of plasmacytoid dendritic cells with age is associated with increased covid-19 severity, possibly because these cells are substantial interferon producers. ten percent of patients with life-threatening covid-19 have autoantibodies against type i interferon. delayed ifn-i response contributes to the pathogenic inflammation (cytokine storm) seen in later stages of covid-19 disease. application of ifn-i prior to (or in the very early stages of) viral infection can be protective, as can treatment with pegylated ifn-λiii, which should be validated in randomized clinical trials. interferon therapy three vials filled with human leukocyte interferon diseases interferon beta-1a and interferon beta-1b are used to treat and control multiple sclerosis, an autoimmune disorder. this treatment may help in reducing attacks in relapsing-remitting multiple sclerosis and slowing disease progression and activity in secondary progressive multiple sclerosis. interferon therapy is used (in combination with chemotherapy and radiation) as a treatment for some cancers. this treatment can be used in hematological malignancy, such as in leukemia and lymphomas including hairy cell leukemia, chronic myeloid leukemia, nodular lymphoma, and cutaneous t-cell lymphoma. patients with recurrent melanomas receive recombinant ifn-α2b. both hepatitis b and hepatitis c can be treated with ifn-α, often in combination with other antiviral drugs. some of those treated with interferon have a sustained virological response and can eliminate hepatitis virus in the case of hepatitis c. the most common strain of hepatitis c virus (hcv) worldwide—genotype i— can be treated with interferon-α, ribavirin and protease inhibitors such as telaprevir, boceprevir or the nucleotide analog polymerase inhibitor sofosbuvir. biopsies of patients given the treatment show reductions in liver damage and cirrhosis. control of chronic hepatitis c by ifn is associated with reduced hepatocellular carcinoma. a single nucleotide polymorphism (snp) in the gene encoding the type iii interferon ifn-λ3 was found to be protective against chronic infection following proven hcv infection and predicted treatment response to interferon-based regimens. the frequency of the snp differed significantly by race, partly explaining observed differences in response to interferon therapy between european-americans and african-americans. unconfirmed results suggested that interferon eye drops may be an effective treatment for people who have herpes simplex virus epithelial keratitis, a type of eye infection. there is no clear evidence to suggest that removing the infected tissue (debridement) followed by interferon drops is an effective treatment approach for these types of eye infections. unconfirmed results suggested that the combination of interferon and an antiviral agent may speed the healing process compared to antiviral therapy alone. when used in systemic therapy, ifns are mostly administered by an intramuscular injection. the injection of ifns in the muscle or under the skin is generally well tolerated. the most frequent adverse effects are flu-like symptoms: increased body temperature, feeling ill, fatigue, headache, muscle pain, convulsion, dizziness, hair thinning, and depression. erythema, pain, and hardness at the site of injection are also frequently observed. ifn therapy causes immunosuppression, in particular through neutropenia and can result in some infections manifesting in unusual ways. drug formulations pharmaceutical forms of interferons generic namebrand name interferon alfamultiferon interferon alpha 2aroferon a interferon alpha 2bintron a/reliferon/uniferon human leukocyte interferon-alpha (huifn-alpha-le)multiferon interferon beta 1a, liquid formrebif interferon beta 1a, lyophilizedavonex interferon beta 1a, biogeneric (iran)cinnovex interferon beta 1bbetaseron / betaferon interferon gamma 1bactimmune pegylated interferon alpha 2apegasys pegylated interferon alpha 2a (egypt)reiferon retard pegylated interferon alpha 2bpegintron ropeginterferon alfa-2bbesremi pegylated interferon alpha 2b plus ribavirin (canada)pegetron several different types of interferons are approved for use in humans. one was first approved for medical use in 1986. for example, in january 2001, the food and drug administration (fda) approved the use of pegylated interferon-alpha in the usa; in this formulation, pegylated interferon-alpha-2b (pegintron), polyethylene glycol is linked to the interferon molecule to make the interferon last longer in the body. approval for pegylated interferon-alpha-2a (pegasys) followed in october 2002. these pegylated drugs are injected once weekly, rather than administering two or three times per week, as is necessary for conventional interferon-alpha. when used with the antiviral drug ribavirin, pegylated interferon is effective in treatment of hepatitis c; at least 75% of people with hepatitis c genotypes 2 or 3 benefit from interferon treatment, although this is effective in less than 50% of people infected with genotype 1 (the more common form of hepatitis c virus in both the u.s. and western europe). interferon-containing regimens may also include protease inhibitors such as boceprevir and telaprevir. there are also interferon-inducing drugs, notably tilorone that is shown to be effective against ebola virus. history sidney pestka of rutgers university, seen here receiving the national medal of technology. interferons were first described in 1957 by alick isaacs and jean lindenmann at the national institute for medical research in london; the discovery was a result of their studies of viral interference. viral interference refers to the inhibition of virus growth caused by previous exposure of cells to an active or a heat-inactivated virus. isaacs and lindenmann were working with a system that involved the inhibition of the growth of live influenza virus in chicken embryo chorioallantoic membranes by heat-inactivated influenza virus. their experiments revealed that this interference was mediated by a protein released by cells in the heat-inactivated influenza virus-treated membranes. they published their results in 1957 naming the antiviral factor they had discovered interferon. the findings of isaacs and lindenmann have been widely confirmed and corroborated in the literature. furthermore, others may have made observations on interferons before the 1957 publication of isaacs and lindenmann. for example, during research to produce a more efficient vaccine for smallpox, yasu-ichi nagano and yasuhiko kojima—two japanese virologists working at the institute for infectious diseases at the university of tokyo—noticed inhibition of viral growth in an area of rabbit-skin or testis previously inoculated with uv-inactivated virus. they hypothesised that some "viral inhibitory factor" was present in the tissues infected with virus and attempted to isolate and characterize this factor from tissue homogenates. independently, monto ho, in john enders's lab, observed in 1957 that attenuated poliovirus conferred a species specific anti-viral effect in human amniotic cell cultures. they described these observations in a 1959 publication, naming the responsible factor viral inhibitory factor (vif). it took another fifteen to twenty years, using somatic cell genetics, to show that the interferon action gene and interferon gene reside in different human chromosomes. the purification of human beta interferon did not occur until 1977. y.h. tan and his co-workers purified and produced biologically active, radio-labeled human beta interferon by superinducing the interferon gene in fibroblast cells, and they showed its active site contains tyrosine residues. tan's laboratory isolated sufficient amounts of human beta interferon to perform the first amino acid, sugar composition and n-terminal analyses. they showed that human beta interferon was an unusually hydrophobic glycoprotein. this explained the large loss of interferon activity when preparations were transferred from test tube to test tube or from vessel to vessel during purification. the analyses showed the reality of interferon activity by chemical verification. the purification of human alpha interferon was not reported until 1978. a series of publications from the laboratories of sidney pestka and alan waldman between 1978 and 1981, describe the purification of the type i interferons ifn-α and ifn-β. by the early 1980s, genes for these interferons had been cloned, adding further definitive proof that interferons were responsible for interfering with viral replication. gene cloning also confirmed that ifn-α was encoded by a family of many related genes. the type ii ifn (ifn-γ) gene was also isolated around this time. interferon was first synthesized manually at rockefeller university in the lab of dr. bruce merrifield, using solid phase peptide synthesis, one amino acid at a time. he later won the nobel prize in chemistry. interferon was scarce and expensive until 1980, when the interferon gene was inserted into bacteria using recombinant dna technology, allowing mass cultivation and purification from bacterial cultures or derived from yeasts. interferon can also be produced by recombinant mammalian cells. before the early 1970s, large scale production of human interferon had been pioneered by kari cantell. he produced large amounts of human alpha interferon from large quantities of human white blood cells collected by the finnish blood bank. large amounts of human beta interferon were made by superinducing the beta interferon gene in human fibroblast cells. cantell's and tan's methods of making large amounts of natural interferon were critical for chemical characterisation, clinical trials and the preparation of small amounts of interferon messenger rna to clone the human alpha and beta interferon genes. the superinduced human beta interferon messenger rna was prepared by tan's lab for cetus corp. to clone the human beta interferon gene in bacteria and the recombinant interferon was developed as 'betaseron' and approved for the treatment of ms. superinduction of the human beta interferon gene was also used by israeli scientists to manufacture human beta interferon. human interferons ifna1 ifna2 ifna4 ifna5 ifna6 ifna7 ifna8 ifna10 ifna13 ifna14 ifna16 ifna17 ifna21 ifnb1 ifnw ifne1 ifnk teleost fish interferons ifna ifnb ifnc ifnd ifne ifnf ifng (gamma) ifnh