Interleukins. Clinical pharmacokinetics and practical implications.

Interleukins and tumour necrosis factor (TNF) are a complex group of proteins and glycoproteins able to exert pleiotropic effects with respect to a number of different target cells. In physiological conditions, they are induced and released in basal amounts only in restricted microenvironments where they have paracrine activity. Any small amounts reaching the circulation do not disturb homoeostasis. During therapy, particularly when these cytokines are administered via conventional routes, it has become apparent that their presence in nonphysiological plasma concentrations and their unselective action cause toxic effects with small benefits. The pharmacokinetics of interleukins-1, -2, -3 and -6 and TNF have been evaluated, and their disappearance from plasma after intravenous administration is very rapid (i.e. the distribution half-life is measured in minutes; the elimination half-life is several hours). The efficiency of catabolic pathways such as renal filtration and/or liver uptake is interpreted as a salutary mechanism for extracting proteins that should not be in the circulation. However, because these cytokines are very potent immunomodulatory agents there is a need to improve their therapeutic index, and to this end a number of possible formulations and routes of administration are now available and may eventually be of practical use.     

Controlling the kinetics of interferon transgene expression for improved gene therapy

Interferon (IFN) gene based therapy has been studied for the treatment of many diseases such as viral infections, cancer and allergic diseases. Non-viral vectors, like plasmid DNA, are promising ways for delivering IFN genes, because of their low immunogenicity and toxicity compared with viral vectors. Potent therapeutic effects of IFN gene transfer will depend on the level and duration of transgene expression after in vivo administration. Therefore, controlling the kinetics of transgene expression of IFNs is a rational approach for improved gene therapy. The design and optimization of plasmid vectors, as well as their route/method of administration, is the key to obtaining high and persistent transgene expression. In this review, we aim to present experimental evidence about the relationships among the properties of plasmid vectors expressing IFNs, the kinetics of transgene expression, and therapeutic effects as well as safety issues.     

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.     

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.     

Interferon-based therapy of hepatitis C

In 2007, the world celebrated the 50th anniversary of the discovery of interferon (IFN). The first clinical trial of recombinant IFN-alpha in patients with chronic hepatitis C was published in 1986. This article reviews the classification of IFNs, IFN production during viral infections, IFN signaling pathways and the mechanisms of their antiviral and immunomodulatory properties. Hepatitis C virus infection treatment is currently based on the combination of pegylated IFN-alpha and ribavirin. The pegylated IFN-alpha molecules are described, as well as the putative mechanisms of action of ribavirin. Current treatment guidelines are discussed and new results suggesting that the treatment schedule should be tailored to the early virological response during therapy are presented. Finally, insights into new hepatitis C drug developments are given.     

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.     

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.     

Interferon: cellular executioner or white knight?

Interferons (IFNs) are a family of pleiotropic cytokines that typically exhibit antiviral, antiproliferative, antitumor, and immunomodulatory properties. While their complex mechanisms of action remain unclear, IFNs are used clinically in the treatment of viral infections, such as hepatitis B and hepatitis C, and remain the primary treatment for a limited number of malignancies, such as melanoma, hairy cell leukemia, and non-Hodgkin's lymphoma and in autoimmune diseases such as multiple sclerosis. IFNs not only regulate somatic cell growth and division but also influence cell survival through the modulation of apoptosis. Paradoxically, IFNs are described to be both pro- and anti-apoptotic in nature. The biological effects of IFNs are primarily mediated via activation of the JAK/STAT pathway, formation of the ISGF3 and STAT1:STAT1 protein complexes, and the subsequent induction of IFN-stimulated genes. However, the activation of JAK/STAT-independent signal transduction pathways also contribute to IFN-mediated responses. To further demonstrate the complexity of the downstream events following stimulation, oligonucleotide microarray studies have shown that in excess of 300 genes are induced following treatment with IFN, some of which are crucial to the induction of apoptosis and cell growth control. In this review we describe the recent advances made in elucidating the various signaling pathways that are activated by IFNs and how these diverse signals contribute to the regulation of cell growth and apoptosis and inhibition of viral replication. Furthermore, we highlight the role of specific signaling molecules and the function(s) of particular IFN-stimulated genes that have been implicated in determining cell fate in response to IFN, as well as the clinical experience of IFN immunotherapy.     

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.     

Interferons in relapsing-remitting multiple sclerosis: are there benefits from long-term use?

Multiple sclerosis (MS) is one of the most common chronic neurological diseases in young adults in western countries. An important aspect of treatment of this disease is the use of interferons (IFNs). These are molecules with antiviral, immunomodulatory, antiproliferative and hormonal activities. IFNbeta, a class I IFN, has been used extensively in the therapy of MS, particularly in its relapsing-remitting (RRMS) phase, the most frequent clinical form of the disease.Although the available evidence from published clinical trials is difficult to evaluate because of methodological differences, an unbiased review of the data reveals sufficient evidence to conclude that treatment with IFNbeta in RRMS is both efficacious and safe, at least over the periods so far investigated (up to 4-6 years). While there is no reason to suspect that IFNbeta should not continue to be efficacious and safe over the longer term, studies investigating these questions over longer periods and including greater numbers of patients are needed.     

Biodegradable nanogels for oral delivery of interferon for norovirus infection

Norwalk virus (NV) replicon-harboring cells have provided an excellent tool to the development of antivirals. Previously we demonstrated that the expression levels of replicon RNA and proteins were significantly reduced in the presence of various interferons (IFNs) including IFN-α and IFN-γ in a dose-dependent manner in the NV replicon-harboring cells, and suggested that IFNs could be therapeutic options for norovirus infection. It was also demonstrated that innate immunity including IFNs is crucial in the replication and pathogenicity of murine norovirus (MNV) in vitro (RAW267.4 cells) and in vivo. IFNs have a short half-life in vitro and in vivo due to low stability. Thus it is important to have a good delivery system to improve the stability of IFNs. Nanogels are nanosized networks of chemically cross-linked polymers that swell in physiologic solutions and provide improved stability and bioavailability to drugs. We have synthesized nanogels based on cross-linked polyethyleneimine (PEI)-polyethylenglycol (PEG). The PEI/PEG nanogels were further acetylated (AcNg) to reduce cellular penetration and cytotoxicity. The IFN-AcNg complex was prepared by incubating two components together at 4 °C and lyophilization. The IFN activity of IFN-AcNg was evaluated in the NV- and HCV-replicon-harboring cells and against MNV-1 in RAW267.4 cells in comparison to IFN without AcNg. The AcNg improved the stability of IFN stored at 4 °C, and was well tolerated in the cells. Furthermore, the activity of IFN was significantly higher when combined with AcNg in the replicon-harboring cells and against MNV-1 in RAW267.4 cells. We concluded that AcNg may be pursued further as a vehicle for oral delivery of IFNs in norovirus infection.     

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。     

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.     

Combined antiviral options for the treatment of chronic hepatitis C

In the absence of antiviral treatment, chronic hepatitis C virus (HCV) infection is a liver disease characterized by the development of necroinflammatory changes and progressive liver fibrosis, leading to cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC). The approval of ribavirin in combination therapy regimens with interferon (IFN) dramatically improved therapy. Another advance was the introduction of pegylated IFNs, which allow a once-weekly subcutaneous administration and show more favorable pharmacokinetics and greater efficacy. Two forms are available: pegylated IFN alpha-2b (12 kDa) (1.5 microg/kg) and pegylated IFN alpha-2a (40 kDa) (fixed dosage of 180 microg). Ribavirin is administered orally, at doses > or =10.6 mg/kg, resulting in higher sustained virological responses (SVR) than IFN monotherapy. The highest SVR rates are attained with pegylated IFNs in combination with ribavirin. Factors associated with treatment outcome include HCV genotype, viral load, body weight, age, cirrhosis or bridging fibrosis, coinfection with HIV or hepatitis B virus, and treatment adherence and tolerance. Currently, the main therapeutic challenges ahead are: (a) the dosage optimization of pegylated IFNs and ribavirin according to the patients' characteristics; and (b) to evaluate the efficacy and safety of this combination therapy for difficult-to-treat patients, such as nonresponders, cirrhotics, transplant recipients, renal disease patients or those coinfected with HIV.     

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.     

Drugs in development for hepatitis B

The management of chronic hepatitis B (CHB) has improved dramatically over the last decade with the development of new drugs such as lamivudine and adefovir dipivoxil, in addition to the now standard interferon (IFN)-alpha therapy. These new drugs can achieve a significant reduction or inhibit replication of hepatitis B virus (HBV) DNA during therapy. However, in the majority of patients, particularly in those who are hepatitis B e antigen (HBeAg)-negative, the sustained off-therapy suppression of HBV DNA is rare. For this reason, several new antiviral and immunomodulatory agents are currently being evaluated. Among the immunomodulatory agents, pegylated IFNalpha (peginterferon-alpha) has been shown to be more effective for HBeAg-positive CHB than either lamivudine or standard IFNalpha monotherapy, particularly in those patients infected by HBV genotypes A and B. The new antivirals entecavir, tenofovir disoproxil fumarate and telbivudine exhibit a more potent viral inhibitory effect than the currently approved drugs (IFNs, lamivudine and adefovir dipivoxil). However, the emergence of viral resistance has been witnessed and this could be one of the major limitations to the clinical use of these new drugs, particularly during prolonged therapy. In HBeAg-negative patients it is more and more common for oral antiviral therapy to be administered for prolonged periods, as the sustained off-therapy response rates of short-term therapy are very low. Different studies are currently evaluating combination therapy, using lamivudine with adefovir dipivoxil or peginterferon-alpha with lamivudine; the preliminary results show virological responses no better than those achieved by monotherapy. However, as combination therapy is associated with a low likelihood of developing HBV drug resistance, this could result in a higher virological response during prolonged therapy. In the near future the most realistic therapeutic option for the majority of patients with CHB will be long-term use of these new, more potent antiviral drugs, if they can achieve good safety profiles while maintaining low resistance rates at affordable costs.     

Hypopigmentary skin disorders: current treatment options and future directions

Alterations of skin and hair pigmentation are important features that have warranted treatment from ancient history on up to modern time. In some cultures, even today patients with vitiligo are regarded as social outcasts and are affected considerably both emotionally and physically. This article presents current options and future directions for the treatment of hypopigmentary disorders. Whereas with congenital disorders, such as albinism and phenylketonuria, no causal therapy has been established up to now, several treatment options for acquired hypopigmentary disorders have been investigated. In particular, in vitiligo, one of the most prevalent hypopigmentary disorders, a number of treatment modalities have been employed in the past 30 years. However, most of them are only able to palliate, not cure, the disease. Depending on the distribution of the hypopigmented lesions (localised or generalised) and the state of the disease (active or stable), several therapeutic options, for example phototherapy, surgical skin grafts, autologous melanocyte transplantation and immunomodulators, can be applied alone or in combination. For phototherapy, because of unfavourable results and adverse effects, ultraviolet (UV) A has been largely replaced by narrow-band UVB for repigmentation of generalised vitiligo. Although immunomodulators, such as corticosteroids, have been used both topically and systemically over the past 3 decades for the treatment of disseminated vitiligo, they are only suitable for the treatment of acrofacial and localised forms because of adverse effects. Hence, new immunomodulatory agents, such as calcineurin antagonists, have recently been introduced as new promising tools to treat acquired hypopigmentary disorders. However, all therapeutic approaches are hampered by the fact that the pathophysiology of hypopigmentary disorders is still poorly understood.     

Pegylated interferon with ribavirin therapy for chronic infection with the hepatitis C virus

Chronic infection with the hepatitis C virus is common. In the past, therapy involved a combination of thrice-weekly interferon (IFN) injections combined with oral ribavirin. This therapy was expensive, poorly tolerated and poorly effective, only curing approximately 40% of treated patients. Long-acting IFNs have recently been developed by linking IFN to polyethylene glycol and these 'pegylated' IFNs are now the standard of care for patients with chronic hepatitis C (CHC). Two pegylated (PEG) IFNs are available; 40 kDa PEG-IFNalpha(2a) (Pegasys, Hoffmann-La Roche) and the 12 kDa PEG-IFN-alpha(2b) (Peg-Intron, Schering-Plough). They have different physicochemical, pharmacokinetic and pharmacodynamic properties. The 40 kDa PEG-IFN-alpha(2a) is dispensed as a solution and used at a fixed dose whereas the 12 kDa PEG-IFN-alpha(2b) is a dry powder, which is reconstituted prior to administration, and the dose is dependent upon body weight. Both PEG-IFNs are given by a once-weekly injection and as monotherapy, they are more effective than standard IFN-alpha. The 40 kDa PEGIFN-alpha(2a) cures 36 - 39% of patients and the 12 kDa pegylated-IFN-alpha(2b) cures 23 - 25%. When combined with ribavirin, the two PEG-IFNs have acceptable safety profiles and cure > 50% of treated patients (56 and 54% for the 40 kDa PEG-IFN-alpha(2a) and 12 kDa PEG-IFN-alpha(2b), respectively). For the 40 kDa PEG-IFN-alpha(2a) it is possible to predict the outcome of therapy after 12 weeks of treatment. The new PEG-IFNs are a significant advance in the therapy of CHC infection. Their ease of administration, coupled with their improved efficacy, is likely to lead to an increase in the proportion of infected patients who wish to receive treatment.