{"id":10331,"date":"2020-04-23T05:03:15","date_gmt":"2020-04-23T02:03:15","guid":{"rendered":"https:\/\/www.synevo.ro\/product\/analiza-polimorfismului-genei-interleukinei-28b-il-28b\/"},"modified":"2025-01-30T15:31:20","modified_gmt":"2025-01-30T13:31:20","slug":"analiza-polimorfismului-genei-interleukinei-28b-il-28b","status":"publish","type":"product","link":"https:\/\/old.synevo.md\/ru\/shop\/analiza-polimorfismului-genei-interleukinei-28b-il-28b\/","title":{"rendered":"\u0410\u043d\u0430\u043b\u0438\u0437 \u043f\u043e\u043b\u0438\u043c\u043e\u0440\u0444\u0438\u0437\u043c\u0430 \u0433\u0435\u043d\u0430 \u0438\u043d\u0442\u0435\u0440\u043b\u0435\u0439\u043a\u0438\u043d\u0430 28B (IL-28B)"},"content":{"rendered":"

\u041e\u0431\u0449\u0430\u044f \u0438\u043d\u0444\u043e\u0440\u043c\u0430\u0446\u0438\u044f<\/em><\/strong><\/span><\/p>\n

Terapia standard \u00een infec\u0163ia cronic\u0103 cu virusul hepatitei C (HCV) const\u0103 \u00een admistrarea combinat\u0103 de interferon alfa pegylat<\/em> \u0438 ribavirina<\/em>. Cu toate acestea, numai 40% dintre pacien\u0163ii infec\u0163ati cu genotipul 1 HCV \u2013 cel mai frecvent genotip din Europa, America de Nord \u015fi Japonia \u2013 prezint\u0103 o eradicare a virusului \u00een urma acestui tratament (r\u0103spuns virusologic sus\u0163inut, SVR, la 6 luni de la \u00eencheierea terapiei). Mai mult, terapia este asociat\u0103 cu o toxicitate considerabil\u0103. Din aceste motive, identificarea pacien\u0163ilor ce prezint\u0103 \u015fanse mai mari de a r\u0103spunde la tratment ar putea aduce un beneficiu clinic important.<\/span><\/p>\n

Studiile au dovedit c\u0103 anumi\u0163i factori ce \u0163in de virus sau de organismul gazd\u0103 exercit\u0103 o influen\u0163\u0103 asupra r\u0103spunsului la terapia antiviral\u0103 combinat\u0103. Ace\u015ftia includ: nivelul viremiei bazale, v\u00e2rsta, sexul, indicele de mas\u0103 corporal\u0103 (BMI), rezisten\u0163a la insulin\u0103, steatoza hepatic\u0103 \u015fi fibroza hepatic\u0103. Originea afro-american\u0103 este un factor cu valoare predictiv negativ\u0103 pentru SVR. Rata de sc\u0103dere a ARN-ului viral plasmatic \u00een cursul tratamentului, r\u0103spunsul virusologic rapid (RVR, la 4 s\u0103pt\u0103m\u00e2ni de tratament) \u015fi r\u0103spunsul virusologic precoce (EVR, la 12 s\u0103pt\u0103m\u00e2ni) sunt de asemenea elemente importante cu valoare predictiv\u0103 asupra evolu\u0163iei terapeutice. Pe de alt\u0103 parte, rolul determinan\u0163ilor genetici ai r\u0103spunsului la tratament nu este suficient cunoscut1<\/sup>.<\/span><\/p>\n

Recent, \u00een urma unor studii largi de asociere la nivelul genomului uman a fost identificat un polimorfism nucleotidic unic (SNP) situat \u00een regiunea promotorului IL28B, la 3 kb \u00een amonte de gena IL28B (rs12979860) ce a fost asociat cu o diferen\u0163\u0103 semnificativ\u0103 \u00een ratele de SVR la pacien\u0163ii infecta\u0163i cu HCV tip 1 de origine european\u0103, afro-american\u0103 \u015fi hispanic\u0103. In acest sens, purt\u0103torii genotipului CC prezint\u0103 o rat\u0103 de succes a tratamentului de 2-3 ori mai mare \u00een compara\u0163ie cu purt\u0103torii genotipurilor TT sau CT (55-80% vs 20-40%)4<\/sup>. Importan\u0163a acestei regiuni genetice ca determinant al r\u0103spunsului la tratmentul antiviral standard a fost confirmat\u0103 \u015fi de alte studii independente ale genomului. Printre acestea se num\u0103r\u0103 \u015fi studiul condus de McCarthy \u015fi colaboratorii s\u0103i care a demonstrat c\u0103 genotipul CC reprezint\u0103 factorul predictiv bazal cel mai puternic \u00een ceea ce prive\u015fte r\u0103spunsul la tratament, independent de al\u0163i factori clinici pretratament \u015fi de genotipul HCV8<\/sup>.<\/span><\/p>\n

Pe de alt\u0103 parte, genotipul C\/C a fost asociat \u015fi cu o rat\u0103 de 3 ori mai mare de eliminare spontan\u0103 a virusului10<\/sup>.<\/span><\/p>\n

IL28B \u2013 gena care codific\u0103 interferonul \u03bb3 (INF-\u03bb3) \u2013\u00a0formeaz\u0103 \u00eempreun\u0103 cu IL28A \u015fi IL29 un cluster de gene localizat pe cromozomul 19 (19q13). IL28B este situat\u0103 \u00een amonte \u015fi orientat\u0103 invers fa\u0163\u0103 de IL28A; polimorfismul rs12979860 se g\u0103se\u015fte \u00een amonte de cele dou\u0103 gene, fiind mai apropiat de IL28B (vezi fig. 1<\/em>). INF-\u03bb3 apar\u0163ine familiei INF-\u03bb, \u00eempreun\u0103 cu INF-\u03bb1 \u015fi INF-\u03bb2 ce sunt codificate de IL29 \u015fi respectiv IL28A. Interferonii \u03bb sunt considera\u0163i interferoni de tip 3 \u015fi constituie citokine antivirale endogene potente; prezint\u0103 de asemenea multe caracteristici \u00een comun cu interferonii tip I. Ac\u0163iunile INF-\u03bb sunt mediate printr-un receptor unic, INF- \u03bbR, care are o distribu\u0163ie hepatic\u0103 mai specific\u0103 decat receptorii pentru interferonii tip I ubicuitari. Receptorii prezint\u0103 o cale comun\u0103 de transduc\u0163ie a semnalului prin intermediul Janus-kinazelor \u015fi activatorilor de transcip\u0163ie (JAK-STAT); aceasta va conduce la activarea intranuclear\u0103 a genelor stimulate de interferon. Studiile au ar\u0103tat c\u0103 INF-\u03bb1\/2 prezint\u0103 in vitro<\/em> o activitate antiviral\u0103 \u00eempotriva HCV; de\u015fi efectul este slab comparativ cu cel al INF-alfa este posibil ca \u00een asociere s\u0103 exercite un efect sinergic.<\/span><\/p>\n

Mecanismele biologice prin care polimorfismul IL28B intervine \u00een r\u0103spunsul la terapia antiviral\u0103 \u015fi la clearance-ul spontan al virusului nu sunt cunoscute. Pare plauzabil\u0103 ipoteza c\u0103 acesta ar afecta sistemul INF-\u03bb. Complexitatea interac\u0163iunii dintre HCV \u015fi sistemul imun al gazdei sugereaz\u0103 c\u0103 acest efect ar fi iterativ \u015fi s-ar exercita la mai multe niveluri2;9<\/sup>.<\/span><\/p>\n

\"analiza<\/a><\/span><\/p>\n

Fig. 1 Clusterul de gene IL28B, IL28A, IL29 de pe cromozomul 19 \u015fi localizarea polimorfismului rs12979860<\/em><\/span><\/p>\n

(Adaptare dup\u0103 Ashwin Balagopal et al, IL28B and the Control of Hepatitis C Infection)<\/em><\/span><\/p>\n

Ge \u015fi colaboratorii au constatat c\u0103 de\u015fi alelele C sunt asociate cu SVR, \u00een mod paradoxal sunt asociate \u015fi cu niveluri mai \u00eenalte de ARN viral \u00een compara\u0163ie cu alelele T. Niveluri mai mari de ARN HCV au fost observate \u015fi la pacien\u0163i care nu se aflau sub tratament \u015fi care erau purt\u0103tori ai alelei C. De\u015fi diferen\u0163ele nu sunt mari, nivelurile mai mari de ARN HCV la pacien\u0163ii cu genotip C\/C ar putea facilita activarea sistemului imun \u00eenn\u0103scut \u015fi controlul infec\u0163iei \u00een cursul tratamentului. \u00cen plus fa\u0163\u0103 de nivelul bazal de ARN HCV, se pare c\u0103 genotipul IL28B ar influen\u0163a \u015fi cinetica r\u0103spunsului la tratament. Thompson \u015fi colaboratorii au comparat datele de cinetic\u0103 viral\u0103 la 2 s\u0103pt\u0103m\u00e2ni dup\u0103 ini\u0163ierea terapiei antivirale standard la persoanele cu genotip C\/C, C\/T \u015fi T\/T. Indiferent de ras\u0103, subiec\u0163ii cu genotipul C\/C au prezentat cea mai mare rat\u0103 de reducere a nivelurilor de ARN HCV; aceasta se traduce \u00eentr-o rat\u0103 mai mare de RVR \u015fi EVR. Cea mai mare parte a efectului genotipului IL28B este evident \u00een primele 48 ore de la ini\u0163ierea terapiei, indic\u00e2nd faptul c\u0103 polimorfismul ar stimula r\u0103spunsul gazdei la HCV \u015fi ar reduce pragul pentru controlul virusologic. O alt\u0103 ipotez\u0103 este c\u0103 genotipul IL28B ar fi un marker pentru niveluri bazale mai ridicate de interferon.<\/span><\/p>\n

Majoritatea studiilor efectuate ini\u0163ial s-au focalizate pe infec\u0163ia HCV cu genotipul 1; recent, studiile polimorfismului IL28B la pacien\u0163i infecta\u0163i cu alte genotipuri HCV au produs date discordante. Se pare c\u0103 efectul genotipului IL28B asupra r\u0103spunsului la tratament ar putea fi atenuat pentru genotipurile HCV 2 \u015fi 3, \u00eens\u0103 sunt necesare mai multe date pentru a clarifica aceast\u0103 asociere2<\/sup>.<\/span><\/p>\n

Frecven\u0163a alelei C rs12979860 este diferit\u0103 \u00een func\u0163ie de grupul etnic \u015fi rasial. Astfel, alela C este \u00eenregistrat\u0103 cel mai frecvent la persoanele din Asia de Est \u015fi cel mai rar la indivizii de origine african\u0103; frecven\u0163a este intermediar\u0103 \u00een popula\u0163iile caucazian\u0103 \u015fi hispanic\u0103. Aceast\u0103 distribu\u0163ie a alelelor ar putea fi responsabil\u0103 de ratele \u00eenalte de SVR constatate la persoanele est-asiatice. Cu toate acestea, atunci cand polimorfismul a fost studiat cu ajutorul unor modele variate de clearance spontan sau indus de tratament s-a constatat c\u0103 acesta este responsabil doar de ~ 50-60% din diferen\u0163ele etnice \u00een controlul infec\u0163iei HCV. In acest sens, numai 53% din indivizii de ras\u0103 neagr\u0103 cu genotipul C\/C au ob\u0163inut un SVR \u00een compara\u0163ie cu 82% din indivizii de ras\u0103 alb\u0103. Acest fapt demonstreaz\u0103 c\u0103 \u015fi al\u0163i factori genetici \u00een afara polimorfismului IL28B ar media clerance-ul viral, de\u015fi \u00eentr-o popula\u0163ie de anumit\u0103 de origine etnic\u0103 genotipul IL28B are valoare predictiv\u0103 asupra evolu\u0163iei infec\u0163iei2;7<\/sup>.<\/span><\/p>\n

Introducerea agen\u0163ilor antivirali cu ac\u0163iune direct\u0103 (DAAV) reprezint\u0103 cel mai recent progres terapeutic \u00een infec\u0163ia HCV ce va conduce la o \u00eembun\u0103t\u0103\u0163ire semnificativ\u0103 a ratei globale de SVR9<\/sup>. Cele 2 studii \u2013 SPRINT 2 \u015fi RESPOND 2 \u2013 au analizat efectul asupra SVR al ad\u0103ug\u0103rii inhibitorului de proteaz\u0103 Boceprevir (BOC) la terapia antiviral\u0103 standard cu peginterferon<\/em> \u0438 ribavirina<\/em> (P\/R) dup\u0103 primele 4 s\u0103pt\u0103m\u00e2ni de tratament comparativ cu placebo, la dou\u0103 loturi de pacien\u0163i infecta\u0163i cu HCV genotip 1: unul care a inclus pacien\u0163i netrata\u0163i p\u00e2n\u0103 \u00een acel moment (\u201enaivi\u201d), iar cel\u0103lalt care a inclus pacien\u0163i ce nu au ob\u0163inut SVR la o terapie anterioar\u0103 cu P\/R; a fost studiat de asemena \u015fi rolul polimorfimului IL28B. Fiecare din cele dou\u0103 studii s-a desfa\u015furat pe 3 direc\u0163ii de tratament:<\/span><\/p>\n

-1: lotul de control \u2013 4 s\u0103pt\u0103m\u00e2ni de tratament P\/R urmate de 44 s\u0103pt\u0103m\u00e2ni de P\/R + BOC placebo;<\/span><\/div>\n
-2: lotul care a primit BOC, cu o durat\u0103 individualizat\u0103 a tratmentului stabilita \u00een func\u0163ie de detectarea HCV-ARN \u00een s\u0103pt\u0103m\u00e2nile 8-24 (\u201cresponse-guided therapy\u201d);<\/span><\/div>\n
-3: lotul care a primit BOC, cu o durata fix\u0103 a tratmentului \u2013 4 s\u0103pt\u0103m\u00e2ni de tratment P\/R urmate de 44 s\u0103pt\u0103m\u00e2ni de P\/R + BOC.<\/span><\/div>\n

Concluziile<\/span> au fost urm\u0103toarele:<\/span><\/p>\n

    \n
  • genotipul C\/C a fost un factor predictiv puternic pentru r\u0103spunsul virusologic ob\u0163inut la 4 \u015fi 8 s\u0103pt\u0103m\u00e2ni de tratament \u00een ambele studii;<\/span><\/li>\n
  • aproximativ 80-90% dintre pacien\u0163ii \u201enaivi\u201d sau trata\u0163i anterior, purt\u0103tori ai genotipului C\/C, au fost eligibili pentru o durat\u0103 mai scurt\u0103 a tratamentului PR\/BOC;<\/span><\/li>\n
  • r\u0103spunsul precoce \u00een cursul tratamentului cu interferon (\u201clead-in response\u201d la 4 s\u0103pt\u0103mani) constituie un factor predictiv mai puternic pentru SVR decat orice alt\u0103 variabil\u0103 bazal\u0103, inclusiv polimorfismul IL28B; din acest motiv, la pacien\u0163ii cu genotip non-C\/C \u201clead-in response\u201d define\u015fte mai departe probabilitatea SVR;<\/span><\/li>\n
  • polimorfismul IL-28B + \u201clead-in response\u201d sunt factori predictivi puternici pentru SVR3<\/sup>.<\/span><\/li>\n<\/ul>\n

    Integrarea genotipului IL28B \u00een profilul care include alte variabile clinice cum ar fi stadiul de fibroz\u0103, v\u00e2rsta, rezisten\u0163a la insulin\u0103, viremia bazal\u0103 \u015fi rasa poate avea valoare predictiv\u0103 \u00een ceea ce prive\u015fte r\u0103spunsul la tratament \u015fi poate deveni astfel un instrument pentru personalizarea terapiei. Deoarece se preconizeaz\u0103 ca \u00een viitor num\u0103rul op\u0163iunilor terapeutice aceast\u0103 abordare va putea simplifica \u015fi optimiza algoritmurile terapeutice9<\/sup>.<\/span><\/p>\n

    Specimen recoltat<\/em><\/strong> \u2013 s\u00e2nge venos6<\/sup>.<\/span><\/p>\n

    Recipient de recoltare<\/em><\/strong>\u00a0\u2013 vacutainer ce contine EDTA ca anticoagulant6<\/sup>.<\/span><\/p>\n

    Cantitate recoltat\u0103 <\/em><\/strong>\u2013\u00a0 3 mL s\u00e2nge6<\/sup>.<\/span><\/p>\n

    Cauze de respingere<\/em><\/strong> a probei <\/em><\/strong>\u2013 folosirea heparinei ca anticoagulant; probe coagulate sau hemolizate6<\/sup>.<\/span><\/p>\n

    Stabilitate prob\u0103<\/em><\/strong> - 7 zile<\/em> la 2-8\u00baC6<\/sup>.<\/span><\/p>\n

    Metod\u0103<\/em><\/strong> - Real-time PCR (LightCycler)<\/span>: reac\u0163ie de polimerizare \u00een lan\u0163 cu detec\u0163ie \u00een timp real a produsului PCR\u00a0 acumulat, prin m\u0103surarea fluorescen\u0163ei emise; detec\u0163ia se realizeaz\u0103 cu ajutorul unei sonde marcate cu flouresceina (SimpleProbe) care hibridizeaz\u0103 la secven\u0163a \u0163int\u0103 ce con\u0163ine SNP de interes (alela C); la sf\u00e2r\u015fitul ciclurilor de amplificare se efectueaz\u0103 genotiparea, prin analiza curbei de topire6<\/sup>.<\/span><\/p>\n

    Raportarea \u015fi interpretarea rezultatelor<\/em><\/strong><\/span><\/p>\n

    Pentru un pacient, se raporteaz\u0103 unul din cele 3 rezultate posibile:<\/span><\/p>\n

      \n
    • genotip C\/C homozigot;<\/span><\/li>\n
    • genotip C\/T heterozigot;<\/span><\/li>\n
    • genotip T\/T homozigot6<\/sup>.<\/span><\/li>\n<\/ul>\n

      1) Pacien\u0163ii cu genotipul IL28B C\/C au o probabilitate de 80% de a r\u0103spunde la tratamentul antiviral standard. Aceast\u0103 informa\u0163ie poate contribui la cre\u015fterea complian\u0163ei pacien\u0163ilor \u015fi la asigurarea suportului necesar pentru continuarea tratmentului atunci c\u00e2nd apar reac\u0163ii adverse care necesit\u0103 sau nu reducerea dozelor.<\/span><\/p>\n

      2) Este posibil ca pacien\u0163ii cu genotipul favorabil C\/C s\u0103 prezinte o rat\u0103 adecvat\u0103 de SVR la administrarea tratamentului standard pe o perioad\u0103 mai scurt\u0103 (24 s\u0103pt\u0103m\u00e2ni vs. 48 s\u0103pt\u0103m\u00e2ni). Alternativ, ad\u0103ugarea de agen\u0163i antivirali direc\u0163i \u00a0(DAAV) la pacien\u0163ii cu genotip C\/C poate contribui \u015fi mai mult la reducerea duratei de tratment.<\/span><\/p>\n

      3) Pacien\u0163ii cu genotipul 1 HCV care nu au ob\u0163inut un RVR, dar care prezint\u0103 genotipul favorabil C\/C au \u015fansa de 65% de eradicare a infec\u0163iei9<\/sup>.<\/span><\/p>\n

      4) Genotipul C\/C este asociat cu afectare mai redus\u0103 a metabolismului lipidic, reflectat\u0103 \u00een prevalen\u0163\u0103 mai sc\u0103zut\u0103 a steatozei hepatice asociat\u0103 infec\u0163iei HCV5<\/sup>.<\/span><\/p>\n

      5) Pe baza datelor disponibile pacien\u0163ii care prezint\u0103 un genotip nefavorabil (C\/T sau T\/T) ar trebui s\u0103 fie inclu\u015fi \u00een categoria \u201edificil de tratat\u201d \u00een acela\u015fi mod \u00een care sunt considera\u0163i \u015fi al\u0163i factori de prognostic negativ (ca de exemplu, fibroza avansat\u0103). Este posibil ca ad\u0103ugarea de DAAV s\u0103 atenueze efectul genotipului asupra SVR; cu toate acestea sunt necesare studii suplimentare pentru confirmarea acestui efect9<\/sup>.<\/span><\/p>\n

      Limite \u015fi interferen\u0163e <\/em><\/strong><\/span><\/p>\n

      Genotipul IL28B nu<\/strong> are o valoare predictiv\u0103 pozitiv\u0103 de 100% pentru SVR, de aceea nu trebuie utilizat ca factor predictiv unic \u00een stabilirea deciziilor terapeutice2;7<\/sup>.<\/span><\/div>\n
      Un studiu recent a demonstrat c\u0103 riscul de rec\u0103dere dup\u0103 tratmentul antiviral standard este dependent de viremia rezidual\u0103 minim\u0103 \u015fi nu de genotipul IL28B5<\/sup>.<\/span><\/div>\n
      Polimorfismul IL28B nu a fost asociat cu clerance-ul altor infec\u0163ii virale cronice (HBV sau HIV)2<\/sup>.<\/span><\/div>\n
      <\/div>\n

      \u0411\u0438\u0431\u043b\u0438\u043e\u0433\u0440\u0430\u0444\u0438\u044f<\/span><\/strong><\/p>\n

      1. Alexander J. Thompson, et al. Interleukin-28B Polymorphism Improves Viral Kinetics and Is the Strongest Pretreatment Predictor of Sustained Virologic Response in Genotype 1 Hepatitis C Virus. In Gastroenterology 2010;139:120-129.<\/span><\/span><\/div>\n
      2. Ashwin Balagopal, David L. Thomas, Chloe L. Thio. IL28B and the Control of Hepatitis C Infection. In Gastroenterology 2010;139:1865-1876.<\/span><\/div>\n
      3. F. Poordad, et al. IL28B Polymorphism Predicts Virologic Response in Patients with Hepatitis C Genotype 1 Treated with Boceprevir Combination Therapy, 46th Annual Meeting of the European Association for the Study of the Liver (EASL), Berlin, April 2011.<\/span><\/div>\n
      4. Ge D, Fellay J, Thompson AJ, et al, \u201cGenetic Variation in IL28B Predicts Hepatitis C Treatment-Induced Viral Clearance\u201d. In Nature, 2009, 461:399-401.<\/span><\/div>\n
      5. H. L. Tillman, et al. The relathionship between hepatic steatosis and IL28B response in patients with chronic hepatitis C, 46th Annual Meeting of the European Association for the Study of the Liver (EASL), Berlin, April 2011.<\/span><\/div>\n
      5. J. Wiegand, et al. Prediction of relapse after peginterferon alfa-2B?ribavirin therapy in chronic HCV genotype 1 patients is dependent on minimal residual viremia but not on IL28B genotype, 46th Annual Meeting of the European Association for the Study of the Liver (EASL), Berlin, April 2011.<\/span><\/div>\n
      6. Laborator Synevo. Referin\u0163ele specifice tehnologiei de lucru utilizate 2011. Ref Type: Catalog.<\/span><\/div>","protected":false},"excerpt":{"rendered":"

      \u041e\u0431\u0449\u0430\u044f \u0438\u043d\u0444\u043e\u0440\u043c\u0430\u0446\u0438\u044f<\/strong><\/p>\n

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      \u0413\u0435\u043d\u0435\u0442\u0438\u0447\u0435\u0441\u043a\u0438\u0435 \u0432\u0430\u0440\u0438\u0430\u043d\u0442\u044b, \u0441\u0432\u044f\u0437\u0430\u043d\u043d\u044b\u0435 \u0441 \u0444\u0443\u043d\u043a\u0446\u0438\u044f\u043c\u0438 \u043e\u043f\u0440\u0435\u0434\u0435\u043b\u0435\u043d\u043d\u044b\u0445 \u0446\u0438\u0442\u043e\u043a\u0438\u043d\u043e\u0432, \u0432\u043b\u0438\u044f\u044e\u0442 \u043d\u0430 \u0438\u043d\u0434\u0438\u0432\u0438\u0434\u0443\u0430\u043b\u044c\u043d\u044b\u0435 \u043e\u0441\u043e\u0431\u0435\u043d\u043d\u043e\u0441\u0442\u0438 \u0438\u043c\u043c\u0443\u043d\u043d\u043e\u0433\u043e \u043e\u0442\u0432\u0435\u0442\u0430 \u043d\u0430 \u0434\u0430\u043d\u043d\u0443\u044e \u0438\u043d\u0444\u0435\u043a\u0446\u0438\u044e. IL28B \u043f\u0440\u0435\u0434\u0441\u0442\u0430\u0432\u043b\u044f\u0435\u0442 \u0441\u043e\u0431\u043e\u0439 \u0438\u043d\u0442\u0435\u0440\u0444\u0435\u0440\u043e\u043d-\u03bb-3 \u0438 \u044f\u0432\u043b\u044f\u0435\u0442\u0441\u044f \u043b\u0438\u0433\u0430\u043d\u0434\u043e\u043c \u0446\u0438\u0442\u043e\u043a\u0438\u043d\u043e\u0432\u043e\u0433\u043e \u0440\u0435\u0446\u0435\u043f\u0442\u043e\u0440\u0430 II \u043a\u043b\u0430\u0441\u0441\u0430. \u042d\u0442\u0438 \u043b\u0438\u0433\u0430\u043d\u0434\u044b \u0437\u0430\u043f\u0443\u0441\u043a\u0430\u044e\u0442 JAK\/STAT \u0441\u0438\u0433\u043d\u0430\u043b\u044c\u043d\u044b\u0439 \u043a\u0430\u0441\u043a\u0430\u0434, \u0430\u043a\u0442\u0438\u0432\u0438\u0440\u0443\u044f \u0441\u0438\u043d\u0442\u0435\u0437 2\u2019,5\u2019-\u043e\u043b\u0438\u0433\u043e\u0430\u0434\u0435\u043d\u0438\u043b\u0430\u0442-\u0441\u0438\u043d\u0442\u0435\u0442\u0430\u0437\u044b, \u043a\u043e\u0442\u043e\u0440\u044b\u0439 \u0430\u043a\u0442\u0438\u0432\u0438\u0440\u0443\u0435\u0442 \u044d\u043d\u0434\u043e-\u043d\u0443\u043a\u043b\u0435\u0430\u0437\u0443. \u042d\u043d\u0434\u043e\u043d\u0443\u043a\u043b\u0435\u0430\u0437\u0430, \u0432 \u0441\u0432\u043e\u044e \u043e\u0447\u0435\u0440\u0435\u0434\u044c, \u0443\u0447\u0430\u0441\u0442\u0432\u0443\u0435\u0442 \u0432 \u043f\u0440\u043e\u0446\u0435\u0441\u0441\u0430\u0445 \u0441\u0442\u0438\u043c\u0443\u043b\u044f\u0446\u0438\u0438 \u043e\u0431\u0440\u0430\u0437\u043e\u0432\u0430\u043d\u0438\u044f \u0444\u0435\u0440\u043c\u0435\u043d\u0442\u0430 \u043f\u0440\u043e\u0442\u0435\u0438\u043d\u043a\u0438\u043d\u0430\u0437\u044b, \u043a\u043e\u0442\u043e\u0440\u044b\u0439 \u0431\u043b\u043e\u043a\u0438\u0440\u0443\u0435\u0442 \u0441\u0438\u043d\u0442\u0435\u0437 \u0432\u0438\u0440\u0443\u0441\u043d\u044b\u0445 \u0431\u0435\u043b\u043a\u043e\u0432.<\/p>\n

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