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the 9th letter of the Roman alphabet (同)i

PrepTutorEJDIC

『私は』私が
iodineの化学記号
intermediate frequency (無電の)中間周波

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/01/20 03:25:47」(JST)

wiki ja

インターフェロン（英: Interferon、略号：IFN）とは動物体内で病原体（特にウイルス）や腫瘍細胞などの異物の侵入に反応して細胞が分泌する蛋白質のこと。ウイルス増殖の阻止や細胞増殖の抑制、免疫系および炎症の調節などの働きをするサイトカインの一種である。

医薬品としては、ウイルス性肝炎等の抗ウイルス薬として、多発性骨髄腫等の抗がん剤として用いられている。

ヒト白血球インターフェロン

歴史

長野泰一-小島保彦の実験。長野泰一,小島保彦らは、1940年代から、生体において抗ウイルス免疫が発現する正確な時期を知ろうとして精密な実験を重ねた｡兎の皮膚の多数の個所にワクシニアウイルスを接種し､その同じ個所へ種々の時期にワクチンを注射し､皮膚病変の起こるのが阻止される状況を観察した｡この際のワクチンは兎のワクシニアウイルス感染組織のホモジェネートに紫外線を当て、ウイルスを不活化たものであり、動物組織成分と不活性ウイルスとの混合物である｡ワクシニアウイルスが選ばれた理由は比較的粒径が大きく、濾過で除去できるからである。実験の結果以下のことが判った。*ワクチン（実線）の効果のピークは注射後1日目と二週後の二個ある。*ワクチンの遠心上清の効果のピークは1日目のみである。遅い方のピークは通常の免疫効果と考えられるが､早期のピークは非免疫性の効果と考えられる（1957年)。早期のピークの因子はウイルス抗原でもなく､抗ウイルス抗体でもない事が重ねて証明された(1958年)。本因子は後にインターフェロンと言われることになる。

1954年に、伝染病研究所所長（当時）の長野泰一と小島保彦が「ウイルス干渉因子」として発見し報告した。1957年には、イギリスのアリック・アイザックス（Alick Isaacs）たちもウイルス増殖を非特異的に（抗体ではない）抑制する因子として確認し、ウイルス干渉（Interference）因子という意味で「Interferon（インターフェロン）」と命名した。 1980年頃に、インターフェロンが悪性腫瘍に効果があることが発見され、抗がん剤として発展していった。

種類

ヒトでは大きく分けて3つのタイプがある。

IFN typeⅠ

多くの場合「インターフェロン」というとIFN typeⅠ（I型インターフェロン）を指す。IFN typeⅠには以下が知られている。

IFN-α：13種類（1,2,4,5,6,7,8,10,13,14,16,17,21）
IFN-β：1種類 - IFN-β1（※IFN-β2＝IL-6）
IFN-ω：1種類 - IFN-ω1
IFN-ε：1種類 - IFN-ε1
IFN-κ：1種類 - IFN-κ

相同な分子が哺乳類のほか鳥類、爬虫類、魚類で見つかっている。これらに加えマウスでリミチン（LimitinまたはIFN-ζ）、ウシなどでIFN-τ、ブタでIFN-δが見つかっている。タイプIインターフェロンはすべてIFNAR（IFNAR1とIFNAR2に分けられる）という細胞表面の特異的な受容体複合体に結合する。

IFN typeⅡ

IFN-γのみからなる。成熟したIFNγは反対向きに結合したホモ二量体でIFNγ受容体複合体（IFNGR：サブユニットIFNGR1とIFNGR2の1個ずつからなる）に結合する。

IFN typeⅢ

IFN-λで3つのアイソフォーム（IFN-λ1、IFN-λ2、IFN-λ3）からなる。これらは発見当初インターロイキンIL28A、IL28B、IL29としても命名された。

作用機序

ウイルスの感染や2本鎖RNAなどによって直接誘導されることが知られている。これらの細胞外での受容体としてはToll様受容体（TLR）でその中でもエンドソームに存在するTLR3、TLR7、TLR9である。また、細胞内に存在する受容体としてはRIG-I、MDA-5が関与し、これらがI型インターフェロンの発現を高めると考えられる。また体内にいろいろな抗原が侵入したときそれに反応してIL-1、IL-2、IL-12、TNF、CSFなどのサイトカインが産生される。インターフェロンの産生はこれらのサイトカインによっても誘導される。

インターフェロンにより調節される細胞内シグナル伝達経路の代表的なものとしてはJAK-STAT経路が知られるが、それ以外の経路も関与していると考えられる。

インターフェロンαとβはリンパ球（T細胞、B細胞）、マクロファージ、線維芽細胞、血管内皮細胞、骨芽細胞など多くのタイプの細胞で産生され特に抗ウイルス応答の重要な要素である（詳しくはI型インターフェロンの項を参照）。インターフェロンαとβはマクロファージとNK細胞をともに刺激し、腫瘍細胞に対しても直接的に増殖抑制作用を示す。

インターフェロンγは活性化されたT細胞で産生され免疫系と炎症反応に対して調節作用を有する。IFN-γにも抗ウイルス作用と抗腫瘍作用があるが弱く、その代わりIFN-αとβの効果を増強する作用がある。IFN-γは腫瘍のある局所で働く必要があり、がん治療への有効性は低い。IFN-γはTh1細胞からも分泌され、白血球を感染局所にリクルートして炎症を強化する作用がある。またマクロファージを刺激して細菌を貪食殺菌させる。Th1細胞から分泌されたIFN-γはTh2反応を調節する作用でも重要である。免疫応答の調節にも関わっており、過剰な産生は自己免疫疾患につながる可能性がある。IFN-ωは白血球からウイルス感染または腫瘍の局所で分泌される。

医薬品

インターフェロンはかつては希少で高価だったが、遺伝子操作により細菌や培養細胞での大量生産が可能になった。現在医薬品として多くのインターフェロンが承認され、B型肝炎・C型肝炎などのウイルス性肝炎、またいくつかの腫瘍の治療や白血病の治療に用いられている。

種類

IFNα

スミフェロン®：腎癌・多発性骨髄腫・慢性骨髄性白血病・ヘアリー細胞白血病・亜急性硬化性全脳炎・HTLV-1脊髄症・B型肝炎・C型肝炎
オーアイエフ®：慢性骨髄性白血病・B型肝炎・C型肝炎

IFNα2b

イントロンA®：B型肝炎・C型肝炎

PEG-IFNα2a

ペガシス®：B型肝炎・C型肝炎

PEG-IFNα2b

ペグイントロン®：C型肝炎

C-IFNα

アドバフェロン®：C型肝炎

IFNβ

IFN®：膠芽腫・髄芽腫・星細胞腫・悪性黒色腫・亜急性硬化性全脳炎・B型肝炎・C型肝炎
フエロン®：膠芽腫・髄芽腫・星細胞腫・悪性黒色腫・亜急性硬化性全脳炎・B型肝炎・C型肝炎

IFNβ1a

アボネックス®：多発性硬化症

IFNβ1b

ベタフェロン®：多発性硬化症

IFNγ1a

イムノマックス®：腎癌・慢性肉芽腫症

IFNγn1

オーガンマ®：菌状息肉症・成人T細胞性白血病

副作用

副作用としては発熱、だるさ、疲労、頭痛、筋肉痛、けいれんなどのインフルエンザ様症状、また投与部位の紅斑、痛み、痒みが多い。まれに脱毛、蛋白尿、めまいや抑鬱もある。

多くの症状は可逆的で治療終了後数日で回復する。しかし重篤なものとして間質性肺炎・抑鬱による自殺がある。また、小柴胡湯との併用で間質性肺炎が起こりやすいので併用は禁忌である。

外部リンク

肝炎に効果的なインターフェロン治療や核酸アナログ製剤治療利用しやすくするための医療費助成制度をご存じですか - 政府広報オンライン

学術団体

日本インターフェロン・サイトカイン学会

この項目は、薬学に関連した書きかけの項目です。この項目を加筆・訂正などしてくださる協力者を求めています（プロジェクト:薬学／Portal:医学と医療）。

wiki en

[Wiki en表示]

Interferons (IFNs) are a group of signaling proteins^[1] made and released by host cells in response to the presence of several pathogens, such as viruses, bacteria, parasites, and also tumor cells. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

IFNs belong to the large class of proteins known as cytokines, molecules used for communication between cells to trigger the protective defenses of the immune system that help eradicate pathogens.^[2] Interferons are named for their ability to "interfere" with viral replication^[2] by protecting cells from virus infections. IFNs also have various other functions: they activate immune cells, such as natural killer cells and macrophages; they increase host defenses by up-regulating antigen presentation by virtue of increasing the expression of major histocompatibility complex (MHC) antigens. Certain symptoms of infections, such as fever, muscle pain and "flu-like symptoms", are also caused by the production of IFNs and other cytokines.

More than twenty distinct IFN genes and proteins have been identified in animals, including humans. They are typically divided among three classes: Type I IFN, Type II IFN, and Type III IFN. IFNs belonging to all three classes are important for fighting viral infections and for the regulation of the immune system.

Types of interferon

Based on the type of receptor through which they signal, human interferons have been classified into three major types.

Interferon type I: All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α/β receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains.^[3] The type I interferons present in humans are IFN-α, IFN-β, IFN-ε, IFN-κ and IFN-ω.^[4] In general, type I interferons are produced when the body recognizes a virus has invaded it. They are produced by fibroblasts and monocytes. However, the production of type I IFN-α is prohibited by another cytokine known as Interleukin-10. Once released, type I interferons will activate molecules which prevent the virus from producing and replicating its RNA and DNA. Overall, IFN-α can be used to treat hepatitis B and C infections, while IFN-β can be used to treat multiple sclerosis.^[2]
Interferon type II (IFN-γ in humans): This is also known as immune interferon and is activated by Interleukin-12.^[2] Furthermore, type II interferons are released by T helper cells, type 1 specifically. However, they block the proliferation of T helper cells type two. The previous results in an inhibition of T_h2 immune response and a further induction of T_h1 immune response, which leads to the development of debilitating diseases such as multiple sclerosis.^[5] IFN type II binds to IFNGR, which consists of IFNGR1 and IFNGR2 chains and has a different receptor than type I IFN.^[2]
Interferon type III: Signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12). Although discovered more recently than type I and type II IFNs,^[6] recent information demonstrates the importance of Type III IFNs in some types of virus infections.^[7]^[8]

In general, type I and II interferons are responsible for regulating and activating the immune response.^[2] Expression of type I and III IFNs can be induced in virtually all cell types upon recognition of viral components, especially nucleic acids, by cytoplasmic and endosomal receptors, whereas type II interferon is induced by cytokines such as IL-12, and its expression is restricted to immune cells such as T cells and NK cells.

Function

All interferons share several common effects: they are antiviral agents and they modulate functions of the immune system. Administration of Type I IFN has been shown to inhibit tumor growth in experimental animals, but the beneficial action in human tumors has not been widely documented. A virus-infected cell releases viral particles that can infect nearby cells. However, the infected cell can prepare neighboring cells against a potential infection by the virus by releasing interferons. In response to interferon, cells produce large amounts of an enzyme known as protein kinase R (PKR). This enzyme phosphorylates a protein known as eIF-2 in response to new viral infections; the phosphorylated eIF-2 forms an inactive complex with another protein, called eIF2B, to reduce protein synthesis within the cell. Another cellular enzyme, RNAse L—also induced by interferon action—destroys RNA within the cells to further reduce protein synthesis of both viral and host genes. Inhibited protein synthesis destroys both the virus and infected host cells. In addition, interferons induce production of hundreds of other proteins—known collectively as interferon-stimulated genes (ISGs)—that have roles in combating viruses and other actions produced by interferon.^[9]^[10] They also limit viral spread by increasing p53 activity, which kills virus-infected cells by promoting apoptosis.^[11]^[12] The effect of IFN on p53 is also linked to its protective role against certain cancers.^[11]

Another function of interferons is to upregulate major histocompatibility complex molecules, MHC I and MHC II, and increase immunoproteasome activity. Higher MHC I expression increases presentation of viral peptides to cytotoxic T cells, while the immunoproteasome processes viral peptides for loading onto the MHC I molecule, thereby increasing the recognition and killing of infected cells. Higher MHC II expression increases presentation of viral peptides to helper T cells; these cells release cytokines (such as more interferons and interleukins, among others) that signal to and co-ordinate the activity of other immune cells.

Interferons, such as interferon gamma, directly activate other immune cells, such as macrophages and natural killer cells.

Induction of interferons

Production of interferons occurs mainly in response to microbes, such as viruses and bacteria, and their products. Binding of molecules uniquely found in microbes—viral glycoproteins, viral RNA, bacterial endotoxin (lipopolysaccharide), bacterial flagella, CpG motifs—by pattern recognition receptors, such as membrane bound Toll like receptors or the cytoplasmic receptors RIG-I or MDA5, can trigger release of IFNs. Toll Like Receptor 3 (TLR3) is important for inducing interferons in response to the presence of double-stranded RNA viruses; the ligand for this receptor is double-stranded RNA (dsRNA). After binding dsRNA, this receptor activates the transcription factors IRF3 and NF-κB, which are important for initiating synthesis of many inflammatory proteins. RNA interference technology tools such as siRNA or vector-based reagents can either silence or stimulate interferon pathways.^[13] Release of IFN from cells (specifically IFN-γ in lymphoid cells) is also induced by mitogens. Other cytokines, such as interleukin 1, interleukin 2, interleukin-12, tumor necrosis factor and colony-stimulating factor, can also enhance interferon production.^[14]

Downstream signaling

By interacting with their specific receptors, IFNs activate signal transducer and activator of transcription (STAT) complexes; STATs are a family of transcription factors that regulate the expression of certain immune system genes. Some STATs are activated by both type I and type II IFNs. However each IFN type can also activate unique STATs.^[15]

STAT activation initiates the most well-defined cell signaling pathway for all IFNs, the classical Janus kinase-STAT (JAK-STAT) signaling pathway.^[15] In this pathway, JAKs associate with IFN receptors and, following receptor engagement with IFN, phosphorylate both STAT1 and STAT2. As a result, an IFN-stimulated gene factor 3 (ISGF3) complex forms—this contains STAT1, STAT2 and a third transcription factor called IRF9—and moves into the cell nucleus. Inside the nucleus, the ISGF3 complex binds to specific nucleotide sequences called IFN-stimulated response elements (ISREs) in the promoters of certain genes, known as IFN stimulated genes ISGs. Binding of ISGF3 and other transcriptional complexes activated by IFN signaling to these specific regulatory elements induces transcription of those genes.^[15] A collection of known ISGs is available on Interferome, a curated online database of ISGs (www.interferome.org);^[16] Additionally, STAT homodimers or heterodimers form from different combinations of STAT-1, -3, -4, -5, or -6 during IFN signaling; these dimers initiate gene transcription by binding to IFN-activated site (GAS) elements in gene promoters.^[15] Type I IFNs can induce expression of genes with either ISRE or GAS elements, but gene induction by type II IFN can occur only in the presence of a GAS element.^[15]

In addition to the JAK-STAT pathway, IFNs can activate several other signaling cascades. For instance, both type I and type II IFNs activate a member of the CRK family of adaptor proteins called CRKL, a nuclear adaptor for STAT5 that also regulates signaling through the C3G/Rap1 pathway.^[15] Type I IFNs further activate p38 mitogen-activated protein kinase (MAP kinase) to induce gene transcription.^[15] Antiviral and antiproliferative effects specific to type I IFNs result from p38 MAP kinase signaling. The phosphatidylinositol 3-kinase (PI3K) signaling pathway is also regulated by both type I and type II IFNs. PI3K activates P70-S6 Kinase 1, an enzyme that increases protein synthesis and cell proliferation; phosphorylates of ribosomal protein s6, which is involved in protein synthesis; and phosphorylates a translational repressor protein called eukaryotic translation-initiation factor 4E-binding protein 1 (EIF4EBP1) in order to deactivate it.^[15]

Virus resistance to interferons

Many viruses have evolved mechanisms to resist interferon activity.^[17] They circumvent the IFN response by blocking downstream signaling events that occur after the cytokine binds to its receptor, by preventing further IFN production, and by inhibiting the functions of proteins that are induced by IFN.^[18] Viruses that inhibit IFN signaling include Japanese Encephalitis Virus (JEV), dengue type 2 virus (DEN-2) and viruses of the herpesvirus family, such as human cytomegalovirus (HCMV) and Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8).^[18]^[19] Viral proteins proven to affect IFN signaling include EBV nuclear antigen 1 (EBNA1) and EBV nuclear antigen 2 (EBNA-2) from Epstein-Barr virus, the large T antigen of Polyomavirus, the E7 protein of Human papillomavirus (HPV), and the B18R protein of vaccinia virus.^[19]^[20] Reducing IFN-α activity may prevent signaling via STAT1, STAT2, or IRF9 (as with JEV infection) or through the JAK-STAT pathway (as with DEN-2 infection).^[18] Several poxviruses encode soluble IFN receptor homologs—like the B18R protein of the vaccinia virus—that bind to and prevent IFN interacting with its cellular receptor, impeding communication between this cytokine and its target cells.^[20] Some viruses can encode proteins that bind to double-stranded RNA (dsRNA) to prevent the activity of RNA-dependent protein kinases; this is the mechanism reovirus adopts using its sigma 3 (σ3) protein, and vaccinia virus employs using the gene product of its E3L gene, p25.^[21]^[22]^[23] The ability of interferon to induce protein production from interferon stimulated genes (ISGs) can also be affected. Production of protein kinase R, for example, can be disrupted in cells infected with JEV ^[18] Some viruses escape the anti-viral activities of interferons by gene (and thus protein) mutation. The H5N1 influenza virus, also known as bird flu, has resistance to interferon and other anti-viral cytokines that is attributed to a single amino acid change in its Non-Structural Protein 1 (NS1), although the precise mechanism of how this confers immunity is unclear.^[24]

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 is effective for reducing attacks in relapsing-remitting multiple sclerosis and slowing disease progression and activity in secondary progressive multiple sclerosis.^[25]

Interferon therapy is used (in combination with chemotherapy and radiation) as a treatment for some cancers.^[26] This treatment can be used in hematological malignancy; leukemia and lymphomas including hairy cell leukemia, chronic myeloid leukemia, nodular lymphoma, and cutaneous T-cell lymphoma.^[26] Patients with recurrent melanomas receive recombinant IFN-α2b.^[27] Both hepatitis B and hepatitis C are treated with IFN-α, often in combination with other antiviral drugs.^[28]^[29] Some of those treated with interferon have a sustained virological response and can eliminate hepatitis virus. The most harmful strain—hepatitis C genotype I virus—can be treated with a 60-80% success rate with the current standard-of-care treatment of interferon-α, ribavirin and recently approved protease inhibitors such as Telaprevir (Incivek) May 2011, Boceprevir (Victrelis) May 2011 or the nucleotide analog polymerase inhibitor Sofosbuvir (Sovaldi) December 2013.^[30] Biopsies of patients given the treatment show reductions in liver damage and cirrhosis. Some evidence shows giving interferon immediately following infection can prevent chronic hepatitis C, although diagnosis early in infection is difficult since physical symptoms are sparse in early hepatitis C infection. Control of chronic hepatitis C by IFN is associated with reduced hepatocellular carcinoma.^[31]

Interferon treatment was evaluated in individuals suffering from herpes simplex virus epithelial keratitis. Topical interferon therapy was shown to be an effective treatment, especially with higher concentrations.^[32] Interferon, either used alone or in combination with debridement, appears to be as effective as a nucleoside antiviral agent.^[32] The combination of interferon and another nucleoside antiviral agent may speed the healing process.^[32]

When used in the systemic therapy, IFNs are mostly administered by an intramuscular injection. The injection of IFNs in the muscle or under 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 on the spot of injection are also frequently observed. IFN therapy causes immunosuppression, in particular through neutropenia and can result in some infections manifesting in unusual ways.^[33]

Drug formulations

Pharmaceutical forms of interferons
Generic name	Trade name
Interferon alpha 2a	Roferon A
Interferon alpha 2b	Intron A/Reliferon/Uniferon
Human leukocyte Interferon-alpha (HuIFN-alpha-Le)	Multiferon
Interferon beta 1a, liquid form	Rebif
Interferon beta 1a, lyophilized	Avonex
Interferon beta 1a, biogeneric (Iran)	Cinnovex
Interferon beta 1b	Betaseron / Betaferon
Interferon gamma 1b	Actimmune
PEGylated interferon alpha 2a	Pegasys
PEGylated interferon alpha 2a (Egypt)	Reiferon Retard
PEGylated interferon alpha 2b	PegIntron
PEGylated interferon alpha 2b plus ribavirin (Canada)	Pegetron

Several different types of interferons are now approved for use in humans. For example, in January 2001, the Food and Drug Administration (FDA) approved the use of PEGylated interferon-alpha in the USA; in this formulation, polyethylene glycol is linked to the interferon molecule to make the interferon last longer in the body. Initially used for PEGylated interferon-alpha-2b (Pegintron), 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).^[34]^[35]^[36] Interferon-containing regimens may also include protease inhibitors such as boceprevir and telaprevir.

History

Sidney Pestka of Rutgers University, seen here receiving the National Medal of Technology, is sometimes referred to as the "father of interferon"

Interferons were first described in 1957 by Alick Isaacs and Jean Lindenmann at the National Institute for Medical Research in London;^[37]^[38]^[39] 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.^[38] The findings of Isaacs and Lindenmann have been widely confirmed and corroborated in the literature.^[40]

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.^[41] 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).^[42] 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.^[43]^[44]^[45] The purification of human beta interferon did not occur until 1977. Chris 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.^[46]^[47] Tan's laboratory isolated sufficient amounts of human beta interferon to perform the first amino acid, sugar composition and N-terminal analyses.^[48] 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.^[48]^[49]^[50]^[51] 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.^[39] By the early 1980s, genes for these interferons had been cloned, adding further definitive proof that interferons were responsible for interfering with viral replication.^[52]^[53] Gene cloning also confirmed that IFN-α was encoded by a family of many related genes.^[54] The type II IFN (IFN-γ) gene was also isolated around this time.^[55]

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^[56] or derived from yeasts. Interferon can also be produced by recombinant mammalian cells.^[57] 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.^[58] Large amounts of human beta interferon were made by superinducing the beta interferon gene in human fibroblast cells.^[59]^[60]

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

^[4]^[61]

References

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UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. Principles of interferon therapy in liver disease and the induction of autoimmunity
2. Interferon alfa for the treatment of chronic myeloid leukemia
3. 慢性B型肝炎ウイルス感染に対する従来型インターフェロンおよびペグインターフェロン standard and pegylated interferon for chronic hepatitis b virus infection
4. インターフェロンα + リバビリン療法関連の神経精神学的副作用：治療および予防 neuropsychiatric side effects associated with interferon alfa plus ribavirin therapy treatment and prevention
5. C型肝炎治療のためのインターフェロン＋リバビリン療法関連の神経精神学的副作用：認知と危険因子 neuropsychiatric side effects associated with interferon plus ribavirin for treatment of hepatitis c recognition and risk factors

English Journal

Thalidomide with peginterferon alfa-2b and ribavirin in the treatment of non-responders genotype 1 chronic hepatitis C patients: proof of concept.

B Pardo-Yules, R Gallego-Durán, M Eslam, C García-Collado, L Grande, C Paradas, R Morillo, B Dorantes, M Romero-Gómez.AbstractBackground: fewer than half of patients infected with hepatitis C virus (HCV) achieve sustained viral clearance after peginterferon alfa/ribavirin (Peg-IFN/RBV) therapy.Aims: thalidomide posses anti-inflammatory and immunomodulatory properties through inhibition of tumor necrosis factor and costimulatory effect on human CD8+ T cells.Methods: we started a prospective, open label trial of retreatment of very-difficult-to-treat genotype 1 chronic hepatitis C patients (CHC) patients, who had failed to respond to the (Peg-IFN/RBV), with a triple therapy consisting in these same antivirals plus thalidomide 200 mg/day (the TRITAL study).Results: none of the eleven patients fulfilling the inclusion criteria and included in the trial reached complete early virological response or sustained virological response. Viral load decline after 12 weeks of triple therapy thalidomide-based retreatment did not differ from viral dynamics during the first course. The triple therapy was well tolerated and only one patient developed mild bilateral neuropathy.Conclusions: thalidomide addition to standard therapy is tolerated and did not increase the SVR rate in very-difficult-to-treat genotype 1 CHC patients. Different schedules are warranted to improve attempting retreatment of non responder CHC patients.
Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva.Rev Esp Enferm Dig.2012 Dec;103(12):619-625.
Background: fewer than half of patients infected with hepatitis C virus (HCV) achieve sustained viral clearance after peginterferon alfa/ribavirin (Peg-IFN/RBV) therapy.Aims: thalidomide posses anti-inflammatory and immunomodulatory properties through inhibition of tumor necrosis factor and costimul
PMID 22217345

A sulfated polysaccharide, fucoidan, enhances the immunomodulatory effects of lactic acid bacteria.

Kawashima T, Murakami K, Nishimura I, Nakano T, Obata A.SourceResearch and Development Division, Kikkoman Corporation, 399 Noda, Noda City, Chiba 278-0037, Japan.
International journal of molecular medicine.Int J Mol Med.2012 Mar;29(3):447-53. doi: 10.3892/ijmm.2011.854. Epub 2011 Dec 5.
Fucoidan, a sulfated polysaccharide contained in brown algae, has a variety of immunomodulatory effects, including antitumor and antiviral effects. On the other hand, lactic acid bacteria (LAB) also have immunomodulatory effects such as anti-allergic effects. In t
PMID 22160132

Newcastle disease virus induces pro-inflammatory conditions and type I interferon for counter-acting Treg activity.

Fournier P, Arnold A, Wilden H, Schirrmacher V.SourceGerman Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
International journal of oncology.Int J Oncol.2012 Mar;40(3):840-50. doi: 10.3892/ijo.2011.1265. Epub 2011 Nov 16.
Newcastle disease virus (NDV) is a negative sense RNA paramyxovirus of birds which in human tumor cells, in contrast to human non-tumor cells, has shown replication competence leading to tumor cell death (i.e., tumor selectivity and viral oncolysis). Our study dem
PMID 22102168

Japanese Journal

B型肝炎に対する新薬開発の最新情報 (第1土曜特集 B型肝炎 : 最新治療コンセンサス2012) -- (治療の最新情報)

大石和佳,茶山一彰
医学のあゆみ 242(5), 460-464, 2012-08-04
NAID 40019355942

B型急性肝炎に対する抗ウイルス治療 (第1土曜特集 B型肝炎 : 最新治療コンセンサス2012) -- (治療の最新情報)

黒崎雅之
医学のあゆみ 242(5), 409-413, 2012-08-04
NAID 40019355845

Related Pictures

★リンクテーブル★

リンク元	「肝炎」「インターフェロン」「リポ多糖」「サイトカイン療法」
拡張検索	「IFN-beta」「IFN-β」「IFN-α」「IFN-gamma production」
関連記事	「I」「IF」

「肝炎」

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Interferon alpha/beta domain
	The molecular structure of human interferon-alpha
Identifiers
Symbol	Interferons
Pfam	PF00143
InterPro	IPR000471
PROSITE	PDOC00225
SCOP	1au1
SUPERFAMILY	1au1
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

　　[★]

英: hepatitis
関: 肝炎ウイルス、肝臓の病理

概念

肝臓に炎症を生じた状態

疫学

B型肝炎：感染者数は約110～140万人、患者数は約7万人(慢性肝炎：約5万人、肝硬変・肝がん：約2万人)　(参考1)
C型肝炎：感染者数は約190～230万人、患者数は約37万人(慢性肝炎：28万人、肝硬変・肝がん：約9万人)　(参考1)　　→　　肝細胞癌の80%がC型肝炎ウイルスによる

病因

薬物性
アルコール性
細菌性
ウイルス性
自己免疫性

病理

肝臓の病理

細菌

ウイルス

A型肝炎：A型肝炎ウイルス：ピコルナウイルス科ヘパト属

形態･増殖などピコルナウイルス参考
他のピコルナウイルスと異なり細胞培養では､ CPEを起こさない｡
感染経路:主に経口､糞便にウイルスを排世
発熱を伴う｡慢性化しない｡
予防:A型肝炎ワクチン(不活化ワクチン)

B型肝炎：B型肝炎ウイルス：ヘパドナウイルス(Hepadona)

逆転等酵素を有するDNAウイルス｡エンベロープあり｡
抗HBs抗体一中和抗体･感染防止抗体　　B型肝炎ワクチンによる予防　　3TC
感染経路:血液､体液､垂直感染　慢性化　約10%
Gianotti病(extrahepatic)

C型肝炎：C型肝炎ウイルス：約10K b､ +鎖ssRNA

感染経路:血液体液､
慢性化:50-70%
インターフェロン療法HCV I FN昔効例全体で約30%
日-t V型　f FN曹効例　2a60%､ 2b45%､日本で多い1b15%)

D型肝炎:D型肝炎ウイルス：1 . 7K bRNA

HBVと同時に感染する｡
Rib ozyme活性(RNAがRNAを切断)
慢性化

E型肝炎：E型肝炎ウイルス：7.6K bRNA　+戟

E nterically-transmitted､ E ndemic
RNAウイルス
妊婦での死亡率高い(10-20%)他　　　(HAV　約0-1%)
人畜共通感染症(豚､イノシシ､鹿)

G型肝炎　肝炎との関連は当初考えられたほど高くない
TTV　　　1本鎖(-)DNA9歳以下8%､ 10-20代50%、30代以降70%以上感染者
サイトメガロウイルス、アデノウイルス、EBウイルス、水痘・帯状疱疹ウイルス、単純ヘルペスウイルス、B19ウイルスなど

肝炎ウイルスまとめ

肝炎ウイルス.xls

感染症		A型肝炎	B型肝炎	C型肝炎	D型肝炎	E型肝炎
ウイルス		HAV	HBV	HCV	HDV	HEV
科		ピコルナウイルス科	ヘパドナウイルス科	フラビウイルス科	未分類	ヘペウイルス科
属		ヘパトウイルス属	オルソヘパドナ属	ヘパシウイルス属	デルタウイルス属	ヘペウイルス属
ゲノム		ssRNA+	dsDNA	ssRNA+	ssRNA-	ssRNA+
エンベロープ		-	+	+	+	-
逆転写酵素		-	+	-	-	-
潜伏期	文献1	15-40days	50-180days	1-5months	21-90days	2-9weeks
	文献2	約4週	1-6ヶ月	平均6-8週	平均7週	平均5-6週

type of onset		急性	潜行性	潜行性	急性	急性
前駆症状			関節炎、皮疹	関節炎、皮疹
感染経路	経口・糞光	○	無	無	無	○
	非腸管	稀	○	○	○	無
	その他	食物、水	性的接触、周産期感染。血液、体液、垂直感染	性的接触(稀)。血液、体液	性的接触(稀)	水
後遺症	キャリアー	×	○(約10%)	○(約50-70%)	○(重複感染:2-20%)	×
	慢性肝炎	×	○	○	○	×
	肝硬変→肝細胞癌	×	2.5-3 %/年	5-7 %/年		×
劇症肝炎		0.1%	0.2　％	0.2　％		0.3-5.0%
死亡率		0.1-0.2%	0.5-2.0%(健常者)	1-2%(健常者)	2-20%	2%(一般)。20%(妊婦)
発熱		○	?	?	?	?
予防		A型肝炎ワクチン(不活化)	B型肝炎ワクチン(成分, HBs抗原)、HBIG	なし	B型肝炎ワクチン(成分, HBs抗原)	ワクチン
治療		なし	IFN ラミブジンアデフォビルエンテカビルテルビブジン	INF+リバビリン IFN(著効率：30%。2a 60%, 2b 45%, 1b 15%)	IFN？	なし
その他		CPEなし	Gianotti病		HBVと同時感染、Ribozyme活性	風土病。人獣共通感染症(豚､イノシシ､鹿)

参考

1. 肝炎対策の経緯と今後 ―B 型肝炎訴訟・C 型肝炎訴訟を中心に― 国立国会図書館 ISSUE BRIEF NUMBER 702(2011. 2.22.)

2011年以前までの状況がサマリーしてあってよい

http://www.ndl.go.jp/jp/data/publication/issue/pdf/0702.pdf

2. 肝炎総合対策の推進 - 健康局疾病対策課肝炎対策推進室

http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou09/index.html

「インターフェロン」

　　[★]

英: interferon interferons IFN
商: オーアイエフ、ＩＦＮβモチダ、アドバフェロン、アボネックス、イムノマックス-γ、イントロンＡ、スミフェロン、フエロン、ベタフェロン、ペガシス、ペグイントロン

概念

サイトカインの一種で抗ウイルス作用、免疫修飾作用、抗増殖活性を有する。(GOO.1261)

種類

I型インターフェロン

ウイルスに感染して誘導され、強い抗ウイルス作用を有する

II型インターフェロン

非ウイルス誘導性

表(SMB.426)

		産生細胞	種類	誘発因子	作用
I型インターフェロン	IFN-α	好中球、マクロファージなど	14種類以上	ウイルス、細菌内毒素	抗ウイルス効果、抗腫瘍効果
I型インターフェロン	IFN-β	線維芽細胞、上皮細胞など	1種類	ウイルス、2本鎖RNA	抗ウイルス効果、抗腫瘍効果
II型インターフェロン	IFN-γ	T細胞、NK細胞など	1種類	抗原刺激、サイトカイン	免疫細胞の活性化、免疫系の制御

各インターフェロンについて

GOO.1261

インターフェロンα、インターフェロンβ

ウイルス感染に対する非特異的な初期防御に関わる
意義：ウイルス感染に対する非特異的な初期防御に関わる
産生細胞：ほとんど全ての細胞
産生のトリガー：二本鎖RNA、ある種のサイトカイン(IL-1, IL-2, TNF)
作用：抗ウイルス作用、抗増殖作用：(1) リンパ球、NK細胞、およびマクロファージの細胞障害作用の亢進、(2) MHC class Iの発現の亢進作用　　←　抗ウイルス活性

インターフェロンγ：

意義：マクロファージの活性化
産生細胞：T細胞、NK細胞、マクロファージのみ！
産生のトリガー：抗原刺激、mitogen、特定のサイトカイン
作用：抗ウイルス作用は弱い。強力な免疫調整作用：(1) マクロファージの強力な活性化、(2) MHC class IIの発現の亢進、(3) 局所炎症反応の仲介(madiation)

インターフェロンの抗ウイルス作用

インターフェロンをシグナルとして受け取った細胞は以下の物質を産生して抗ウイルス作用を発揮する。

適応

B型肝炎
C型肝炎
多発性骨髄腫
(ときに)慢性骨髄性白血病

副作用

発熱	ほぼ必発
甲状腺機能異常	約10%
間質性肺炎	非常に稀
精神症状	約10%
白血球減少	ほぼ必発
血小板減少	ほぼ必発
蛋白尿	約10%
糖尿病	0.1-5%
口腔内病変	約20%
脱毛	約5%
眼底出血	約20%

「リポ多糖」

　　[★]

英: lipopolysaccharide, LPS
同: リポ多糖類、リポポリサッカライド

エンドトキシン endotoxinである

主にマクロファージを刺激して多彩な生理作用を表す

グラム陰性菌の細胞成分
O抗原多糖体-Rコア-リピドA

LPSの生物活性 (SMB.115-117)

1. B細胞マイトジェン活性：B細胞の分裂を誘導

DNA合成の促進

2. ポリクローナルB細胞活性化：B細胞を刺激し、抗原非特異的に抗体産生細胞へと分化誘導。IgMクラスの抗体を産生させる。
3. マクロファージの活性化：サイトカイン(IL-1、TNF-α、IFN、コロニー刺激因子(CSF)など)、フリーラジカルを放出させる。
4. 補体の古典的経路、別経路を活性化
5. アラキドン酸代謝経路の刺激：ロイコトリエン、プロスタグランジンの産生亢進
6. 白血球との結合：生体ではLPS投与後1時間目に顆粒球減少(白血球凝集や末梢血管への貯留による)。2-4時間後、急激に白血球増加(骨髄の顆粒球の放出や顆粒球産

生の増加による)

7. 血小板の活性化と破壊：セロトニン、核酸、血小板因子3などを放出。LPSにより破壊されやすい
8. NK細胞やNKT細胞によるIFN-γの産生亢進

リポ多糖の受容体

→リポ多糖受容体=CD14

リポ多糖のクリアランス(SMB.117)

血流に入ったLPSは、LPS結合タンパク質(LBP)や遊離CD14と結合し、ついで血清タンパク質(特に高比重リポタンパク質(HDL)と結合し、速やかに主に肝臓に取り込まれる。肝臓、脾臓などのマクロファージ系の貪食細胞がLPSを捕獲し、比較的長い時間かかって分解するらしい。

リポ多糖の臨床的意義 (SMB.117-118)

エンドトキシンショック

1. マクロファージ、単球、好中球、NK細胞、血管内皮細胞、線維芽細胞などに作用し、TNF、IFN、IL-1、IL-6、IL-8などのサイトカインを誘導
2. 1.のサイトカインは、標的細胞に作用し、血小板活性化因子(PAF)、ロイコトリエン、プロスタグランジン、活性酸素、NO、プロテアーゼなどを放出させる。
3. 発熱、悪寒、白血球減少、DIC、出血、低血圧、頻脈、アシドーシス、多臓器障害、多臓器不全をもたらす。

抗生物質誘発内毒素遊離

内毒素は菌が増殖するときに、外膜より遊離。
ある種の抗生物質は菌を殺す際、大量の内毒素の遊離を招く

検査

リムルステスト

「サイトカイン療法」

　　[★]

英: cytokine therapy, cytokine-based therapy
関: 免疫療法、サイトカイン

免疫担当細胞産生するサイトカインにより抗悪性腫瘍作用を期待する治療。
IL-2

IFN

TNF

IL-12

参考

1.

http://ganjoho.jp/public/dia_tre/treatment/immunotherapy.html#prg5_1

「IFN-beta」

　　[★]

インターフェロンβ

関: beta-interferon、interferon-beta

「IFN-β」

　　[★] インターフェロンβ、インターフェロンベータ

「IFN-α」

　　[★] インターフェロンα

同: interferon-a

「IFN-gamma production」

　　[★]

インターフェロンγ産生

「I」

　　[★]

「IF」

　　[★]

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匿名

検索

案内

IFN