干扰素-τ的研究进展

摘要了解干扰素τ（interferon tau，IFN-τ）研究现状。综述了近五年来干扰素-τ研究进展。干扰素-τ具有Ⅰ型干扰素的共同特性：具有抗病毒、抗细胞增生、免疫调节等功能。但IFN-τ在生物学功能方面有自身特点，它仅在胚胎滋养层细胞中表达，无需病毒诱导；另外，高浓度IFN-τ表现出较其他Ⅰ型干扰素较小的细胞毒性。IFN-τ作为一种新的Ⅰ型干扰素，它具有抗黄体溶解、抗病毒、免疫调节等生物学功能，特别是对反转录病毒抑制的高度特异性以及对自身免疫性疾病的免疫调节活性，且低细胞毒性这一特点，它将成为新型的分子药物。     

Type I IFNs and their role in the development of autoimmune diseases

Background: Since their initial use in the 1980s, IFNs have become an essential component of the therapy for many diseases such as hepatitis and multiple sclerosis. Although they have been extremely useful in conditions that pose therapeutic challenges, complications associated with their use have been widely reported including emerging reports of several autoimmune diseases. Many of these reports have shed light on the pathogenesis of autoimmune disorders and helped to highlight not only the critical role of type I IFNs in defense against viral infections but also the pivotal role they occupy in the interface between innate and adaptive immunity. Many patients with autoimmune disease have increased responsiveness to type I IFNs (α/β), and therapy with these cytokines has induced or unmasked autoimmune disease in many additional patients. Objective: The objective of this paper is to discuss the role of type I IFNs in autoimmunity. Methods: The literature regarding type I IFNs and autoimmunity was reviewed using the Medline database from 1950 to 2009. Search terms included ‘interferon alpha’ and ‘autoimmune disease’ and ‘interferon beta’ and ‘autoimmune disease’. Case reports, case series, reviews and prospective studies were included in the analysis. Results/conclusions: In the literature a variety of autoimmune disorders have reportedly been induced by the use of type I IFNs, being used, although these are primarily in the form of case reports and case series. Nevertheless, there is a growing body of molecular evidence to support the clinical association. The role of IFNs in the induction of autoimmunity is complex with interplay of many genetic and environmental factors that influence the balance between normal and aberrant immune responsiveness, ultimately leading to the observed clinical manifestations.     

Novel plant-derived recombinant human interferons with broad spectrum antiviral activity

Type I interferons (IFNs) are potent mediators of the innate immune response to viral infection. IFNs released from infected cells bind to a receptor (IFNAR) on neighboring cells, triggering signaling cascades that limit further infection. Subtle variations in amino acids can alter IFNAR binding and signaling outcomes. We used a new gene crossbreeding method to generate hybrid, type I human IFNs with enhanced antiviral activity against four dissimilar, highly pathogenic viruses. Approximately 1400 novel IFN genes were expressed in plants, and the resultant IFN proteins were screened for antiviral activity. Comparing the gene sequences of a final set of 12 potent IFNs to those of parent genes revealed strong selection pressures at numerous amino acids. Using three-dimensional models based on a recently solved experimental structure of IFN bound to IFNAR, we show that many but not all of the amino acids that were highly selected for are predicted to improve receptor binding.     

Novel plant-derived recombinant human interferons with broad spectrum antiviral activity

Type I interferons (IFNs) are potent mediators of the innate immune response to viral infection. IFNs released from infected cells bind to a receptor (IFNAR) on neighboring cells, triggering signaling cascades that limit further infection. Subtle variations in amino acids can alter IFNAR binding and signaling outcomes. We used a new gene crossbreeding method to generate hybrid, type I human IFNs with enhanced antiviral activity against four dissimilar, highly pathogenic viruses. Approximately 1400 novel IFN genes were expressed in plants, and the resultant IFN proteins were screened for antiviral activity. Comparing the gene sequences of a final set of 12 potent IFNs to those of parent genes revealed strong selection pressures at numerous amino acids. Using three-dimensional models based on a recently solved experimental structure of IFN bound to IFNAR, we show that many but not all of the amino acids that were highly selected for are predicted to improve receptor binding.     

The important roles of type I interferon and interferon-inducible genes in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a severe autoimmune disease that causes multiple-organ dysfunction mainly affecting women in their childbearing years. Type I IFN synthesis is usually triggered by viruses, and its production is tightly regulated and limited in time in health individuals. However, many patients with systemic autoimmune diseases including SLE have signs of aberrant production of type I interferon (IFN) and display an increased expression of IFN-inducible genes. Continuous type I IFNs derived from activated plasmacytoid dendritic cells (pDCs) by interferogenic immune complexes (ICs) and migration of these cells to tissues both break immune tolerance and promote an on-going autoimmune reaction in human body. By the means of detecting type I IFNs and IFN-inducible genes, it can help with diagnosis and evaluation of SLE in early stage and more efficiently. Anti-IFN-α monoclonal antibodies in SLE patients were recently reported and is now being investigated in phase II clinical trails. In this review, we focus on recent research progress in type I IFN and IFN-inducible genes. Possible mechanisms behind the dysregulated type I IFN system in SLE and how they contribute to the development of an autoimmune process, and act as a biomarker and therapeutic target will be reviewed.     

Interferons and their role In inflammation.

Cytokines are pleiotropic molecules showing a wide variety of biologic functions on various cells and tissues, and several different cytokines exert similar and overlapping functions on certain cells. Interferons (IFNs), among the first cytokines identified, play a crucial role in human disease. The IFN cytokine family consists of type I IFNs (IFN-a and IFN-b) and type II IFN (IFN-g). In the first decades of IFN research, type I IFNs were considered primarily as viral inhibitors, whereas type II IFN, also termed "immune IFN", was generally considered to be uniquely involved in immune reactions. This view has changed considerably in the last years. The importance of type I IFNs in inflammation, immunoregulation and T-cell responses has been identified and has changed dramatically our interpretation of the biological relevance of type I and II IFNs. Recent data suggest that IFN-a is a multifunctional immunomodulatory cytokine with profound effects on the cytokine cascade including several anti-inflammatory properties, whereas IFN-g remains a classical proinflammatory cytokine. These different effects on critical mediators of inflammation may also explain why type I and II IFNs are clinically successful in different diseases. These newly identified immunoregulatory and anti-inflammatory functions of type I IFNs may be of importance in the treatment of diseases such as chronic viral hepatitis or multiple sclerosis and help to explain some of the mechanisms of IFNs.     

Interferons in multiple sclerosis. A review of the evidence.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, characterised clinically by relapses and remissions, and leading eventually to chronic disability. Despite an enormous amount of research, the cause of MS remains unknown; however, pathological, genetic, and immunological features have been identified that suggest the disease has an autoimmune basis. Accordingly, current therapy of MS includes corticotrophin or corticosteroids for acute exacerbations, and more potent immunosuppressive drugs for severe cases unresponsive to steroids. All of these agents can cause serious adverse reactions. There is an urgent need for immunotherapy that is less toxic, that can be given early and perhaps indefinitely, and that will prevent relapses and progression of the disease. Our current knowledge of the effects of interferons (IFNs) in MS is based on the results of laboratory research and clinical therapeutic trials carried out over the past decade. Existing evidence points to the conclusion that the effects of the IFNs in MS are mediated by immunoregulatory rather than antiviral or nonspecific mechanisms. Administration of IFN gamma increases the exacerbation rate, and IFN gamma as well as other cytokines may be involved in the pathogenesis of MS lesions. In contrast, studies of IFN beta show that it tends to inhibit the activity of IFN gamma and appears to prevent disease activity. Intrathecal administration of IFN beta, although effective, is cumbersome and potentially hazardous. A large multicentre placebo-controlled trial of systemic recombinant IFN beta was recently conducted in the US, and the results of the first 2 years of treatment were considered sufficiently encouraging that an application for licensing was submitted to the Food and Drug Administration in June 1992. If approved, it will be the first new agent licensed for clinical use in MS in over 20 years. The study will continue under double-blind conditions for at least another year, and a second trial of systemic recombinant IFN beta therapy is also in progress. These studies should provide definitive answers to questions about the role of IFNs in the pathogenesis of MS, as well as the place of recombinant IFN beta as an effective therapeutic agent.     

Antiviral activity of type I interferons and interleukins 29 and 28a (type III interferons) against Apeu virus

Interferons (IFNs) are cytokines with important immunomodulatory activity in vertebrates. Although type I IFNs and interleukins (IL) 29 and 28a (type III IFNs) bind to different cellular receptors and have distinct structures, most of their biological activities are redundant. Apeu virus (APEUV) is a member of the Bunyaviridae family isolated from the Brazilian rain forest. In this paper we evaluated the antiviral activity of type I and type III IFNs against APEUV. All tested IFNs were able to induce an antiviral state against the virus in a dose-dependent way. The activity of type III IFNs did not need the presence of type I IFNs. Mixing both types of IFNs did not improve the biological activity of each type alone. The tested IFNs were also able to protect human peripheral blood mononuclear cells from infection. IFN alpha2, IFN beta, IL-29 and IL-28a induced the expression of 2′,5′-oligoadenylate synthetase (2′5′OAS) and 6–16 genes. Although MxA gene was related to antiviral activity against Bunyaviruses, there was no induction of MxA in our model. We were able to show activity of type I and type III IFNs against a RNA virus, and that this activity is not dependent on MxA gene.     

Emerging therapies for hepatitis C virus infection

Hepatitis C virus (HCV) has infected millions of people worldwide and has emerged as a global health crisis. The currently available therapy is interferon (IFN) either alone or in combination with ribavirin. However, the disappointing efficacy of IFN has led to the considerable need for improved treatments and a number of new therapies are under evaluation in clinical trials. These include pegylated IFNs, which have altered physiochemical characteristics allowing once-weekly dosing. Combination of pegylated IFN with ribavirin should further improve sustained response rates. However, not all patients are successfully treated with IFNs, particularly those infected with genotype 1 of the virus, and it is likely that potent, specific drugs will be required. The majority of new approaches currently trying to combat this viral disease are aimed at inhibition of viral targets. Most effort has been directed towards inhibition of the NS3 serine protease, and potent inhibitors have now been described. However, a clinical candidate is yet to emerge against this difficult target. Considerable work by leading researchers has provided crystal structures of the key replicative enzymes, NS3 protease, NS3 helicase, NS5B polymerase and full-length NS3 protease-helicase, and there is much hope that such structural information will bear fruit. More recently, inhibition of host targets, particularly inosine monophosphate dehydrogenase (IMPDH), has become of interest and there are on-going clinical trials with such inhibitors. Research aimed at novel treatments for HCV disease is gathering pace and very recent developments in cell-based assay systems can only hasten the discovery of improved therapies.     

IFN-α subtypes: distinct biological activities in anti-viral therapy

During most viral infections, the immediate host response is characterized by an induction of type I IFN. These cytokines have various biological activities, including anti-viral, anti-proliferative and immunomodulatory effects. After induction, they bind to their IFN-α/β receptor, which leads to downstream signalling resulting in the expression of numerous different IFN-stimulated genes. These genes encode anti-viral proteins that directly inhibit viral replication as well as modulate immune function. Thus, the induction of type I IFN is a very powerful tool for the host to fight virus infections. Many viruses evade this response by various strategies like the direct suppression of IFN induction or inhibition of the IFN signalling pathway. Therefore, the therapeutic application of exogenous type I IFN or molecules that induce strong IFN responses should be of great potential for future immunotherapies against viral infections. Type I IFN is currently used as a treatment in chronic hepatitis B and C virus infection, but as yet is not widely utilized for other viral infections. One reason for this restricted clinical use is that type I IFN belongs to a multigene family that includes 13 different IFN-α subtypes and IFN-β, whose individual anti-viral and immunomodulatory properties have so far not been investigated in detail to improve IFN therapy against viral infections in humans. In this review, we summarize the recent achievements in defining the distinct biological functions of type I IFN subtypes in cell culture and in animal models of viral infection as well as their clinical usage in chronic hepatitis virus infections.     

Antiviral activity of type I interferons and interleukins 29 and 28a (type III interferons) against Apeu virus

Interferons (IFNs) are cytokines with important immunomodulatory activity in vertebrates. Although type I IFNs and interleukins (IL) 29 and 28a (type III IFNs) bind to different cellular receptors and have distinct structures, most of their biological activities are redundant. Apeu virus (APEUV) is a member of the Bunyaviridae family isolated from the Brazilian rain forest. In this paper we evaluated the antiviral activity of type I and type III IFNs against APEUV. All tested IFNs were able to induce an antiviral state against the virus in a dose-dependent way. The activity of type III IFNs did not need the presence of type I IFNs. Mixing both types of IFNs did not improve the biological activity of each type alone. The tested IFNs were also able to protect human peripheral blood mononuclear cells from infection. IFN alpha2, IFN beta, IL-29 and IL-28a induced the expression of 2′,5′-oligoadenylate synthetase (2′5′OAS) and 6–16 genes. Although MxA gene was related to antiviral activity against Bunyaviruses, there was no induction of MxA in our model. We were able to show activity of type I and type III IFNs against a RNA virus, and that this activity is not dependent on MxA gene.     

Type I Interferons as Regulators of Human Antigen Presenting Cell Functions

Type I interferons (IFNs) are pleiotropic cytokines, initially described for their antiviral activity. These cytokines exhibit a long record of clinical use in patients with some types of cancer, viral infections and chronic inflammatory diseases. It is now well established that IFN action mostly relies on their ability to modulate host innate and adaptive immune responses. Work in recent years has begun to elucidate the mechanisms by which type I IFNs modify the immune response, and this is now recognized to be due to effects on multiple cell types, including monocytes, dendritic cells (DCs), NK cells, T and B lymphocytes. An ensemble of results from both animal models and in vitro studies emphasized the key role of type I IFNs in the development and function of DCs, suggesting the existence of a natural alliance between these cytokines and DCs in linking innate to adaptive immunity. The identification of IFN signatures in DCs and their dysregulation under pathological conditions will therefore be pivotal to decipher the complexity of this DC-IFN interaction and to better exploit the therapeutic potential of these cells.     

Interferons in the treatment of malignancies.

Interferons alpha, beta and gamma (IFN) were initially identified as soluble factors able to inhibit infection of chick chorioallantoic membranes by influenza A virus. Although the mechanism(s) of action of IFNs are unclear, these molecules express their biologic properties after binding to specific high-affinity cell membrane receptors. To dates several clinical studies have challenged the therapeutic benefits of using IFNs in the treatment of solid tumours and haematologic malignancies. The reported results have shown a wide range of response rate, and toxicities in general are manageable, predictable and rarely of major clinical significance. These studies have also raised the interesting possibility for improving cancer treatment with combination of IFNs and conventional anticancer regimens, or combinations of IFNs with other Biological Response Modifiers (BRMs), such as interleukin 2. Hopefully, this area of research will lead to an entire rethinking of the use of our existing anticancer treatment modalities, which perhaps could lead to solutions to old clinical problems.     

Distinct functions of IRF-3 and IRF-7 in IFN-alpha gene regulation and control of anti-tumor activity in primary macrophages

Type I IFN (IFN-alpha/beta) have important biological functions ranging from immune cell development and activation, to tumor cell killing and most importantly inhibition of virus replication. Following viral infection or activation of Toll-like receptors (TLRs) via distinct ligands, IFN-alpha/beta are produced. Two members of the interferon regulatory factor (IRF) family - IRF-3 and IRF-7 - are the major modulators of IFN gene expression. Activation of IRF-3 and IRF-7 by TBK1/IKKvarepsilon mediated phosphorylation promotes IFN gene expression and potentiates the production of IFN responsive genes important to the development of an effective antiviral immune response. IFN treatment can augment anti-tumor properties and they are potentially key players in cancer therapy. For example, adoptive transfer of IFN-gamma-activated macrophages can mediate tumor cell killing via direct cell-cell contact, as well as release of soluble cytotoxic pro-inflammatory molecules. A recent study investigated whether IRF-3 and IRF-7 could mediate the acquisition of new anti-tumor effector functions in macrophages. Adenovirus mediated transduction of the active form of IRF-7 into primary macrophages resulted in the production of type I IFN, upregulation of target genes including TRAIL and increased tumoricidal activity of macrophages; in contrast, the active form of IRF-3 led to induction of cell death. These studies indicate that IRF-7 transduced macrophages may be an attractive candidate for in vivo adoptive therapy of cancer.     

Mechanisms of interferon mediated anti-viral resistance

Interferons (IFNs) are an important part of immune responses and are believed to protect the host from viral and bacterial pathogens as well as having a role in rejection of malignancies. The well-known anti-viral and cytostatic properties of IFNs have led to the clinical use of these proteins to treat some cancers and viral infections. Extensive research has begun to unravel much of the molecular basis for the biological effects of IFNs, and this information could now be used as a foundation for the development of novel therapeutic strategies that avoid some of the acknowledged shortcomings of cytokine therapies. This review explains the current model of IFN action, during viral infections and the potential for well-established and emerging groups of IFN inducible genes as therapeutic targets is highlighted.     

Interferon-omega: Current status in clinical applications

Since 1985, interferon (IFN)-ω, a type I IFN, has been identified in many animals, but not canines and mice. It has been demonstrated to have antiviral, anti-proliferation, and antitumor activities that are similar to those of IFN-α. To date, IFN-ω has been explored as a treatment option for some diseases or viral infections in humans and other animals. Studies have revealed that human IFN-ω displays antitumor activities in some models of human cancer cells and that it can be used to diagnose some diseases. While recombinant feline IFN-ω has been licensed in several countries for treating canine parvovirus, feline leukemia virus, and feline immunodeficiency virus infections, it also exhibits a certain efficacy when used to treat other viral infections or diseases. This review examines the known biological activity of IFN-ω and its clinical applications. We expect that the information provided in this review will stimulate further studies of IFN-ω as a therapeutic agent.