{"id":52,"date":"2018-05-14T15:56:43","date_gmt":"2018-05-14T12:56:43","guid":{"rendered":"http:\/\/www.mebid.org\/?p=52"},"modified":"2018-05-15T10:08:48","modified_gmt":"2018-05-15T07:08:48","slug":"asi-teknolojisi-geleneksel-asidan-guncel-biyoteknolojik-asiya","status":"publish","type":"post","link":"https:\/\/www.mebid.org\/tr\/yayin\/asi-teknolojisi-geleneksel-asidan-guncel-biyoteknolojik-asiya\/","title":{"rendered":"A\u015f\u0131 Teknolojisi: Geleneksel A\u015f\u0131dan G\u00fcncel Biyoteknolojik A\u015f\u0131ya"},"content":{"rendered":"

A\u015f\u0131 Teknolojisi: Geleneksel A\u015f\u0131dan G\u00fcncel Biyoteknolojik A\u015f\u0131ya<\/h1>\n
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S. \u0130smet Delilo\u011flu G\u00fcrhan | Pelin Sa\u011flam Metiner | Ayt\u00fcl G\u00fcl | Ilg\u0131n K\u0131m\u0131z<\/strong><\/em><\/p>\n

Giri\u015f<\/strong><\/p>\n

Belirli bir hastal\u0131\u011fa kar\u015f\u0131 spesifik koruma sa\u011flamak \u00fczere tasarlanm\u0131\u015f biyolojik maddeler a\u015f\u0131 olarak tan\u0131mlan\u0131r. A\u015f\u0131lar, bula\u015f\u0131c\u0131 hastal\u0131klardan korunmak i\u00e7in as\u0131rlard\u0131r yararlan\u0131lan ve son zamanlar\u0131n en \u00f6l\u00fcmc\u00fcl hastal\u0131klar\u0131ndan biri olan kanseri \u00f6nlemek, tedavi etmek ve yok etmek i\u00e7in kullan\u0131m\u0131 artan bir yakla\u015f\u0131md\u0131r. A\u015f\u0131n\u0131n uygulama s\u00fcreci \u201ca\u015f\u0131lama\u201d olarak adland\u0131r\u0131l\u0131r (Aubrit et al., 2015; Lahariya 2016; Nevagi et al., 2018). A\u015f\u0131lama, insanl\u0131k tarihinin en \u00f6nemli halk sa\u011fl\u0131\u011f\u0131 etkeni olup, bu yolla her y\u0131l milyonlarca insan hastal\u0131k ve \u00f6l\u00fcmden korunmaktad\u0131r (Karch and Burkhar, 2016). D\u00fcnya Sa\u011fl\u0131k \u00d6rg\u00fct\u00fc\u2019n\u00fcn (DS\u00d6) verilerine g\u00f6re a\u015f\u0131 uygulamas\u0131 sayesinde 100 milyonun \u00fczerinde \u00e7ocuk bir ya\u015f\u0131ndan \u00f6nce a\u015f\u0131lanmakta ve her y\u0131l 2,5 milyon \u00e7ocuk \u00f6l\u00fcmden korunmaktad\u0131r (Arg\u00fct ve ark., 2016). Gene pek \u00e7ok salg\u0131n hayvan hastal\u0131\u011f\u0131 a\u015f\u0131lama sayesinde eradike edilmi\u015f ya da kontrol alt\u0131na al\u0131nm\u0131\u015ft\u0131r.<\/p>\n

Di\u011fer farmas\u00f6tiklerin aksine a\u015f\u0131 geli\u015ftirme \u00e7al\u0131\u015fmalar\u0131, etkili n\u00fcfus eri\u015fimini sa\u011flamak i\u00e7in gereken s\u00fcreyi hesaba katmaks\u0131z\u0131n 15-20 y\u0131la kadar s\u00fcrebilmektedir. Bir a\u015f\u0131, yirmiye yak\u0131n klinik test gerektirmektedir ve bu i\u015flemler a\u015f\u0131 \u00fcretim birimi ba\u015f\u0131na 900 milyon dolara mal olabilmektedir. \u00dcretim ba\u015fl\u0131 ba\u015f\u0131na karma\u015f\u0131k ve uzun bir s\u00fcre\u00e7tir. Yeni bir \u00fcretim zinciri olu\u015fturmak ve nitelendirmek en az 5 y\u0131l s\u00fcrebilir ve muazzam bir yat\u0131r\u0131m anlam\u0131na gelir. Tek bir biyolojik \u00fcretim alan\u0131n\u0131n ortalama maliyeti konumuna ve \u00fcr\u00fcne ba\u011fl\u0131 olmakla birlikte, 100 milyon ila 600 milyon dolar aras\u0131nda de\u011fi\u015fmektedir. A\u015f\u0131 geli\u015ftirme \u00e7al\u0131\u015fmalar\u0131nda, umut verici erken-a\u015fama a\u015f\u0131 adaylar\u0131n\u0131n, \u00f6zellikle de GMP \u00fcretim potansiyelini de\u011ferlendirmek ve klinik geli\u015fim planlar\u0131 tasarlamak ad\u0131na fizibilite \u00e7al\u0131\u015fmalar\u0131 ile klinik uygulamalara ge\u00e7i\u015f i\u00e7in fonlara ihtiya\u00e7lar\u0131 vard\u0131r. KOB\u0130’ler (K\u00fc\u00e7\u00fck ve Orta \u00d6l\u00e7ekli \u0130\u015fletmeler), temel ke\u015fif ile erken klinik geli\u015fim aras\u0131ndaki Ar-Ge bo\u015fluklar\u0131 aras\u0131nda k\u00f6pr\u00fc rol\u00fc oynarlar. \u00c7al\u0131\u015ft\u0131klar\u0131 a\u015f\u0131lar\u0131n pazarlanmas\u0131 birka\u00e7 y\u0131l s\u00fcrmesine ra\u011fmen, KOB\u0130’ler teknolojilere ve tesislere kolayca eri\u015febilmekte ve bu s\u00fcrecin nas\u0131l kolayla\u015ft\u0131r\u0131labilece\u011fini iyi bilmektedirler (Medaglini et al. 2018).<\/p>\n

Tarihsel Geli\u015fim<\/strong><\/p>\n

Edward Jenner 1796 y\u0131l\u0131nda ilk a\u015f\u0131 aday\u0131n\u0131 geli\u015ftirdi\u011finden beri bu alanda olduk\u00e7a ilerleme kaydedilmi\u015ftir (Karch and Burkhar, 2016). 20. y\u00fczy\u0131l\u0131n ba\u015flar\u0131nda a\u015f\u0131lar, \u00e7o\u011funlukla tav\u015fan, koyun veya ke\u00e7i gibi hayvanlardan elde edilen sinir dokular\u0131nda, yeni do\u011fan fare, s\u0131\u00e7an veya tav\u015fan beyninde ve de enfekte hayvanlar\u0131n kan serumu kullan\u0131larak \u00fcretilmekteydi. 1930 y\u0131l\u0131nda laboratuvar hayvanlar\u0131n\u0131n yerini, vir\u00fcslerin \u00fcretimi i\u00e7in, embriyolu tavuk yumurtas\u0131 alm\u0131\u015ft\u0131r. G\u00fcn\u00fcm\u00fczde bu y\u00f6ntem mevsimsel grip a\u015f\u0131s\u0131 \u00fcretimi i\u00e7in kullan\u0131l\u0131yor olsa da, \u00fcretimdeki zaman al\u0131c\u0131 ve stabil olmayan proses, yetersiz besleme, y\u00fcksek \u00fcretim maliyeti ve yumurtan\u0131n bile\u015fenlerindeki alerjik potansiyel baz\u0131 k\u0131s\u0131tlamalar getirmektedir. \u0130lk olarak 1954 y\u0131l\u0131nda polio vir\u00fcs\u00fc \u00fcretiminde denenen h\u00fccre k\u00fclt\u00fcr\u00fc tekni\u011fi ile bu limitlerin \u00fcstesinden gelebilmek ama\u00e7lanm\u0131\u015f, a\u015f\u0131 \u00fcretimi i\u00e7in h\u00fccre k\u00fclt\u00fcr\u00fc teknolojisinin kullan\u0131lmas\u0131 kilit bir kilometre ta\u015f\u0131 olarak g\u00f6r\u00fclm\u00fc\u015ft\u00fcr (Aubrit et al., 2015). Ba\u015flang\u0131\u00e7ta bu ama\u00e7la primer h\u00fccreler kullan\u0131l\u0131rken, \u00fcretim veriminin artt\u0131r\u0131lmas\u0131, g\u00fcvenli ve ucuz hale getirilmesi i\u00e7in diploit [WI-38 (k\u0131zam\u0131k\u00e7\u0131k a\u015f\u0131s\u0131) ve MRC5 (kuduz, polio, hepatit-A, a\u015f\u0131s\u0131) h\u00fccreleri] ve s\u00fcrekli [MDCK (mevsimsel grip a\u015f\u0131s\u0131) ve Vero (rotavir\u00fcs, \u00e7i\u00e7ek, polio, kuduz a\u015f\u0131s\u0131) h\u00fccreleri] h\u00fccre hatlar\u0131n\u0131n kullan\u0131lmas\u0131 g\u00fcndeme gelmi\u015ftir. Diploit h\u00fccreler primerden kaynakl\u0131 olup d\u00fczenli ve normal karyotipe sahiptirler. Fakat s\u0131n\u0131rl\u0131 kapasitede seri pasajlanabilmeleri ve \u00fcremelerinde serum ve daha zengin ortam i\u00e7eri\u011fi gerekti\u011finden GMP kurallar\u0131na uygun biyoreakt\u00f6rlerde \u00f6l\u00e7ek b\u00fcy\u00fctme i\u015flemi kolay ger\u00e7ekle\u015ftirilememektedir. S\u00fcrekli h\u00fccre hatlar\u0131 ise s\u0131n\u0131rs\u0131z pasajlama \u00f6zelli\u011fi ile h\u00fccre bankas\u0131 sisteminde \u00fcretime, maliyetli ve alan sorunu olsa da d\u00f6ner h\u00fccre k\u00fclt\u00fcr\u00fc \u015fi\u015feleri, \u00e7oklu pleyt h\u00fccre fabrikasyon sistemleri ve de mikrota\u015f\u0131y\u0131c\u0131 sistemleri kullan\u0131larak biyoreakt\u00f6rlerde b\u00fcy\u00fck \u00f6l\u00e7ekte \u00fcretime izin verirken, ilerleyen pasaj numaralar\u0131nda t\u00fcm\u00f6rojenik \u00f6zellik kazanabilmektedirler. Bu s\u0131n\u0131rlamalar nedeni ile d\u00fc\u015f\u00fck maliyetli \u00f6zel \u00fcretimlere uygun s\u00fcspanse halde biyoreakt\u00f6rlerde \u00fcretimi yap\u0131labilen, insan retina kaynakl\u0131 PER.C6 (Bat\u0131 Nil vir\u00fcs\u00fc, grip a\u015f\u0131s\u0131) gibi yeni tasar\u0131m h\u00fccre hatlar\u0131 geli\u015ftirilmi\u015ftir (Li et al., 2014; Aubrit et al., 2015; Mili\u00e1n and Kamen 2015). H\u00fccre k\u00fclt\u00fcr\u00fc temelli a\u015f\u0131lar\u0131n yan\u0131 s\u0131ra son zamanlarda \u00e7oklukla biyoteknolojik y\u00f6ntemlerle geli\u015ftirilen ve genellikle rekombinant tekniklere dayal\u0131 yeni d\u00f6nem a\u015f\u0131lar da \u00e7al\u0131\u015f\u0131lmaktad\u0131r (Alt\u0131nta\u015f ve ark., 2017; Moyle, 2017).<\/p>\n

G\u00fcn\u00fcm\u00fczde bir\u00e7ok hastal\u0131\u011fa kar\u015f\u0131 a\u015f\u0131 geli\u015ftirilmi\u015f olsa da; Dang hummas\u0131, lenfatik filariaz, edinilmi\u015f ba\u011f\u0131\u015f\u0131kl\u0131k yetersizli\u011fi sendromu (AIDS), s\u0131tma, romatizmal kalp hastal\u0131\u011f\u0131 (RHD) ve \u00e7e\u015fitli kanserler i\u00e7in hen\u00fcz etkin bir a\u015f\u0131 bulunamam\u0131\u015ft\u0131r (Moyle, 2017). Bu nedenle a\u015f\u0131 \u00e7al\u0131\u015fmalar\u0131; geleneksel, biyoteknolojik ve her ikisinin de kullan\u0131ld\u0131\u011f\u0131 kombine a\u015f\u0131 teknikleriyle geli\u015ftirilmeye devam etmektedir.<\/p>\n

A\u015f\u0131 \u00dcretim Tekniklerine Genel Bak\u0131\u015f<\/strong><\/p>\n

Aktif ba\u011f\u0131\u015f\u0131kl\u0131k i\u00e7in kullan\u0131lan a\u015f\u0131lar\u0131n en eski ve temeli say\u0131lan geleneksel a\u015f\u0131lar; canl\u0131 zay\u0131flat\u0131lm\u0131\u015f (aten\u00fce), inaktif (\u00f6l\u00fc) ve inaktif toksin (toksoit) a\u015f\u0131lard\u0131r ve bu a\u015f\u0131larda organizman\u0131n t\u00fcm\u00fc kullan\u0131lmaktad\u0131r (Moyle, 2017; Francis, 2018). Canl\u0131 aten\u00fce a\u015f\u0131lar, hastal\u0131k etmeni canl\u0131 mikroorganizmalar\u0131n laboratuvar ko\u015fullar\u0131nda zay\u0131flat\u0131lmas\u0131 ile elde edilmekte olup do\u011fal enfeksiyonu taklit etti\u011fi i\u00e7in etkili bir a\u015f\u0131lama stratejisi olu\u015ftururlar. T\u00fcberk\u00fcloza kar\u015f\u0131 BCG a\u015f\u0131s\u0131 ve k\u0131zam\u0131k, kabakulak ve k\u0131zam\u0131k\u00e7\u0131k karma (MMR) a\u015f\u0131lar\u0131 canl\u0131 aten\u00fce a\u015f\u0131lara \u00f6rnektir (Kallerup and Foged, 2015). \u0130naktif a\u015f\u0131lar, genellikle yumurta veya h\u00fccre k\u00fclt\u00fcr\u00fcnde \u00fcretilmekte, \u00fcretim s\u0131v\u0131s\u0131ndan ultrafiltrasyon, ultrasantrif\u00fcgasyon ve kromatografi y\u00f6ntemleri ile safla\u015ft\u0131r\u0131lan hastal\u0131k etkeninin seyreltik B-propiolakton gibi kimyasal, \u0131s\u0131l i\u015flem veya radyasyon ile \u00f6ld\u00fcr\u00fclmesi (inaktive edilmesi) sonucu olu\u015fturuldu\u011fundan canl\u0131 aten\u00fce a\u015f\u0131lara g\u00f6re k\u0131smen daha g\u00fcvenli a\u015f\u0131lard\u0131r. Hepatit A, grip, polio ve kuduz a\u015f\u0131lar\u0131 inaktif a\u015f\u0131lara \u00f6rnektir (Li et al., 2014; Aubrit et al., 2015; Kallerup and Foged, 2015; Mili\u00e1n and Kamen, 2015). Bakteriyel toksinlerin kimyasal veya \u0131s\u0131l i\u015flem ile inaktive edilmesi sonucunda toksoit a\u015f\u0131lar\u0131 elde edilir. Yayg\u0131n olarak kullan\u0131lan toksoit a\u015f\u0131lar\u0131; difteri i\u00e7in Corynebacterium diphteria ve tetanoz i\u00e7in Clostridium tetani\u2019den \u00fcretilen a\u015f\u0131lard\u0131r (Besnard et al., 2016).<\/p>\n

Canl\u0131 aten\u00fce a\u015f\u0131lar\u0131n tekrar vir\u00fclens \u00f6zellik kazanma riski ve imm\u00fcn yetmezli\u011fi olanlarda enfeksiyon riski ta\u015f\u0131mas\u0131; inaktif a\u015f\u0131lar\u0131n aten\u00fce a\u015f\u0131lara g\u00f6re daha az etkili olmas\u0131; toksoitlere (inaktif toksin) dayal\u0131 ticari a\u015f\u0131lar\u0131n ise k\u00fclt\u00fcr ortam\u0131nda karma\u015f\u0131k bile\u015fenlere gereksinimi gibi geleneksel a\u015f\u0131lar\u0131n bir \u00e7ok dezavantaj\u0131 bulunmaktad\u0131r (Jorge and Dellagostin, 2017). Bunlara ek olarak, organizmalar\u0131n t\u00fcm\u00fcn\u00fcn kullan\u0131ld\u0131\u011f\u0131 a\u015f\u0131 sistemlerinin (canl\u0131 aten\u00fce ve inaktif a\u015f\u0131) \u00fcretiminin b\u00fcy\u00fck miktarlarda bula\u015f\u0131c\u0131 ajanlar\u0131n k\u00fclt\u00fcr\u00fcn\u00fc i\u00e7ermesi ve bu nedenle ilgili personel ve \u00e7evre i\u00e7in potansiyel bir tehlike olu\u015fturmas\u0131, yumurtalarda yeti\u015ftirilen veya hayvan h\u00fccre k\u00fclt\u00fcr\u00fc teknikleri ile \u00fcretilen bu a\u015f\u0131larda imm\u00fcnojenikli\u011fin etkilenebilmesi veya potansiyel olarak alerjik\/reaktojenik olabilecek istenmeyen “yabanc\u0131” proteinleri i\u00e7ermesi s\u00f6z konusu olabilir (Francis, 2018). A\u015f\u0131 bile\u015fiminde, hastal\u0131\u011fa \u00f6zg\u00fc antijen d\u0131\u015f\u0131nda antijen sunma kapasiteleri serokonversiyon oranlar\u0131n\u0131 ve koruyucu etkinli\u011fi art\u0131rmas\u0131 bak\u0131m\u0131ndan potansiyel bir fayda sa\u011flasa da, beraberinde ilgili hastal\u0131k i\u00e7in ihtiya\u00e7 duyulmayan bir\u00e7ok bile\u015fenin de aktar\u0131ld\u0131\u011f\u0131 bilinmektedir. Bu bile\u015fenler, koruyucu antijenlere kar\u015f\u0131 ba\u011f\u0131\u015f\u0131kl\u0131\u011f\u0131 d\u00fc\u015f\u00fcrerek a\u015f\u0131 etkinli\u011fini azaltabilir, imm\u00fcn sistemi uygunsuz ya da etkisiz cevaplara y\u00f6nlendirebilir ve baz\u0131 durumlarda hastal\u0131klara (\u00f6rn, Streptococcus pyogenes’de grup A karbonhidrat ve M proteini romatizmal kalp hastal\u0131\u011f\u0131 ile ili\u015fkilendirilmi\u015ftir.) neden olabilir (Moyle, 2017).<\/p>\n

Geleneksel a\u015f\u0131lar\u0131n bahsedilen bu s\u0131n\u0131rlamalar\u0131ndan dolay\u0131, aktif ba\u011f\u0131\u015f\u0131kl\u0131k i\u00e7in hastal\u0131klar\u0131n \u00f6nlenmesi, kontrol\u00fc veya yok edilmesi ad\u0131na, son y\u0131llarda teknolojinin ilerlemesi ile daha fazla miktarda, saf ve g\u00fcvenli \u00fcr\u00fcn\u00fcn daha k\u0131sa s\u00fcrede \u00fcretildi\u011fi biyoteknolojik y\u00f6ntemler ile geli\u015ftirilen a\u015f\u0131lar \u00e7al\u0131\u015f\u0131lmaktad\u0131r (Alt\u0131nta\u015f ve ark., 2017; Moyle, 2017).<\/p>\n

Rekombinant a\u015f\u0131 teknolojisi, proteinlerin rekombinant ekspresyonunu ve viral vekt\u00f6rleri i\u00e7ermektedir. Bu sayede, k\u00fclt\u00fcrlenmesi zor olan veya k\u00fclt\u00fcr\u00fc yap\u0131lamayan vir\u00fcslere kar\u015f\u0131 a\u015f\u0131 geli\u015ftirilebilmektedir. Geleneksel y\u00f6ntemlere g\u00f6re daha kontroll\u00fc biyoproseslerde k\u0131sa s\u00fcrede \u00fcretim sa\u011fland\u0131\u011f\u0131ndan g\u00fcvenlik riskleri elimine edilebilmektedir (Hudu et al., 2016).<\/p>\n

Subunit a\u015f\u0131lar:<\/em>\u00a0Rekombinant DNA teknolojisi kullan\u0131larak, k\u00fclt\u00fcrlenemeyen, y\u00fcksek oranda patojen olan ya da k\u00fclt\u00fcr a\u00e7\u0131s\u0131ndan son derece pahal\u0131 olan organizmalardan bir veya birden fazla antijenik proteinler \u00fcretilerek olu\u015fturulur. Subunit a\u015f\u0131lar, zay\u0131flat\u0131lm\u0131\u015f a\u015f\u0131lar\u0131n yeniden vir\u00fclens kazanmas\u0131 ve antijenik peptitlerin inaktive a\u015f\u0131larla denat\u00fcre edilmesi gibi yan etkileri azaltmaktad\u0131r. Subunit a\u015f\u0131lar daha az imm\u00fcnojenik etki g\u00f6sterir. \u0130mm\u00fcnostim\u00fclat\u00f6r molek\u00fcller veya a\u015f\u0131lara kar\u015f\u0131 ba\u011f\u0131\u015f\u0131kl\u0131k tepkisini artt\u0131ran adjuvantlar eklenerek imm\u00fcnojenikli\u011fi artt\u0131r\u0131labilir. Bu a\u015f\u0131lara ticari \u00f6rnek olarak Hepatit B vir\u00fcs\u00fcne kar\u015f\u0131 Sci-B-Vac\u2122; insan papilloma vir\u00fcs\u00fcne (HPV) kar\u015f\u0131 Cervarix\u00ae, Gardasil\u00ae ve Gardasil9\u00ae ve ayr\u0131ca s\u0131tmaya kar\u015f\u0131 Mosquirix\u2122 verilebilir (Karch and Burkhard, 2016; Mohsen et al., 2017).<\/p>\n

N\u00fckleik asit bazl\u0131 a\u015f\u0131lar:<\/em>\u00a0Canl\u0131 aten\u00fce ve subunit a\u015f\u0131lar\u0131n pozitif \u00f6zelliklerini birle\u015ftiren bir ara\u00e7 olarak geli\u015ftirilmi\u015ftir. Viral vekt\u00f6r ve plazmit DNA a\u015f\u0131lar\u0131 ruhsata sahip olmamas\u0131na ra\u011fmen insan klinik deneylerinde yo\u011fun olarak de\u011ferlendirilmi\u015f, g\u00fcvenli ve imm\u00fcnojenik oldu\u011fu g\u00f6sterilmi\u015ftir (Ulmer and Geal, 2016).<\/p>\n

N\u00fckleik asitler aras\u0131nda mRNA’n\u0131n genomik entegrasyon, anti-DNA otoantikorlar\u0131n\u0131n uyar\u0131lmas\u0131 ve uzun vadeli antijen ekspresyonunun neden oldu\u011fu imm\u00fcn tolerans\u0131 gibi DNA tabanl\u0131 a\u015f\u0131lara k\u0131yasla bir\u00e7ok avantaj\u0131 bulunmaktad\u0131r. Dahas\u0131, mRNA n\u00fckleer giri\u015fe ihtiya\u00e7 duymaks\u0131z\u0131n, yava\u015f\u00e7a veya b\u00f6l\u00fcnmeyen dendritik h\u00fccrelere etkili bir \u015fekilde transfekte edilebilmektedirler (Uchida et al., 2018).<\/p>\n

DNA a\u015f\u0131s\u0131; \u00f6karyotik h\u00fccre promotoru ve koruyucu antijen kodlayan genleri i\u00e7eren, rekombinant bakteriyel plazmit omurgas\u0131nda yer alan DNA a\u015f\u0131 vekt\u00f6r\u00fcn\u00fcn \u00f6karyotik h\u00fccrelerine transfeksiyonu ve gerekli transkripsiyon, translasyon basamaklar\u0131ndan sonra kodlanan a\u015f\u0131 antijenlerinin MHC-I ve MHC-II yolaklar\u0131 \u00fczerinden antijen sunucu h\u00fccreler ile sunumunu ve b\u00f6ylelikle h\u00fccresel ve humoral immun yan\u0131t\u0131n ikisinin de uyar\u0131lmas\u0131n\u0131 kapsayan, genellikle protein a\u015f\u0131lar\u0131na g\u00f6re daha etkili sitotoksik T h\u00fccre yan\u0131t\u0131 ind\u00fckleyen, geleneksel a\u015f\u0131lara g\u00f6re de daha g\u00fcvenilir ve tan\u0131mlanabilir immun yan\u0131t\u0131 uyarmay\u0131 sa\u011flayan a\u015f\u0131 \u00e7e\u015fitidir (Gregory et al., 2013; Silveira et al., 2017; Zahm et al., 2017). DNA a\u015f\u0131lar\u0131 veteriner a\u015f\u0131lar\u0131nda kullan\u0131lmak \u00fczere 2005 y\u0131l\u0131nda lisanslanmas\u0131na ra\u011fmen, d\u00fc\u015f\u00fck transfeksiyon verimlili\u011fi, g\u00fc\u00e7lendirici dozlara gereksinimi ve az olan imm\u00fcnojenitesi nedeniyle hen\u00fcz insan klinik denemelerini engelleyen bir s\u0131n\u0131rlamaya sahiptir (Gulce et al., 2013, 2014); Silveira et al., 2017). Nanoteknoloji kullanarak olu\u015fturulan yeni adjuvant sistemler ile \u00e7\u0131plak DNA a\u015f\u0131s\u0131 sonras\u0131 elde edilen nispeten d\u00fc\u015f\u00fck immun yan\u0131t artt\u0131r\u0131labilmekte ve uygun kompleks sistemlerle olu\u015fturulan bu adjuvant sistemleri \u00e7al\u0131\u015fmalarda umut vaad etmektedir (Gregory et al., 2013). DNA a\u015f\u0131lar\u0131 \u00e7ok farkl\u0131 t\u00fcrdeki enfeksiy\u00f6z hastal\u0131klara kar\u015f\u0131 oldu\u011fu gibi \u00e7e\u015fitli kanser t\u00fcrlerine kar\u015f\u0131 \u201cDNA a\u015f\u0131s\u0131 tabanl\u0131 kanser immunoterapisi\u201d olarak da adland\u0131r\u0131lan kanser a\u015f\u0131s\u0131 olarak da kullan\u0131lmaktad\u0131r (Zahm et al., 2017).<\/p>\n

Dentritik h\u00fccre (DC) a\u015f\u0131lar\u0131:<\/em>\u00a0DC\u2019ler, ba\u011f\u0131\u015f\u0131kl\u0131k tepkisi ba\u015flatmak i\u00e7in T h\u00fccrelerini uyar\u0131c\u0131 antijenleri sunan h\u00fccrelerdir (Galati and Zanotta, 2017). Hastal\u0131\u011f\u0131n \u00f6nlenmesini ama\u00e7layan geleneksel bula\u015f\u0131c\u0131 hastal\u0131k a\u015f\u0131lar\u0131n\u0131n aksine, dentritik h\u00fccre a\u015f\u0131lar\u0131 CD8 + T h\u00fccresi tepkilerini uyarma \u00fczerine odaklan\u0131r. 2010 y\u0131l\u0131nda ABD G\u0131da ve \u0130la\u00e7 Dairesi (FDA), ilk kez kastrasyona diren\u00e7li prostat kanserli hastalar\u0131n genel sa\u011f kal\u0131m\u0131n\u0131 art\u0131ran Provenge dentritik h\u00fccre kanser a\u015f\u0131s\u0131n\u0131 onaylam\u0131\u015ft\u0131r. Sipuleucel-T (Provenge), PA2024 olarak adland\u0131r\u0131lan rekombinant f\u00fczyon proteini ile ex vivo\u2019da aktive edilen otolog periferal kan monon\u00fckleer h\u00fccrelerinden (PBMC) olu\u015fmaktad\u0131r (Gardner and Ruffell, 2016). Provenge \u00fcretimi bir ka\u00e7 ad\u0131mda ger\u00e7ekle\u015fmektedir. \u00d6nce hastan\u0131n kan\u0131ndan l\u00f6koferez i\u015flemi ile ba\u011f\u0131\u015f\u0131k h\u00fccreleri toplanmakta, bu ba\u011f\u0131\u015f\u0131kl\u0131k h\u00fccreleri daha sonra kendilerini prostat kanserine kar\u015f\u0131 uyaracak ve y\u00f6nlendirecek olan proteine (rekombinant insan proteini PAP-GM-CSF) maruz b\u0131rak\u0131larak aktive edilmi\u015f dentritik h\u00fccreler elde edilmektedir. Son olarak, aktive edilmi\u015f ba\u011f\u0131\u015f\u0131kl\u0131k h\u00fccreleri daha sonra hastaya geri verilerek tedavi ger\u00e7ekle\u015ftirilmi\u015f olmaktad\u0131r (FDA, 2018). Bug\u00fcne kadar korunmu\u015f etkili t\u00fcm\u00f6r reddi antijeni ve ekzojen antijen kaynaklar\u0131n\u0131n \u00e7apraz sunumu g\u00fcvenilir \u015fekilde \u00f6l\u00e7\u00fclemedi\u011fi i\u00e7in bu de\u011fi\u015fkenler s\u0131n\u0131rlay\u0131c\u0131 ve\/veya s\u0131kl\u0131kla \u00f6l\u00e7\u00fclebilir de\u011fildir. Bu antijenlerin k\u00fclt\u00fcrlenmi\u015f DC’lere daha sa\u011flam bir \u015fekilde girilmesini sa\u011flayacak hedef mRNA uygulamas\u0131, viral olarak arac\u0131l\u0131k eden genomik modifikasyonlar ve DC-t\u00fcm\u00f6r hibrit h\u00fccrelerin olu\u015fturulmas\u0131 gibi genetik manip\u00fclasyonlar ger\u00e7ekle\u015ftirilebilmektedir. Genetik modifikasyonlar sayesinde DC\u2019ler t\u00fcm\u00f6r h\u00fccrelerinden veya sentetik peptitlerden veya proteinlerden ekzojen olarak verilen antijenler yerine, t\u00fcm\u00f6r antijen genini ta\u015f\u0131yan genetik vekt\u00f6rlerin transfeksiyonu ile endojen antijen i\u015fleme makinesini kullanarak proteinleri i\u015fleyebilmekte ve sunabilmektedir. B\u00f6ylece rekombinant DC\u2019ler yenilenebilir antijen kayna\u011f\u0131 sa\u011flayarak daha etkili hedefleme ger\u00e7ekle\u015ftirebilmektedir (Abraham and Mitchell, 2016). Faz III \u00e7al\u0131\u015fmalar\u0131nda klinik etkinlik g\u00f6steren terap\u00f6tik kanser a\u015f\u0131s\u0131 olmamas\u0131na ra\u011fmen, neoantijenlere dayal\u0131 ki\u015fiselle\u015ftirilmi\u015f kanser a\u015f\u0131 geli\u015fmeleri, t\u00fcm\u00f6r regresyonunu ind\u00fcklemek i\u00e7in etkili bir yol olarak ortaya \u00e7\u0131km\u0131\u015ft\u0131r. Mutasyonla ili\u015fkili neoantijenler, t\u00fcm\u00f6r s\u0131zd\u0131ran lenfositi aktive etmek ve t\u00fcm\u00f6r regresyonunu ind\u00fcklemek \u00fczere tan\u0131mlanm\u0131\u015ft\u0131r. Fakat y\u00fcksek mutasyon g\u00f6steren baz\u0131 hastalar imm\u00fcn check point blokaj\u0131na yetersiz yan\u0131t g\u00f6stermi\u015ftir (Song et al., 2018). Ki\u015fiselle\u015ftirilmi\u015f imm\u00fcnoterapi alanlar\u0131n\u0131, k\u00f6k h\u00fccrelerden DC farkl\u0131la\u015fmas\u0131, derin dizilim teknolojisi (deep sequencing technology) ve CRISPR\/Cas9 genomunun d\u00fczenlenmesi gibi yeni teknolojilerin de\u011fi\u015ftirece\u011fi d\u00fc\u015f\u00fcn\u00fclmektedir (Saxena and Bhardwaj, 2018).<\/p>\n

Sentetik peptit a\u015f\u0131lar:<\/em>\u00a0Mikroorganizmalar\u0131n koruyucu immun yan\u0131t olu\u015fturan antijenik b\u00f6lgelerinin peptit dizinini belirleyerek sentezlenmesi ile elde edilen yap\u0131n\u0131n a\u015f\u0131 olarak kullan\u0131lmas\u0131 da DS\u00d6 taraf\u0131ndan benimsenmi\u015ftir. Bu ba\u011flamda, ba\u015flang\u0131\u00e7 materyalinin spesifikasyonu, \u00fcretim s\u00fcreci ve final \u00fcr\u00fcn\u00fcn kalite kontrol\u00fcne y\u00f6nelik k\u0131lavuz da olu\u015fturulmu\u015ftur (WHO, 2014). Tamamen sentetik olmalar\u0131, bu a\u015f\u0131lar\u0131n mutasyon, yabanc\u0131 patojenlerle veya toksik materyellerle kontaminasyon, vb. risklerinin olmamas\u0131n\u0131n yan\u0131nda k\u00fclt\u00fcr ortamlar\u0131nda zor \u00fcreyen mikroorganizmalara kar\u015f\u0131 a\u015f\u0131 geli\u015ftirilmesine olanak sa\u011flamalar\u0131 da \u00f6nemli \u00fcst\u00fcnl\u00fckleri gibi g\u00f6r\u00fcnmektedir. Ancak, antijenik epitopun ilgili aminoasit dizini yan\u0131nda \u00e7e\u015fitli proteinlerin de kat\u0131l\u0131m\u0131yla ortaya \u00e7\u0131kan \u00fc\u00e7 boyutlu yap\u0131dan olu\u015fmas\u0131 modellemede baz\u0131 sorunlara neden olmaktad\u0131r. Bunun yan\u0131nda, g\u00fc\u00e7l\u00fc immun yan\u0131t alabilmek i\u00e7in ta\u015f\u0131y\u0131c\u0131 partik\u00fclerin ya da g\u00fc\u00e7l\u00fc adjuvantlar\u0131n se\u00e7imi de \u00f6nemli bir basamakt\u0131r (Mo\u012dsa and Kolesanova, 2011; Weidang et al., 2014). Halen \u00e7al\u0131\u015fmalar\u0131 devam eden malaria, hepatitis C, insan immun yetmezlik virusu (HIV), \u015fap hastal\u0131\u011f\u0131, Afrika domuz vebas\u0131, influenza, antraks, insan papilloma virus (HPV), baz\u0131 terap\u00f6tik anti-kanser a\u015f\u0131lar\u0131 gibi pek \u00e7ok hastal\u0131k mevcuttur.<\/p>\n

Yenebilir a\u015f\u0131lar:<\/em>\u00a0Vitamin, protein ve di\u011fer besleyici \u00f6zellikler a\u00e7\u0131s\u0131ndan zengin olup ayn\u0131 zamanda a\u015f\u0131 g\u00f6revi g\u00f6ren g\u0131dalard\u0131r. Bir bitkinin par\u00e7as\u0131, meyvesi veya bu bitkiden t\u00fcretilen alt \u00fcr\u00fcnler gibi yenebilir formatta \u00fcretilen t\u00fcm a\u015f\u0131lar\u0131 i\u00e7ermekte ve bunlar\u0131n oral olarak al\u0131m\u0131 sonras\u0131nda ba\u011f\u0131\u015f\u0131kl\u0131k sistemini uyarmaktad\u0131r (Alt\u0131ndis et al., 2014; Aswathi et al., 2014). Yenebilir as\u0327\u0131 olarak incelenen bir c\u0327ok bitki, rotaviru\u0308s, kolera, gastroenterit, otoimmu\u0308n hastal\u0131klar veya kuduz ic\u0327in antijenleri eksprese etmek u\u0308zere transforme edilmi\u015ftir. Bu ama\u00e7la, domates, m\u0131s\u0131r, t\u00fctu\u0308n, muz, havuc\u0327 ve yer f\u0131st\u0131g\u0306\u0131 gibi bitkiler genetik transformasyon y\u00f6ntemlerinin bas\u0327ar\u0131l\u0131 bir \u015fekilde geli\u015ftirilmesi ve test edilmesinden dolay\u0131 umut verici bir gelece\u011fe sahiptir. D\u00fcnya \u00e7ap\u0131nda bula\u015f\u0131c\u0131 hastal\u0131klar\u0131 azaltmak i\u00e7in, \u00f6zellikle geleneksel a\u015f\u0131laman\u0131n zor oldu\u011fu \u00fclkelerde yenebilir a\u015f\u0131lar alternatif olarak d\u00fc\u015f\u00fcn\u00fclmektedir (Glick et al., 2010; Laere et al., 2016). Burada bir di\u011fer \u00f6nemli konu da, a\u015f\u0131 geli\u015ftirmek \u00fczere transfekte edilecek bitkinin hedef kitle olan insan ya da hayvanlar taraf\u0131ndan sorunsuzca t\u00fcketilebilir olmas\u0131d\u0131r.<\/p>\n

A\u015f\u0131 \u00fcretiminde temizodalar\u0131n \u00f6nemi<\/strong><\/p>\n

Biyolojik \u00fcr\u00fcnler i\u00e7in \u0130yi \u00dcretim Uygulamalar\u0131 (GMP), ilk kez 1992 y\u0131l\u0131nda D\u00fcnya Sa\u011fl\u0131k \u00d6rg\u00fct\u00fc (WHO) taraf\u0131ndan yay\u0131nlanm\u0131\u015ft\u0131r. Belirtilen prosed\u00fcrlerle \u00fcretilen biyolojik \u00fcr\u00fcnler i\u00e7erisinde; allerjenler, antijenler, a\u015f\u0131lar, hormonlar, sitokinler, monoklonal antikorlar, enzimler, hayvan immun serumlar\u0131, fermantasyon \u00fcr\u00fcnleri (rDNA’dan t\u00fcretilmi\u015f \u00fcr\u00fcnler de dahil olmak \u00fczere), in vivo biyolojik te\u015fhis reaktifleri ile gen terapisinde ve h\u00fccre tedavisinde kullan\u0131lan ileri tedavi t\u0131bbi \u00fcr\u00fcnler bulunmaktad\u0131r (WHO, 2016).<\/p>\n

Temizoda kullan\u0131ma uygun olmal\u0131d\u0131r, o ortamda uzun s\u00fcreli \u00e7al\u0131\u015fanlar i\u00e7in ya\u015fam\u0131n kolayla\u015ft\u0131r\u0131lm\u0131\u015f olmas\u0131 gereklidir. A\u015f\u0131 sekt\u00f6r\u00fcndeki temizodalarda herhangi bir hata y\u00fcksek parasal kay\u0131plara neden olur. Do\u011fru bir \u015fekilde uyguland\u0131klar\u0131nda a\u015f\u0131 \u00fcretim y\u00f6ntemleri ve GMP baz\u0131 g\u00fcvenlik \u00f6nlemlerini \u00f6ng\u00f6r\u00fcr. Hatal\u0131 ya da yetersiz atten\u00fcasyon, olas\u0131 kontaminasyonlara kar\u015f\u0131 \u00f6nlem olarak antibiyotik-antimikotik, vb kullan\u0131lmas\u0131, \u00e7evresel kontaminantlar\u0131n b\u00fcy\u00fck \u00f6l\u00e7\u00fcde uzakla\u015ft\u0131r\u0131lmas\u0131 i\u00e7in safla\u015ft\u0131rma s\u00fcre\u00e7leri ve inaktivasyon i\u00e7in baz\u0131 kimyasal inaktivanlar\u0131n kullan\u0131lmas\u0131 bu \u00f6nlemler aras\u0131ndad\u0131r. A\u015f\u0131lar\u0131n \u00fcretim hatalar\u0131na y\u00f6nelik bilinen risklerine kar\u015f\u0131 \u00f6nlem almak, kaliteli \u00fcr\u00fcn \u00e7\u0131kartmak i\u00e7in tan\u0131mlanm\u0131\u015f genel temizoda d\u00fczeyleri \u00f6nerilmektedir (WHO, 2012). Ek olarak, DS\u00d6\u2019n\u00fcn daha g\u00fcncel s\u00fcr\u00fcm\u00fcnde, biyolojik \u00fcr\u00fcnlerin ve \u00f6zellikle a\u015f\u0131lar\u0131n \u00fcretiminde kullan\u0131lan spesifik \u00fcretim proseslerini g\u00f6z \u00f6n\u00fcne alarak, a\u015f\u0131 \u00fcretim tesislerindeki temizodalar\u0131n DS\u00d6 \u00e7evresel izleme; biyolojik \u00fcretim s\u00fcre\u00e7leri i\u00e7in \u00e7evresel s\u0131n\u0131fland\u0131rma gereksinimlerini geli\u015ftirmek ad\u0131na, kullan\u0131labilecek insan a\u015f\u0131 \u00fcreticileri i\u00e7in rehberlik belgesinin dikkate al\u0131nmas\u0131n\u0131 \u00f6nerilmektedir (WHO, 2016).<\/p>\n

Yukar\u0131da k\u0131sa k\u0131sa tan\u0131mlanm\u0131\u015f olan her a\u015f\u0131 tipi i\u00e7in antijenin \u00f6zelli\u011fine, a\u015f\u0131 haz\u0131rlama s\u00fcrecinin t\u00fcr\u00fcne ba\u011fl\u0131 olarak, her \u00fcretim basama\u011f\u0131 i\u00e7in belirlenmi\u015f farkl\u0131 temizoda standartlar\u0131 mevcuttur. Sonu\u00e7ta hedef; \u00fcr\u00fcn\u00fc, etkin kontrol ayg\u0131tlar\u0131n\u0131n da kat\u0131l\u0131m\u0131 ile olas\u0131 kontaminasyonlardan korumaya y\u00f6nelik tasarlanm\u0131\u015f bir ortam olu\u015fturulmas\u0131d\u0131r. Bu nedenle, temizoda kurulumu yapan m\u00fchendislik kurulu\u015flar\u0131 ile o odalar\u0131 kullanacak ara\u015ft\u0131rmac\u0131, \u00fcretici ve teknik personelin aras\u0131nda bilgi aktar\u0131m\u0131 olmak zorundad\u0131r. Bunun i\u00e7in de kullan\u0131c\u0131lar\u0131n kendi proseslerini \u00e7ok iyi bilmesi \u015fartt\u0131r (Sunar, 2005).<\/p>\n

Amerika Birle\u015fik Devletleri\u2019nde (ABD), Amerikan G\u0131da ve \u0130la\u00e7 Kurumu \u00f6zellikle Uluslararas\u0131 Standartlar Kurumu (ISO) standartlar\u0131n\u0131 (ISO 14644-1) kabul etmektedir (ISO, 1999). Avrupa standartlar\u0131 ise, dinlenme a\u015famas\u0131ndaki dura\u011fan ko\u015fullar ile i\u015flemlerin s\u00fcrd\u00fcr\u00fcld\u00fc\u011f\u00fc dinamik \u00fcre\u00e7 aras\u0131nda daha ileri ay\u0131rt edici de\u011ferlendirmeleri i\u00e7erir (European Commission, 2003) . T\u00fcrkiye\u2019de veteriner ve be\u015feri a\u015f\u0131 \u00fcretiminde ilgili bakanl\u0131klar Avrupa standartlar\u0131n\u0131 eas alarak G\u00fcncel \u0130yi \u00dcretim Uygulamalar\u0131 (cGMP) ve Avrupa Farmakopesi\u2019ni kurallar\u0131n\u0131 kabul etmektedirler.<\/p>\n

KAYNAKLAR<\/strong><\/p>\n

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    \n
  • Abraham RS and Mitchell DA. (2016) Gene-modified dendritic cell vaccines for cancer. Cytotherapy, 18(11): 1446-1455.<\/li>\n
  • Alt\u0131ndis E, Gulce Iz S, Ozen MO, Nartop P, Deliloglu Gurhan I and Gurel A. Plant Derived Edible Vaccines and Therapeutics. Frontiers in Clinical Drug Research: Anti-Infectives, vol. 1, Chapter 5, 200-236. Atta-ur-Rahman (Ed), July 2014, Bentham Science Publishers, 367 Pages<\/li>\n
  • Alt\u0131nta\u015f L, Enver H, Tutun H. (2017) Rekombinant DNA Teknolojisi ve Veteriner I\u0307la\u00e7 Gelis\u0327tirmede Kullan\u0131m\u0131. MAK\u00dc Sag. Bil. Enst. Derg. 5(2):193-204.<\/li>\n
  • Arg\u00fct N, Yetim A, G\u00f6k\u00e7ay G. (2016) A\u015f\u0131 Kabul\u00fcn\u00fc Etkileyen Fakt\u00f6rler. \u00c7ocuk Dergisi 16(1-3): 16-24.<\/li>\n
  • Aswathi PB, Bhanja SK, Yadav AS, Rekha V, John JK, Gopinath D, Sadanandan GV, Shinde A, Jacob A. (2014) Plant Based Edible Vaccines against Poultry Diseases: A Review. Adv. Anim. Vet. Sci. 2(5): 305\u2013311.<\/li>\n
  • Aubrit F, Perugi F, L\u00e9on A, Gu\u00e9henneux F, Champion-Arnaud P, Lahmar M, Schwamborn K. (2015) Cell substrates for the production of viral vaccines. Vaccine 33: 5905-5912.<\/li>\n
  • Besnard L, Fabre V, Fettig M, Goussinov E, Kawakami Y, Laroudie N, Scanlan C, Pattnaik P. (2016) Clarification of vaccines: An overview of filter based technology trends and best practices. Biotechnology Advances 34: 1-13.<\/li>\n
  • European Commission, EudraLex Vol. 4: Good manufacturing practice (GMP) Guidelines, Annex 1: Manufacture of Sterile Medicinal Products (2003).<\/li>\n
  • FDA, 2018. \u201cQuestion and Answers-Provegene\u201d. https:\/\/www.fda.gov\/biologicsbloodvaccines\/cellulargenetherapyproducts\/approvedproducts\/ucm210037.htm . ET: 03.03.2018.<\/li>\n
  • Francis MJ. (2018) Recent Advances in Vaccine Technologies. Veterinary Clinics of North America: Small Animal Practice, 48(2): 231-241.<\/li>\n
  • Galati D and Zanotta S. (2017) Hematologic neoplasms: Dendritic cells vaccines in motion. Clinical Immunology, 183: 181-190.<\/li>\n
  • Gardner A and Ruffell B. (2016) Dendritic cells and cancer immunity. Trends in immunology 37(12): 855-865.<\/li>\n
  • Glick BR, Pasternak JJ, Patten CL. (2010) Molecular Biotechnology. Principles and Applications of Recombinant DNA, 4th ed. ASM Press, Herndon, VA, USA, 999 p.<\/li>\n
  • Gregory AE, Titball R, Williamson D. (2013) Vaccine delivery using nanoparticles, Frontiers in Cellular and Infection Microbiology, 3(13): 1-13.<\/li>\n
  • Gulce Iz S, Doskaya M, Borrego B, Rodriguez F, G\u00fcr\u00fcz Y, Delilo\u011flu G\u00fcrhan I, (2013): Co-expression of the Bcl-xL antiapoptotic protein enhances the induction of Th1-like immune responses in mice immunized with DNA vaccines encoding FMDV B and T cell epitopes, Veterinary Research Communications, 37(3):187-96.<\/li>\n
  • Gulce Iz S, Doskaya M, Caner A, Degirmenci Doskaya A, Rodriguez F, Guruz Y, Deliloglu Gurhan, SI (2014): A novel dual promoter DNA vaccine induces CD8+ response against Toxoplasma gondii sporozoite specific surface protein \u201cSporoSAG\u201d through non-apoptotic cells. Trials in Vaccinology, 3, 81-88.<\/li>\n
  • Hudu SA, Shinkafi SH, Umar S. (2016) An overview of recombinant vaccine technology, adjuvantts and vaccine delivery method. International Journal of Pharmacy and Pharmaceutical Sciences 8(11): 19-24.<\/li>\n
  • ISO 14644-1, Cleanrooms and Associated Controlled Environments \u2013 Part 1: Classification of Air Cleanlines Cleanroom Standards (ISO, 1999).<\/li>\n
  • Jorge S and Dellagostin OA. (2017) The development of veterinary vaccines: a review of traditional methods and modern biotechnology approaches. Biotechnology Research and Innovation 1(1): 6-13.<\/li>\n
  • Kallerup RS and Foged C. (2015) Classification of Vaccines. 15-29pp. In: Subunit Vaccine Delivery, Advances in Delivery Science and Technology. Foged C, Rades T, Perrie, Hook S (eds.) CRS, Springer Science and Business Media, New York, 260 p.<\/li>\n
  • Karch CP and Burkhard P. (2016) Vaccine technologies: From whole organisms to rationally designed protein assemblies. Biochemical Pharmacology 120: 1-14.<\/li>\n
  • Laere E, Ling APK, Wong YP, Koh RY, Lila MAM, Hussein S. (2016) Plant-Based Vaccines: Production and Challenges. Journal of Botany. doi:10.1155\/2016\/4928637.<\/li>\n
  • Lahariya C. (2016) Vaccine epidemiology: A review. J Family Med Prim Care 5(1): 7-15.<\/li>\n
  • Li S-M, Bai F-L, Xu W-J, Yang Y-B, An Y, Li T-H, Yu Y-H, Li D-S, Wang W-F. (2014) Removing residual DNA from Vero-cell culture-derived human rabies vaccine by using nuclease. Biologicals 42: 271-276.<\/li>\n
  • Medaglini D, De Azero MR, Leroy O, Bietrix F, Denoel P. (2018) Innovation Partnership for a Roadmap on Vaccines in Europe (IPROVE): Avision for the vaccines of tomorrow. Vaccine 36: 1136-1145.<\/li>\n
  • Milian E and Kamen AA. (2015) Current and Emerging Cell Culture Manufacturing Technologies for Influenza Vaccines. Hindawi Publishing Corporation BioMed Research International, Article ID 504831, 11 pages, http:\/\/dx.doi.org\/10.1155\/2015\/504831.<\/li>\n
  • Mohsen MO, Zha L, Cabral-Miranda G, Bachmann MF. (2017) Major findings and recent advances in virus\u2013like particle (VLP)-based vaccines. Seminars in Immunology 34: 123-132.<\/li>\n
  • Mo\u012dsa AA, Kolesanova EF. (2011 Jan-Feb) Synthetic peptide vaccines, Biomed Khim. ; 57(1):14-30.<\/li>\n
  • Moyle PM. (2017) Biotechnology approaches to produce potent, self-adjuvantting antigen-adjuvantt fusion protein subunit vaccines. Biotechnology Advances 35: 375-389.<\/li>\n
  • Nevagi RJ, Toth I, Skwarczynski M. (2018) Peptide-based vaccines. 327-358 pp. In: Peptide Applications in Biomedicine, Biotechnology and Bioengineering. Koutsopoulos S (ed.) Woodhead Publishing, Elsevier, UK, 639 p.<\/li>\n
  • Saxena M and Bhardwaj N. (2018) Re-Emergence of Dendritic Cell Vaccines for Cancer Treatment. Trends in cancer 4(2): 119-137.<\/li>\n
  • Silveira MM, Oliveira TL, Schuch RA, McBride AJA, Dellagostin OA, Hartwig DD. (2017) DNA vaccines against leptospirosis: A literature review. Vaccine 35:5559\u20135567.<\/li>\n
  • Song Q. Zhang CD, Wu XH. (2018) Therapeutic cancer vaccines: From initial findings to prospects. Immunology letters 196: 11-21.<\/li>\n
  • Sunar D (2005) Makina M\u00fchendisleri Odas\u0131 \u0130stanbul \u015eubesi \u201cTemiz Odalarda Kontrol Parametreleri\u201d \u00c7al\u0131\u015ftay\u0131, 14.07.2005 www.atotest.com.tr\/download\/sunum\/nisan2010\/temoda1.pdf<\/li>\n
  • Uchida S, Yoshinaga N, Yanagihara K, Yuba E, Kataoka K, Itaka K. (2018) Designing immunostimulatory double stranded messenger RNA with maintained translational activity through hybridization with poly A sequences for effective vaccination. Biomaterials 150: 162-170.<\/li>\n
  • Ulmer JB and Geall AJ. (2016). Recent innovations in mRNA vaccines. Current opinion in immunology 41: 18-22.<\/li>\n
  • Weidang Li, Medha DJ, Singhania S, Ramsey KH, and Murthy AK (2014 Sep.), Peptide Vaccine: Progress and Challenges, Vaccines (Basel). 2014 Sep; 2(3): 515\u2013536.<\/li>\n
  • WHO Environmental Monitoring of Clean Rooms in Vaccine Manufacturing Facilities Points to consider for manufacturers of human vaccines November 2012.<\/li>\n
  • WHO, Vaccines, synthetic peptide, Guidelines for the production and quality control of synthetic peptide vaccines; Adopted 1997, TRS No 889, Annex 1, Last update: 10 January 2014 10:57 CET).<\/li>\n
  • WHO (2016) Technical Reports Series No.999. WHO good manufacturing practices for biological products, Annex 2, Replacement of Annex 1 of WHO Technical Report Series, No. 822, 93-130 pp. In: WHO Expert Committee on Biological Standardization, sixty-sixth report. http:\/\/www.who.int\/biologicals\/areas\/vaccines\/Annex_2_WHO_Good_manufacturing_practices_for_biological_products.pdf. ET: 05.03.2018.<\/li>\n
  • Zahm CD, Colluru VT, McNeel DG. (2017) DNA vaccines for prostate cancer. Pharmacology & Therapeutics 174: 27\u201342.<\/li>\n<\/ul>\n

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    Yazarlar Hakk\u0131nda<\/strong><\/p>\n

    S. \u0130smet Delilo\u011flu G\u00fcrhan, 1947 y\u0131l\u0131nda \u0130stanbul\u2019da do\u011fdu. 1969 y\u0131l\u0131nda Ankara \u00dcniversitesi Veteriner Fak\u00fcltesi\u2019nden mezun oldu. Pratisyen veteriner hekim olarak \u00c7ankaya ve Batman il\u00e7elerinde \u00e7al\u0131\u015ft\u0131ktan sonra 1976\u2019da Mikrobiyoloji ve Salg\u0131n Hastal\u0131klar dal\u0131nda uzmanl\u0131k e\u011fitimini, 1993\u2019de S.\u00dc. Veteriner Fak\u00fcltesi\u2019nde \u015fap vir\u00fcslerinin antijenik varyasyonlar\u0131n\u0131n SDS-PAGE ile saptanmas\u0131 konulu tezi ile doktora e\u011fitimini tamamlad\u0131. Bu s\u00fcre\u00e7te 27 y\u0131l T.C. Tar\u0131m Bakanl\u0131\u011f\u0131 Ankara \u015eap Enstit\u00fcs\u00fc\u2019nde h\u00fccre k\u00fclt\u00fcr\u00fc ile a\u015f\u0131 vir\u00fcs\u00fc \u00fcretim laboratuvarlar\u0131nda \u00e7al\u0131\u015ft\u0131, \u00dcretim \u00d6ncesi Kontrol Laboratuvar\u0131\u2019n\u0131, Hayvan H\u00fccre K\u00fclt\u00fcr Koleksiyonu\u2019nu (HUKUK) kurdu. 2001-2014 y\u0131llar\u0131nda E.\u00dc. Biyom\u00fchendislik B\u00f6l\u00fcm\u00fc\u2019nde \u00f6\u011fretim \u00fcyesi olarak bulundu. Halen emekli \u00f6\u011fretim \u00fcyesi olarak ayn\u0131 \u00fcniversitede \u00e7al\u0131\u015fmalar\u0131na devam etmektedir. \u00c7e\u015fitli boyutlar\u0131 ile h\u00fccre k\u00fclt\u00fcr\u00fc teknikleri, monoklonal antikor \u00fcretimi, a\u015f\u0131 \u00fcretimi konular\u0131 temel \u00e7al\u0131\u015fma ve ilgi alanlar\u0131ndand\u0131r.<\/p>\n

    Pelin Sa\u011flam Metiner 1991 y\u0131l\u0131nda \u0130zmir\u2019de do\u011fdu. Ege \u00dcniversitesi Biyom\u00fchendislik B\u00f6l\u00fcm\u00fc\u2019nde lisans ve y\u00fcksek lisans e\u011fitimini tamamlad\u0131. Lisans bitirme projesi kapsam\u0131nda; k\u00fc\u00e7\u00fck \u00f6l\u00e7ekli biyoreakt\u00f6rlerde hayvan h\u00fccre k\u00fclt\u00fcr\u00fc temelli parazit a\u015f\u0131s\u0131 antijeni \u00fcretimi, y\u00fcksek lisans tezinde ise DNA a\u015f\u0131s\u0131 konular\u0131n\u0131 \u00e7al\u0131\u015ft\u0131. Yer ald\u0131\u011f\u0131 \u00e7e\u015fitli projelerde edindi\u011fi deneyimler ile a\u015f\u0131 \u00e7al\u0131\u015fmalar\u0131 konusunda kendisini geli\u015ftirdi. 2017 y\u0131l\u0131nda ayn\u0131 \u00fcniversite ve b\u00f6l\u00fcmde ba\u015flad\u0131\u011f\u0131 doktora e\u011fitimine Hayvan H\u00fccre M\u00fchendisli\u011fi yelpazesinde yer alan geni\u015f \u00e7al\u0131\u015fma alanlar\u0131nda devam etmektedir.<\/p>\n

    Ayt\u00fcl G\u00fcl, 1989 y\u0131l\u0131nda Samsun’da do\u011fdu. Ege \u00dcniversitesi Biyom\u00fchendislik B\u00f6l\u00fcm\u00fc\u2019nde lisans ve y\u00fcksek lisans e\u011fitimini tamamlad\u0131. Lisans tezini, monoklonal antikor ve nanopartik\u00fcl konjugatlanmas\u0131 \u00fczerine yapmas\u0131n\u0131n ard\u0131ndan y\u00fcksek lisans tezinde rekombinant DNA \u00fcretim sistemlerine ve rekombinant h\u00fccre hatt\u0131 geli\u015ftirilmesi \u00fczerine yo\u011funla\u015ft\u0131. Ayr\u0131ca y\u00fcksek lisans\u0131 ve doktoras\u0131 s\u00fcresince meme kanserine kar\u015f\u0131 DNA a\u015f\u0131s\u0131 \u00fcretimi, K\u0131r\u0131m-Kongo kanamal\u0131 ate\u015fi vir\u00fcs\u00fcne (CCHFV) kar\u015f\u0131 a\u015f\u0131 aday\u0131 rekombinant antijenlerinin \u00fcretimi konular\u0131nda yer ald\u0131\u011f\u0131 projelerde edindi\u011fi deneyimler ile rekombinant a\u015f\u0131 \u00e7al\u0131\u015fmalar\u0131 konusunda kendisini geli\u015ftirdi. 2017 y\u0131l\u0131nda ayn\u0131 \u00fcniversite ve b\u00f6l\u00fcmde ba\u015flad\u0131\u011f\u0131 doktora e\u011fitimine Rekombinant Hayvan H\u00fccre M\u00fchendisli\u011fi kapsam\u0131ndaki \u00e7al\u0131\u015fma alanlar\u0131nda devam etmektedir.<\/p>\n

    Ilg\u0131n K\u0131m\u0131z, 1991 y\u0131l\u0131nda \u0130zmir\u2019de do\u011fdu. Ege \u00dcniversitesi Biyom\u00fchendislik B\u00f6l\u00fcm\u00fc\u2019nde lisans ve y\u00fcksek lisans e\u011fitimini tamamlad\u0131. Bu s\u00fcre\u00e7te yer ald\u0131\u011f\u0131 projeler kapsam\u0131nda hibridoma teknolojisi ve karakterizasyon \u00e7al\u0131\u015fmalar\u0131, biyoreakt\u00f6rlerde monoklonal antikor \u00fcretimi ve safla\u015ft\u0131rmas\u0131, serumsuz ortam tasar\u0131m\u0131 ve biyobenzer \u00fcretimi konular\u0131nda deneyim kazand\u0131. Doktora e\u011fitimine de ayn\u0131 \u00fcniversite ve b\u00f6l\u00fcmde Hayvan H\u00fccre M\u00fchendisli\u011fi kapsam\u0131ndaki \u00e7al\u0131\u015fma alanlar\u0131nda devam etmektedir.<\/p>\n<\/div>\n<\/article>\n","protected":false},"excerpt":{"rendered":"

    A\u015f\u0131 Teknolojisi: Geleneksel A\u015f\u0131dan G\u00fcncel Biyoteknolojik A\u015f\u0131ya S. \u0130smet Delilo\u011flu G\u00fcrhan | Pelin Sa\u011flam Metiner | Ayt\u00fcl G\u00fcl | Ilg\u0131n K\u0131m\u0131z Giri\u015f Belirli bir hastal\u0131\u011fa kar\u015f\u0131 spesifik koruma sa\u011flamak \u00fczere tasarlanm\u0131\u015f biyolojik maddeler a\u015f\u0131 olarak tan\u0131mlan\u0131r. A\u015f\u0131lar, bula\u015f\u0131c\u0131 hastal\u0131klardan korunmak i\u00e7in as\u0131rlard\u0131r yararlan\u0131lan ve son zamanlar\u0131n en \u00f6l\u00fcmc\u00fcl hastal\u0131klar\u0131ndan biri olan kanseri \u00f6nlemek, tedavi etmek […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[5],"tags":[],"_links":{"self":[{"href":"https:\/\/www.mebid.org\/tr\/wp-json\/wp\/v2\/posts\/52\/"}],"collection":[{"href":"https:\/\/www.mebid.org\/tr\/wp-json\/wp\/v2\/posts\/"}],"about":[{"href":"https:\/\/www.mebid.org\/tr\/wp-json\/wp\/v2\/types\/post\/"}],"author":[{"embeddable":true,"href":"https:\/\/www.mebid.org\/tr\/wp-json\/wp\/v2\/users\/1\/"}],"replies":[{"embeddable":true,"href":"https:\/\/www.mebid.org\/tr\/wp-json\/wp\/v2\/comments\/?post=52"}],"version-history":[{"count":1,"href":"https:\/\/www.mebid.org\/tr\/wp-json\/wp\/v2\/posts\/52\/revisions\/"}],"predecessor-version":[{"id":53,"href":"https:\/\/www.mebid.org\/tr\/wp-json\/wp\/v2\/posts\/52\/revisions\/53\/"}],"wp:attachment":[{"href":"https:\/\/www.mebid.org\/tr\/wp-json\/wp\/v2\/media\/?parent=52"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.mebid.org\/tr\/wp-json\/wp\/v2\/categories\/?post=52"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.mebid.org\/tr\/wp-json\/wp\/v2\/tags\/?post=52"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}