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PubMedDate not supplied

Immune and clinical outcomes in patients with stage IV melanoma vaccinated with peptide-pulsed dendritic cells derived from CD34+ progenitors and activated with type I interferon.

Twenty-two HLA A*0201 patients with stage IV melanoma were enrolled in a phase 1 safety and feasibility trial using a composite dendritic cell (DC) vaccine generated by culturing CD34 hematopoietic progenitors and activated with IFN-alpha. The DC vaccine was loaded with peptides derived from four melanoma tissue differentiation antigens (MART-1, tyrosinase, MAGE-3, and gp100) and influenza matrix peptide (Flu-MP). Twenty patients were evaluable, 14 of whom received vaccination with peptide-pulsed DCs without keyhole limpet hemocyanin (KLH) and 6 of whom received vaccination with KLH-loaded DCs. Patients were vaccinated until disease progression or until they had received eight vaccinations. None of the analyzed patients showed the expansion of melanoma-peptide-specific circulating effector memory T cells that secrete IFN-gamma in direct ELISPOT. Melanoma-peptide-specific recall memory CD8 T cells able to secrete IFN-gamma and to proliferate could be detected in six of the seven analyzed patients. There were no objective clinical responses. The estimated median overall survival was 12 months (range 2-38), and the median event-free survival was 4 months (range 1-12). There was no statistically significant survival advantage in patients who received KLH-loaded vaccines. As of March 2005, four patients remained alive, 26+, 28+, 28+, and 36+ months. Three of them had received KLH-loaded vaccines and all of them had had additional therapy. Overall, these results suggest that IFN-alpha-activated CD34-DCs are safe but elicit only limited immune responses, underscoring the need to test different DC maturation factors.

Adult↗
PubMed2006

Inhibition of the type I interferon response by the nucleoprotein of the prototypic arenavirus lymphocytic choriomeningitis virus.

The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a formidable battle horse for the study of viral immunology, as well as viral persistence and associated diseases. Investigations with LCMV have uncovered basic mechanisms by which viruses avoid elimination by the host adaptive immune response. In this study we show that LCMV also disables the host innate defense by interfering with beta interferon (IFN-beta) production in response to different stimuli, including infection with Sendai virus and liposome-mediated DNA transfection. Inhibition of IFN production in LCMV-infected cells was caused by an early block in the IFN regulatory factor 3 (IRF-3) activation pathway. This defect was restored in cells cured of LCMV, indicating that one or more LCMV products are responsible for the inhibition of IRF-3 activation. Using expression plasmids encoding individual LCMV proteins, we found that expression of the LCMV nucleoprotein (NP) was sufficient to inhibit both IFN production and nuclear translocation of IRF-3. To our knowledge, this is the first evidence of an IFN-counteracting viral protein in the Arenaviridae family. Inhibition of IFN production by the arenavirus NP is likely to be a determinant of virulence in vivo.

Active Transport, Cell Nucleus↗
PubMed2006

Continuous delivery of human type I interferons (alpha/beta) has significant activity against acute myeloid leukemia cells in vitro and in a xenograft model.

In this study, we focused primarily on the antileukemic activity of interferon-beta (IFN-beta) in a murine xenograft model of acute myeloid leukemia (AML). Bolus administration of recombinant IFN-beta via the subcutaneous or intravenous route failed to show efficacy in mice injected with AML cells despite achieving peak plasma IFN-beta levels of more than 200 IU/mL. In contrast, stable expression of IFN-beta following adeno-associated virus (AAV) vector-mediated gene transfer resulted in significant antileukemic activity against primary AML cells derived from patients with poor prognostic markers. An almost linear relationship was observed with stable plasma levels of IFN-beta and antileukemic activity in mice. Even levels below 10 IU/mL were able to reduce tumor load by 50-fold when compared with control animals. These levels of IFN-beta are likely to be nontoxic in humans. Therefore, approaches capable of maintaining stable plasma levels of IFN-beta merit further clinical evaluation in patients with AML.

Acute Disease↗
PubMed2002

Mechanisms of Type I interferon cell signaling and STAT-mediated transcriptional responses.

The interferons are pleiotropic cytokines that are induced in response to virus infection and act in a paracrine fashion to elicit an antiviral state in nearby cells. Binding of interferons to their cell surface receptors induces a tyrosine kinase signaling cascade that leads to the activation of latent cytoplasmic signal transducer and activator of transcription (STAT) factors. Activated STATs then translocate into the nucleus and are targeted to conserved promoter-enhancer sites to induce the transcription of interferon-responsive genes that encode for proteins with potent antiviral, growth-inhibitory, antitumor, and immunomodulatory properties. Although the signaling and activation phase of the interferon response has been well characterized, several recent findings have further clarified the cellular events that immediately follow STAT activation, including the identification of the amino acid signals that regulate the subcellular distribution of interferon- signaling proteins. To achieve their full transcriptional capacity, members of the STAT family of transcription factors have been shown to require interactions with an assortment of nuclear transcriptional co-activator proteins. A number of the STAT co-activator protein partners have only been identified recently. Some of these interactions suggest cross-talk with other signaling pathways, thereby reaffirming the far-reaching, yet undiscovered, properties of interferons.

Animals↗
PubMed2002

Suppression of type I interferon signaling proteins is an early event in squamous skin carcinogenesis.

PURPOSE: IFN-based therapy has been shown to be active in the treatmentof squamous cell carcinoma (SCC) of the skin, the most aggressive form of non-melanoma skin cancer. Based largely on this activity, we began programmatically examining the expression of IFN-stimulated gene factor 3 (ISGF-3) proteins (signal transducers and activators of transcription 1alpha/beta, signal transducers and activators of transcription 2, and p48), which are important mediators of IFN-alpha signaling, in skin premalignancy and SCC. Our previous preliminary studies suggested suppression of some or all of the ISGF-3 proteins in skin SCC. EXPERIMENTAL DESIGN: To determine the timing of the suppression of IFN-alpha signaling proteins in squamous skin carcinogenesis, we have now compared ISGF-3 expression by immunohistochemical staining in biopsies of actinic keratosis, a form of skin premalignancy, and matched normal skin. RESULTS: We observed a significant decrease in expression of one or more ISGF-3 proteins in 76% of patients with actinic keratosis (19 of 25 patients). In addition, we found a suppression of one or more ISGF-3 proteins in 67% of skin SCC patients tested (12 of 18 patients), confirming our previous observations. CONCLUSIONS: These data have led to the hypothesis that the suppressed expression of ISGF-3 proteins and consequent reduction in responsiveness to endogenous IFN likely are an early event in skin carcinogenesis.

Aged↗
PubMed2004

Increased sensitivity of SARS-coronavirus to a combination of human type I and type II interferons.

There is currently an urgent need to identify effective antiviral agents that will prevent and treat severe acute respiratory syndrome coronavirus (SARS-CoV) infection. In this study, we have investigated and compared the antiviral effect of different interferons (IFNs) on SARS-CoV replication in the epithelial kidney monkey Vero cell line. The results showed that SARS-CoV grown in Vero cells is moderately sensitive to IFN-beta and only weakly sensitive to IFN-alpha and IFN-gamma, in comparison to other IFN-sensitive viruses, such as those for encephalomyocarditis, vesicular stomatitis and Newcastle disease. Simultaneous incubation of Vero cells with IFN-beta and IFN-gamma indicated that they may act synergistically against SARS-CoV replication. The IFN-induced MxA protein was detected in the IFN-treated Vero cells. The data, however, suggest that the antiviral activity of IFN against SARS-CoV virus is independent of MxA expression.

Animals↗
PubMed1993

Combination treatment of 2-chlorodeoxyadenosine and type I interferon on hairy cell leukemia-like cells: cytotoxic effect and MHC-unrestricted killer cell regulation.

Hairy cell leukemia (HCL) is a lymphoproliferative disorder of B lymphocytes. Interferons (IFNs), especially of the alpha (alpha) subtype, have shown a significant antitumor effect in HCL patients. However, the therapeutic effect of IFN-alpha is still rather limited. The purine analogue 2-chlorodeoxy-adenosine (2-CdA) was reported recently to be an effective agent in the treatment of HCL. In the present study, we find that the HCL cell lines HS-1 and HS-2 as well as Eskol and its IFN-resistant clone (IREs-4) are sensitive to the cytotoxic activity of 2-CdA. Combination treatment of IFN-Con1 and 2-CdA results in a synergistic effect at low doses but an additive inhibitory effect at higher concentrations. IREs-4 cells responded only to 2-CdA treatment. All the HCL cell lines are resistant to natural killer (NK) cell-mediated cytotoxicity (CMC) but are relatively sensitive to IFN-Con1-primed or interleukin-2 (IL-2)-primed NK-CMC activities. No inhibition in killing ability was measured when only the effector cells (NK) were treated with 2-CdA. Pretreatment of the HCL target cells with 2-CdA increases their susceptibility to NK-CMC. Pretreatment with IFN-Con1 can reduce the susceptibility of target cells to NK-CMC in HS-1, HS-2, and Eskol cells but not in the IFN-resistant clone IREs-4. 2-CdA abolished this IFN-induced protection against NK-CMC. Normal fibroblasts only responded to treatment with relatively high doses of 2-CdA, and only a moderate additive cell growth inhibitory effect was seen in combination of 2-CdA with IFN-Con1. Only high doses of 2-CdA increased the susceptibility of fibroblast culture to NK-CMC. Thus, combination of IFN-Con1 and 2-CdA results in an in vitro enhancement of the direct antiproliferative/cytotoxic activity of each treatment alone and increases the efficacy of the NK activity against the HCL cell lines.

Cell Division↗
PubMed2006

Human rhinovirus attenuates the type I interferon response by disrupting activation of interferon regulatory factor 3.

The type I interferon (IFN) response requires the coordinated activation of the latent transcription factors NF-kappaB, interferon regulatory factor 3 (IRF-3), and ATF-2, which in turn activate transcription from the IFN-beta promoter. Synthesis and subsequent secretion of IFN-beta activate the Jak/STAT signaling pathway, resulting in the transcriptional induction of the full spectrum of antiviral gene products. We utilized high-density microarrays to examine the transcriptional response to rhinovirus type 14 (RV14) infection in HeLa cells, with particular emphasis on the type I interferon response and production of IFN-beta. We found that, although RV14 infection results in altered levels of a wide variety of host mRNAs, induction of IFN-beta mRNA or activation of the Jak/STAT pathway is not seen. Prior work has shown, and our results have confirmed, that NF-kappaB and ATF-2 are activated following infection. Since many viruses are known to target IRF-3 to inhibit the induction of IFN-beta mRNA, we analyzed the status of IRF-3 in infected cells. IRF-3 was translocated to the nucleus and phosphorylated in RV14-infected cells. Despite this apparent activation, very little homodimerization of IRF-3 was evident following infection. Similar results in A549 lung alveolar epithelial cells demonstrated the biological relevance of these findings to RV14 pathogenesis. In addition, prior infection of cells with RV14 prevented the induction of IFN-beta mRNA following treatment with double-stranded RNA, indicating that RV14 encodes an activity that specifically inhibits this innate host defense pathway. Collectively, these results indicate that RV14 infection inhibits the host type I interferon response by interfering with IRF-3 activation.

Activating Transcription Factor 2↗
PubMed1998

Type I interferons: expression and signalization.

Type I interferon (IFN-A and IFN-B) genes encode a large family of multifunctional secreted proteins involved in antiviral defence, cell growth regulation and immune activation. These cytokines, as a consequence of their biological activities, have been established as effective therapeutic molecules for malignant and viral diseases. Virus infection is the main inducer leading to transient expression of type I IFN (A and B) and the antiviral response appears to proceed through a two-step pathway requiring, first, induction of type I IFN gene expression and, second, transcriptional activation by the synthesized IFN proteins, binding to their specific cell surface receptors, of a large number of genes. The proteins they encode are responsible, in part, for the pleiotropic multiple biological activities of the IFN. In this two-step pathway, the virus-induced IFN genes and the IFN-stimulated gene (ISG) expression seem to share common factors. Even if IFN-A genes are structurally related and very often coordinately induced in virus-infected cells, differences in the expression of the individual IFN-A messenger RNAs of the multigenic IFN-A gene family are observed in human as well as in murine cells, reflecting, in a particular cell type, the transcriptional activity of the corresponding promoter regions. Important studies on interferon regulatory factors and ISG factors have been made in the last decade. However, some factors involved in IFN-A gene regulation remain to be identified. Our goal has been to review the factors involved in the control of the type I IFN gene expression to understand the mechanisms of induction and repression of their transcription and to explain the properties of these cytokines through their signal transduction pathway.

Animals↗
PubMedDate not supplied

Interferon-delta: the first member of a novel type I interferon family.

We have recently described a novel type I interferon (IFN) co-expressed with IFN-gamma by the trophectoderm of the pig conceptus between day 12 and day 18 of gestation, a development stage that corresponds to implantation in the uterus. This IFN, now officially named IFN-delta, is recognized as the first member of a novel type I IFN family. This paper reviews the main published data on IFN-delta, together with some new data, showing that IFN-delta, while being a true type I IFN, has some very specific structural and biological properties. Sequences related to IFN-delta coding sequence were found in the genome of man and other ungulates but the only other potentially functional gene was found, so far, in the horse. The pig IFN-delta mature protein, with 149 amino acids, is the smallest of all known type I IFNs. It is unusually rich in cysteines (seven residues), and has a very basic isoelectric point. Recombinant IFN-delta expressed in insect cells is glycosylated and has a high antiviral activity on porcine cells, but not on human cells. It has high antiproliferative activity, which is significantly enhanced in the presence of IFN-gamma. This new IFN was shown to bind on pig cells to the same type I receptor as IFN-alpha. IFN-delta and IFN-gamma genes are co-regulated in the pig trophectoderm, whose cells on day 14-16 of development simultaneously secrete both IFN proteins. The biological role of porcine IFN-delta in early pregnancy has been found unrelated to the known antiluteolytic effect of trophoblastic IFN-tau in ruminants.

Amino Acid Sequence↗
PubMed1987

Bovine spleen, a convenient source for purifying a type I interferon receptor.

Bovine spleen was investigated for the presence of receptors for radioiodinated human interferon-alpha 2 (125I-labeled HuIFN-alpha 2). Membranes were prepared by homogenization and differential centrifugation and analyzed for labeled IFN binding with recently developed tissue membrane assays. The characteristics of IFN binding included an affinity constant (Ka) of 3.1 +/- 0.99 X 10(10) M-1 and a receptor content of 8.4 +/- 0.74 fmoles/mg (wet weight) of bovine spleen membranes. The labeled IFN-receptor complex on these membranes was chemically cross-linked with 1.0 mM ethylene glycol bis(succinimidyl succinate (EGS), and subjected to SDS-PAGE and autoradiography. The formation of a 137-kD complex observed on autoradiographs was inhibited in a dose-dependent manner by unlabeled HuIFN-alpha 2 at concentrations that inhibited the binding of labeled IFN to the membranes. The products of the cross-linking reaction were purified by gel filtration on a column of Ultragel AcA34 in the presence of SDS and examined by SDS-PAGE and autoradiography. In addition to the 137-kD complex, several low-molecular-weight species were observed in the column profile of radioactivity which migrated to the bottom of 10% polyacrylamide gels. The fractions containing the 137-kD complex were pooled, concentrated, and utilized as a substrate for endoglycosidase digestion assays. Endoglycosidase H (EndoH) had no affect on the migration of the 137-kD complex while peptide:N-glycosidase F (PNGase F) increased the migration of the 137-kD band to a position with an Mr of 105 kD.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Type I interferons produced by dendritic cells promote their phenotypic and functional activation.

Resting dendritic cells (DCs) are resident in most tissues and can be activated by environmental stimuli to mature into potent antigen-presenting cells. One important stimulus for DC activation is infection; DCs can be triggered through receptors that recognize microbial components directly or by contact with infection-induced cytokines. We show here that murine DCs undergo phenotypic maturation upon exposure to type I interferons (type I IFNs) in vivo or in vitro. Moreover, DCs either derived from bone marrow cells in vitro or isolated from the spleens of normal animals express IFN-alpha and IFN-beta, suggesting that type I IFNs can act in an autocrine manner to activate DCs. Consistent with this idea, the ability to respond to type I IFN was required for the generation of fully activated DCs from bone marrow precursors, as DCs derived from the bone marrow of mice lacking a functional receptor for type I IFN had reduced expression of costimulatory and adhesion molecules and a diminished ability to stimulate naive T-cell proliferation compared with DCs derived from control bone marrow. Furthermore, the addition of neutralizing anti-IFN-alpha/beta antibody to purified splenic DCs in vitro partially blocked the "spontaneous" activation of these cells, inhibiting the up-regulation of costimulatory molecules, secretion of IFN-gamma, and T-cell stimulatory activity. These results show that DCs both secrete and respond to type I IFN, identifying type I interferons as autocrine DC activators.

Animals↗
PubMed1994

cDNA sequence identity for the type I interferon receptor subunit from cell lines of widely differing responsiveness to interferon.

Melanoma cell lines exhibit strikingly different sensitivity to the antiproliferative effects of interferon. cDNAs encoding the Type I interferon receptor subunit were amplified by polymerase chain reaction, using as template RNA isolated from three melanoma cell lines displaying greater than 100 fold range in their sensitivity to the antiproliferative effects of IFN-beta. Comparison of the cDNA sequences obtained with the published cDNA sequence from the highly interferon-sensitive lymphoid cell line Daudi revealed only one base change that leads to a conservative amino acid substitution. It is concluded that the cellular differences in responsiveness to interferon, of the melanoma cell lines tested, do not arise from the expression of variants of the cloned Type I interferon receptor subunit.

Base Sequence↗
PubMed2004

Identification and characterization of viral antagonists of type I interferon in negative-strand RNA viruses.

Interferons are cytokines secreted in response to viral infections with potent antiviral activity, and they represent a critical component of the innate immune response against viruses. It has now become apparent that many viruses have evolved different mechanisms to counteract the interferon response, allowing their efficient replication and propagation in their hosts. This review discusses how the development of reverse genetics techniques and the increase in our knowledge of the interferon response have led to the discovery of interferon-antagonistic functions of different genes of viruses belonging to the negative-strand RNA virus group. In many cases, these viral genes encode accessory pro- teins that are not required for viral infectivity but are critical for optimal replication and for virulence in the host.

Animals↗