-alpha Therapy in Adult Patients with Recurrent Respiratory Papillomatosis

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