NHlN Rn THg' Gl(3l
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TE BA 0 TUA:
BAO KIEM CHONG UNG THIT?
TS N G U Y I N O Q C THAI
Khu C6r]q r\ojr\6 cao th^nh phS \r\6 Chf Minfi
Mot trong ba nha khoa hQC do^t Gi^l Nobel Y hQC ndm 2011 la GS Ralph Steinman - nha miin djch hQC va sinh hpc t6' bao ngufofi Canada, nhof phat hien ra te bao Tua (Dendritic Cell, goi tdt la DC) vcfi ddc diem co vai tro chu yeu trong he miin djch. Khain pha cua ong dufgfc xem la da md ra mOt chdn trofi mofi cho vifc nghien cufu va phat trien lieu phap dieu trj cdn bfnh ung thir hiem ngheo.
Bai viet giofi thi6u khai quat ve kh^ ndng trj lieu ung birdfu cua DC va tiem nang u^ng dung of Viet Nam.
Nhung trd ngai ban dau ve kham pha va nghien cihiDC
Trong hdn 3 thdp ky, Ralph Steinman dd Id mdt chdng hiep sy ddn dpc di tim bdo kidm ehdng can benh ung thu hiem ngheo. Khi nhdn dien ra mdt logi td bdo mdi, md ngdy nay dUdc bidt Id DC, Ralph Steinman da phdi mat rd't nhidu kien nhdn vd ndm thdng de k i t qua nghien eUu eua minh dupe edng ddng khoa hpc luu tdm. Trong khoang thdi gian dd da ludn cd nhQng nghi ngai vd ch? trfch ve vai trd chdng ung thU md Ralph Steinman de cii cho DC. 6 nhQng nam dau, cdc bdo cdo eua dng ve DC thudng khdng dUdc chap nhdn hodc ddnh gid thd'p trdn cdc tap san khoa hpc vd ede hpi thdo vd midn djch hpc.
Mdt trong nhQng ly do vi DC Id logi t l bdo hiim trong cd the ndn rd't khd tim kilm vdi dilu kidn ky thudt trudc ddy. NhUng ly do quan trpng hdn Id do tdm nhdn thUe hep hdi eua cdc nhd nghien cUu miin dich hpc trong sudt thdi gian ddi eija nhQng thdp ky trudc.
Hp da qud tin tudng rang khd ndng dd khdng eua hd miin djch dupe ddm trdch ch? bdi 3 logi td bdo chu yeu gdm t l bdo bgch cau B, t l bdo tuyIn ydn T vd dgi thue bdo M. Bd't eU nhQng khdm phd ndo ngodi 3 logi te bdo ndy, rd't khd dUde edng ddng midn dich lUu tdm vd chap nhdn (quan niem ndy tU cdc trung tdm dau ngdnh da lan tran vd an sdu tgi nhidu nUde, trong dd cd Viet Nam; each day tren 2 nam, ehung tdi ed trinh bay ve DC trong hpi nghj sinh hpc d TP
Hd Chf Minh vd cdc nhd nghien cUu cho hay, ddy la Idn ddu tien hp dupe bidt vd vai trd cua DC).
Vd cd chd, khi cd thd bj cdc khdng nguyen Ig hoac vi vd sidu vi xdm nhdp, dgi thpc bdo M tdm lay vd tieu hda ede ngogi nhdn ndy de ngan chdn, ddng thdi kfch hogt td bdo T de tidu diet vd td bdo B tgo khdng the chdng cdc y l u td ngogi xdm. Thd nhung, qua nhOng nghidn cUu xuydn sudt tU thd^ Louis Pasteur cho din nay, chUe ndng eua dgi thpc bdo M chf cd hidu qud rd't gidi hgn d cdc vung bj nhidm, ehU khdng cd tac dpng trdn todn hd
midn djch dd tgo sp bdo ve cdn thilt eho cd the.
Nghien cUu eOa Ralph Steinman vd cdng sp da chUng minh dupe rdng vai trd trpng y l u ndy thupc v l DC, vd cdc nghien cUu cija nhidu trung tdm khdc tren thd gidi da minh xdc DC Id t l bdo ed kha nang tao sUc d l
knang^ manh nhat steinman (tai hdi nghi chuyin di vS cua he mien dich. DC, Kobe, Nhit Bin, 2009)
64 Hoatdong^.,., „ . . _
K H O A H O C S ° * ^ ^ " 9 3 20i2NHiN Rn THE Gl(5l
Miin djch bam sinh (Metchnikoff, 1908):
- T 4 b^o tryc ti6p g§y b§nh - D6 tim vi khuSn m i u
- Kh6ng khang nguydn riSng bi$t
[ K6t n6i DCs (Steinman 2007)
I Mien dich thich nghi (Ahrlich, 1908):
' - T h ^ k h S n g ri6ng bi$t
4 V Bi4n d6i khdng nguydn •£Si2Sci__ _ ,.?. - S y kich thich cua T vd B tA bdo b^ch huyAt
Hlnh 1: khim phi cua GS Ralph Steinman (hlnh trdn) c6 gi^ tri lich SI? vi ddt phi cho nginh miSn djch hqc hidn d^i, vl nghiin cdu DC cua dng da mang l^i mdt giii nghTa hoin chinh trong ca chd dS khing cQa hd midn dich, theo dd DC ddng vai trd trung tdm diSm kdt ndi giOa hd midn djch bim sinh vi hi midn dich thich nghi dd mang l^i sdc di khing cung nhU phdng ngda cho ca thd
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libMTCDU
Hlnh 2: trong ca chd tri lidu cic ung budu, DC duac chdng minh la cd khi nang tdm bat cac khing nguyen nhU hd midn dich phdng vd, ddng thdi kich hoat tebao Tddtao mdt sdtebdo chuyen bidt T, giup ca the diet ung bUdu vi cic tic nhin giy benh. DC cdn cd da chdc nang tic ddng trdn cic td bio miin dich khdc gdm te bio B, NK, TdiSu hoi (Treg)...
TU cdc dgc tfnh tren (hinh 1 vd 2), DC hien dupe coi Id dd'i tdc chu y l u cua he midn dich trong chUe nang logi trU ede phdt sinh ung bUdu vd giup cd the dd phdng sU xdm nhdp eua ede tdc nhdn gdy bdnh do vi vd sieu vi trung. Cdng trinh di tien phong vd khdm phd DC cua Ralph Steinman dupe todn thd gidi ngudng mp vd trao Gidi Nobel Y hpc 2011 trong trudng hdp dUde xem Id ngogi Id vi dng da mat trudc ngdy trao giai (theo quy djnh thi gidi khdng dupe trao eho ngUdi qud co). Tuy nhien, dd cd thd dUa nhQng nghien cUu DC vdo tri lieu da ddi hoi nhQng ddng gdp cdng phu vd gid tri cua nhQng nhd nghien eUu midn djch hpc dau ngdnh; dgc biet phdi ke dd'n hai nhd khoa hpc Id GS Edgar Engleman Gidm ddc Trung tdm Huylt hoc, Dgi hoc Standford, California ddng thdi Id ngUdi sang lap hang Dendreon da dupe
Cd quan qudn ly dupc va thUc pham My (FDA), cho dung te bao DC dau tien de tri ung thu tidn liet tuyen, va GS Jack Bancheraux eua Dai hpc Baylor, Texas.
Vi nhQng thanh tich dat dupe cho nghien cUu DC, nam 2010, Cdng ty Roche da mdi todn bp nhdm nghidn cUu eua GS Jack Bancheraux gdm hdn 100 ngudi ve dgi bdn doanh d New Jersey de trien khai eho tri lieu eac benh ung thu vd nghien cUu cdc vaxin the he mdi.
Cac dac tinh cua DC va kha nang tri lieu ung budu
DC da tgo dupc sU lUu tdm dac biet cua ngdnh midn djch hpc trong nhQng nam gan ddy vi nhQng kdt qud nghien cUu cho thd'y khd nang vupt trdi cua DC trong viec kfch hoat he midn dich. Cdng nghe dung DC de tri lieu dang dupc nghien cUu vd thU nghiem rdng rai cho vide tri lieu cdc benh ung bUdu vd tgo vaxin. TU kham phd dau tien cua Ralph Steinman, cho tdi nay, cdc nghien cUu dung DC da thiet lap dupe nhQng chUc nang chij ydu nhu sau:
Te bdo DC cd kha nang tdm bat vd trinh dien cdc khdng nguyen eija vi, sieu vi vd quan trpng Id eho cdc khdng nguyen cua te bdo ung thU rd't cao vd manh hPn te bdo M. Khd nang tdm bat khdng nguyen nhd cdc thu the (receptors) chuyen biet nhu C-lectin DC SIGN, CD205, CD36, BDCA-2, LOX-1.
Nhd he bieu hien MHC-I/II manh, cdc khdng nguyen dupe trinh dien rdng rdi tren be mat eua DC vd ddy Id Uu diem ma DC ed the lan truydn tfn hieu hieu qud hdn tdi cdc td bdo ed vai trd phdng ve cua he mien djch. Khdc vdi dgi thpc bdo, DC ed tfnh di ddng rd't cao, DC cd the di nhidu ndi trong cd the de bat vd mang cdc khdng nguyen len tuyen T nhd chUe ndng chuyen biet cua thu the CCR7 Tgi ddy, qua ddc tfnh cua cdc thu the CD40, CD80 vd CD86, DC se ddo tgo mpt sd lUdng Idn td bdo T ed khd ndng nhdn dien vd tieu didt cdc td bdo ung budu. DC cung cd khd ndng tgo cytokine IL-12 gdy hieu Ung Th-1 tdc ddng len td bdo T sdt thu (CD4 T cell), NK (natural killer) vd dgi thpe bdo M giup gia tang hieu Ung chdng lai te bdo ung bUdu. Ngodi ra, thu the TLR-2, -4 eua DC ed khd ndng nhdn dien mdt sd Idn vi khuan cija ed hai logi gram (+) vd (-), vd dieu ndy cho thd'y DC ddng mdt vai trd rd't quan trpng vd bdo ve vd phdng chdng cdc benh nhidm trung (hinh 3). Hien DC gdm hai nhdm; nhdm mpt mDC thudc he myeloid md Ralph Steinman tim ra; nhdm hai pDC ed ngudn gdc tU plasmatoid do Y Liu khdm
S6 thang 3.2012 ^TT/-) A R O r ^ 5
NHIN Rn TH€ Gl(3l
phd tu dae tfnh sdn xud't interferon ndn cung Id mdt dd'i tdc quan trpng trong nhdm td bdo DC eua hd midn djch.
M6t s6' t§' bko thg t h i hinh tua cho k§nh dSn khAng nguy6n, xd ly v^ Xhi hi^n tr§n MHC
ldp sSn phim I vd 11
DC-SIGN (C0209) ,/
Ung«lB(CDM7) - ^ / A»liloalyooproteln Receptor 9 , - ' ' - / ^.^u
DEC-20S(CO20$)
TLR-2, TLR-4
- FcrR (activating and lnhlbMory),FaKR
IL.12
Hmh 3: td bdo DC vi mdt sd thu thd ddng vai trd nhin di^n tic nhin giy b$nh ung bUdu ho$c cic sidu vi
Vd tri lidu, phUdng phdp ngogi vi (ex-vivo) thudng dupe dp dung qua vide nudi cd'y te bdo DC tu mdu benh nhdn vd cho tilp can vdi khdng nguyen cung tu ung budu cua ngudi benh vdi nhQng y l u td tang sinh t l bdo gdm IL-4, GM-CSF, sau dd Id kfeh hoat dung TNF-alpha, IL-1, prostaglandin hoac CpG d l tgo thdnh nhdm DC ed hogt tfnh cao. Cdc DC hogt tfnh ndy dUde truyen trd Igi eho benh nhdn de gdy hieu Ung mien djch tri lieu. PhUdng phdp ngogi vi dung ddn bdo de sdn xud't DC, vd t l bdo ddng CD34+, hoac cd the dung t l bdo mdu DC ngogi bien cua benh nhdn, tuy nhien sd lUdng t l bdo thu dUde thudng rd't nhd (hinh 4). Gan ddy, phUdng phdp ndi
T«o ra cAc c«c«< ly
ft bto non dang lua bach au don kMI mtu ngoai vl
U$u phdp DC
NaprfMo dang lua dtdunggUI t i b i a kh&u
B4nhnh*n
nam vAcxln ctw b^nh nhAn
Hlnh 4: chu trinh dung DC ngoai vi dd tri lidu ung bUdu gdm trich ly td bio dan nhin td miu bdnh nhdn; bidt hda thinh DC, sau dd ket hap cic DC nay vdi te bio ung bUdu cua ngudi bdnh; trong dieu kidn nay DC duac kich hoat vi tiem cho nguai bdnh dd giy tic ddng midn djch toin didn tdi cic td bio T vi B dd tieu didt budu ung thu cua ngUdi benh
vi (in-vivo) khdng ly trfch DC md dung Nano vdng ho$c cdc khdng the chuydn bidt eua DC mang cac khdng nguydn ung bUdu d l truyin thing cho bdnh nhdn. Cd hai phUdng phdp d i u dang dUpc nghidn cUu sdu rdng d l hodn chfnh eho Ung dpng tri lidu.
Trong thQ nghidm d md hinh sue vdt, DC cd khd ndng tgo miin djch rd't cao ddi vdi cdc khdi u va Ung dpng tn li^u cua DC cho cdc bdnh nhdn ung budu da mang Igi dupe nhQng k i t qud tdt dgp. Mdt sd nghidn cUu ldm sdng 6 ngUdi cho thd'y, DC co thd logi trU cdc t l bdo ung budu, k l cd d giai dogn dd khdng hodc da lan truyin vd dgt k i t qud trdn 80% nhu cho bdnh u dc tfnh melanoma du d giai dogn 4. Tuy nhidn, hidu ndng DC thay ddi tuy logi b^nh, dilu ki^n sinh ly cua bdnh nhdn vd cdn d mUc thd'p (khodng 10%). Cdc chuydn gia tin tudng rdng, Ung dpng eija DC se rdng Idn vd quan trpng cho nhidu bdnh ung bUdu khi lidu phdp DC dupe cdi tiln tu nhOng nghidn eUu chuydn sdu vd hidn da cd rat nhidu trung tdm nghidn eUu sinh hpc uy tfn qudc td tridn khai cdc chij dd vd DC. Ngodi cdc cdng ty biotech chuyen vd DC, mpt sd dgi edng ty dUdc da tham gia nghidn cUu DC cho tri lieu ung budu nhU Roche, Gladstone Smith Kline (GSK) vd Merk. De dgt hieu Ung cao vd hQu hidu cho tri lidu cdc benh ung budu, ede nhd nghien eUu DC hidn chu trpng vdo nhQng ehid'n lupc chu y l u gdm:
Cdi tiln ky thudt tgo t l bdo DC vd tim kilm nhQng ehung logi DC cd ddc tfnh kfch hogt t l bdo T vd B mgnh nhat.
K i t hpp vdi ede logi cytokine (nhU GM-CSF, IFN) vd td dupe ddc hidu (nhU CpG, LPS ed tac dpng tren thp the TLR ) d l hd trp DC trong chufc nang kfeh hogt hd midn djch.
VI tfnh ddi khdng miin djch cua t l bdo T dieu hod, nghidn cUu v l tUdng tdc eua DC vd t l bdo T dilu hda (Treg) dang ddng gdp nhOng dQ kidn quan trpng trong myc tidu tdi Uu hda chUc ndng cua DC.
Trdnh cdc dilu kidn khiln DC trd thdnh t l bdo ddi khdng (toleronic DC) ed t h i gdy hidu Ung ti/
nhidm vd ddo thdi trong cd t h i .
K i t hpp vdi lidu phdp midn djch khde nhu dung t l bdo T.
Ddnh gid ldm sdng, chUe ndng miin djch cCia benh nhdn vd chpn didu kidn bdnh ly thfch hdp d l tac dpng cua DC vdi he midn djch dgt hidu qud cao. Da cd bdo cdo khd quan ngdn chgn dUde cdc bdc phat cua ung budu khi k i t hdp lidu phdp DC vdi phUdng phdp gidi phdu gidm thilu hoac cat bd khdi u.
i6 KH'oAHo"cS°*h^"9 3-2012
NHiN Rn TH€ G\0\
Trong thue hdnh, tri lieu DC ed dp an todn cao so vdi cac tri lieu ung thu khac. Ddy chinh Id yeu td ndi trdi eija DC khi ehung ta phdi chpn Ipa gidi phdp an todn cho benh nhdn, vi cdc tri lieu ung budu vd xg tri thudng gdy nhQng phdn Ung phu nguy hgi. So vdi vide dung te bdo gdc, DC Id logi td bdo da biet hda dn djnh nen vide kiem sodt chUe ndng vd hieu qud tri lieu ddn gidn vd an todn hdn. Cho tdi nay, da ed hdn 200 \hii nghiem^ lam sdng d cdc trung tdm nghien cUu dung DC de tri lieu nhidu logi ung budu, gdm u dc tfnh, u tuydn tidn liet, ung thu than di cdn, ung thu ngpc, rudt, nao bd va mot sd bdnh ung thu mdu.
Tiem nang ung dung DC tri lieu d Viet Nam
Vai trd chu y l u vd tam quan trpng cija DC da dupe cdng ddng khoa hpc the gidi khang dinh, ehung ta ed t h i ddt trpng tdm nghien cUu vd khai tridn Ung dung DC d Viet Nam cho chUdng trinh tri lieu cdc benh ung budu. Ve phUdng dien khoa hpc vd ky thudt, trong nhQng nam qua, cdc nhd nghien eUu sinh hpc d trong nude da dgt dupe nhQng tidn bd can thid't vd t l bdo hpc, sinh hpc phdn \ii cd tiem ndng Ung dung edng nghe DC. Viet Nam da ed mdt sd cd sd ed didu kien ldm viec theo tieu chuan GMP, ISO; ddc biet Id nhQng phdng thf nghiem te bdo gdc da dupe Nhd nude ddu tu khd day dij, cd the dung de trien khai lieu phdp DC vi cd hai cdng nghe te bdo gdc vd DC ed nhidu diem vd didu kien ky thudt tUdng dUdng.
Hien nay, chi phf tri lieu DC d Hoa Ky rd't cao (gid tri lieu mpt nam Id trdn 90.000 USD). Phan Idn nhQng phf tdn ndy Id trd eho phuc vu y td d phdng mgch vd cac benh vidn. Lfu t h i eua chung ta cd Id gid djch vu y t l thd'p, tuy nhien, cdc phf tdn dung cytokines nhu IL-4, GM-CSF, TNF_cho lieu phdp DC thudng rd't dat vi phdi nhdp khau ede san pham sinh hpc ndy tU nudc ngodi. Chung ta can tu chu trong vide tgo cdc cytokine ndy bang phUdng phdp nhdn bdn, thi ed thd hg gid thdnh xudng de phu hdp cho didu kidn kinh td cua benh nhdn d Viet Nam. Vi nghien eUu DC dang cd nhOng diin tid'n tUng ngdy, vide theo doi vd ddnh gid eac diln tiln nay can sU tham gia eija nhQng nhd nghien cUu chuyen sdu, kinh nghiem vd linh ddng trong dilu kien d Viet Nam de dgt dUde k i t qud trj lieu hQu hieu vd tdt nhat eho cdc benh nhdn.
Thdp nien qua, tU eac cai tiln ky thudt eua ngdnh gidi phau, xg tri vd hod tri vd cdc sdn pham sinh hoc dac tri nhU khdng the ddn ddng, ngdnh y t l da
Phdng thi nghidm td bio gdc, TrUdng Dai hgc Khoa hgc TU nhidn, D^i hqc Qudc gia TP Hd Chi Minh - nai cdng nghe DC diu tidn d Vidt Nam dang duqc tidn hinh qua si/ hudng din cua ThS Phan Kim Ngqc (hlnh giOa, bin phii) vd thi/c hien thi nghidm cua ThS Ph^m VSn Phuc (hlnh cudi, ben phii)
chUng kien nhQng tien bp mdi me vd gid tri trong vide chQa tri cdc benh ung budu; tuy nhien ung thU vdn ludn la can benh rat hiem ngheo vd phUe tap trong y hpc. Lieu phap DC hien cd tiem nang ddng gdp quan trpng trong nd lpc nghien eUu vd tri lieu cdc benh ung budu. Chung tdi tin tudng rang, ndng lUc cua cac nhd khoa hpc Viet Nam vd didu kien vdt chd't san cd, vide trien khai DC d trong nUdc Id kha thi vd cd nhidu tiem ndng thdnh cdng vd mang Igi ed hpi mdi can thilt de hd trp cho viec tri lieu can benh ung thu dang bung phdt d nUde ta. Hien tgi, phdng thf nghiem t l bdo gdc cija TrUdng Dgi hpc Khoa hpc Tp nhien, Dgi hpc Qude gia TP Hd Chf Minh da ed nhQng nghien eUu DC hdp tdc vdi Vien Ung budu thdnh phd cho tri lieu ung thu ngue eua phu nQ. Ddy Id mdt md hinh thuc t l vd hQu hidu, hy vpng se dupe triln khai tdi eac cd sd nghien cUu khdc de cdng nghd DC cd t h i mang Igi nhQng ddng gdp tdt dep cho vide chQa tri bdnh nhdn ung budu vd phdt trien nghien eUu vd benh ly ung thu d Viet Nam •
S6 thang 3.2012 T ^ T T o A M O r 67
