1.

c im chung v c ch ca dung th min dch Ngi ta tm ra nhiu c ch dung th ca t bo B v T i vi khng nguyn bn thn, v nhng c ch ny c th cng c th xy ra i vi khng nguyn ngoi lai. - Dung th min dch c tnh cht c hiu v ch xy ra sau khi khng nguyn c nhn din bi cc lymph bo T c hiu. Ngi ta chng minh iu ny qua nhng m hnh thc nghim. Nhng nm 1950, Medwar v cng s lm nghin cu trn 2 dng chut A v B d loi v nhn thy rng khi ghp da ca dng B ln chut dng A th c hin tng thi ghp xy ra do c s khc bit v MHC. Nhng nu chut A c tim lymph bo dng A trong thi k s sinh th cc t bo tim vo khng b thi b (v chut s sinh thiu ht min dch), v mt s t bo ny vn tn ti trong chut nhn, ngi ta gi nhng con chutt c hai loi t bo lymph ca A v B ny l ng vt c hai tnh cht (chimera). V nh vy dng chut A ny khi ln ln cng c th chp nhn mnh ghp t chut dng B (Hnh 2). Tuy nhin cn lu rng chut dng A s thi b tt c mnh ghp ly t cc dng chut c MHC khc vi dng B. Nh vy, dung th min dch c tnh c hiu.

Hnh 2. To dung th trong th nghim ghp m (Ngun: Abul K. Abbas, 2003)

Chut trng thnh dng A to phn ng thi i vi mnh ghp ly t chut dng B (A). Nu chut s sinh dng A c tim lymph bo dng B (mu ), th khi trng thnh n khng thi ghp i vi dng B (B). Tuy nhin khi ghp mnh m ly t dng chut khc (vd. dng C) th phn ng thi ghp vn xy ra, iu ny chng t dung th cng c tnh c hiu (C).

Th nghim trn y dn n quan im rng vic tip xc ca t bo lymph ang trong giai on pht trin vi khng nguyn s dn n dung th vi khng nguyn . S tn ti ca t bo lymph l v ng loi trong mt vt ch c gi l tnh vi lng gen (microchimerism) trong to mu. Ngi ta ang nghin cu tnh cht ny chng thi ghp ngi. Tuy nhin hiu bit v iu ny vn ang cn rt t. - T dung th c th c to ra trongcc c quan lymph trung ng nh l kt qu ca tnh trng t bo lymph phn ng t thn nhn din khng nguyn bn thn khi cha trng thnh, v ngi ta gi y l dung th trung tm (central tolerance). Trong khi cc c quan lymph ngoi bin th cc t bo lymph trng thnhnhn din khng nguyn bn thn trong nhng iu kin c bit to ra t dung th, v ngi ta gi y l dung th ngoi bin (peripheral tolerance) (Hnh 3). Dung th trung tm m bo cho kho t bo lymph trng thnh khng th nhn din khng nguyn ph bin ca bn thn m chng rt d dng tip xc trong c quan lymph trung ng. C ch ny chu trch nhim chnh trong vic loi b t bo lymph phn ng t thn. Tuy nhin, dung th trung ng khng th gii thch ti sao h thng min dch dung th c vi vi nhng khng nguyn hin din ch trong cc m ngoi bin (khc vi khng nguyn ph bin). V chnh c ch dung th ngoi bin mi chu trch nhim dung th i vi nhng khng nguyn c hiu m ny.

Hnh 3. Dung th trung ng v ngoi bin i vi t khng nguyn (Ngun: Abul K. Abbas, 2003)

Lymph bo non c hiu t khng nguyn c th tip xc vi cc khng nguyn ny trong c quan lymph trung ng v loi b chng ( l trng hp dung th trung ng). Nhng mt s lymph bo phn ng vi t khng nguyn c th thot khi s loi tr ny v trng thnh ri i ra c quan lymph ngoi bin. Ti y chng li mt ln na c th b loi tr khi tip xc vi t khng nguyn ( l trng hp ca dung th ngoi bin). Trong Hnh ch cp n t bo B nhng qu trnh ny cng xy ra cho c t bo T.

- S d dung th trung ng c to ra l nh trong sut thi gian hin din trong c quan lymph trung ng tt c lymph bo tri quan mt giai on tip xc vi khng nguyn c bit dn n dung th ch khng phi l hot ha. Hu nh ton b giai on pht trin lin quan n dung th ca lymph bo u c lin quan gii phu hc vi c quan lymph trung ng (tc l tuyn c i vi t bo T v ty xng i vi t bo B). Loi khng nguyn duy nht tn ti mt cch bnh thng vi nng cao trong cc c quan ny l t khng nguyn bi v tt c khng nguyn ngoi lai u b bt gi v a n cc c quan lymph ngoi bin nh hch bch huyt, lch, m lymph nim mc. Nh vy, trong c quan lymph trung ng, t bo lymph non thng hay tip xc vi khng nguyn bn thn nng cao, v cc cln t bo lymph c th th i lc cao nhn din cc khng nguyn bn thn ny u b tiu dit. Qu trnh ny c gi l s chn la m tnh (negative selection). Dung th trung ng loi b nhiu lymph bo nguy him nht (tc nhng t bo c th th i lc cao i vi nhng khng nguyn ph bin ca c th). Mt s t bo T tip xc vi khng nguyn bn thn trong tuyn c c th pht trin thnh t bo iu ha, c chc nng c ch p ng min dch. - c ch ngoi bin c to ra khi t bo lymph trng thnh nhn din khng nguyn vi mt mc thch hp ca cc ng kch thch cn thit cho s hot ha hoc khi t khng nguyn tn ti lu di hoc to kch thch lp i lp li trong c quan lymph ngoi bin. Dung th ngoi bin rt quan trng cho vic duy tr tnh khng p ng vi nhng khng nguyn bn thn ch hin din trong m ngoi bin m khng c trong c quan lymph trung ng. Kho lymph trng thnh c cha nhng t bo c kh nng nhn din nhng khng nguyn bn thn c hiu m ny, v p ng ca lymph bo i vi nhng khng nguyn ny nhng p ng ca lymph bo i vi chng hoc l khng xy ra hoc c iu ha mt cch cht ch m bo c t dung th. - C ch ch yu ca dung th lymph bo bao gm: cht lp trnh ca t bo (gi l loi b t bo), bt hot chc nng m t bo khng cht (gi l tr t bo); v c ch hot ha t bo cng nh chc nng hiu qu nh cc t bo lymph iu ha. Dung th truing ng chu trch nhim chnh v c ch loi b t bo, trong khi dung th ngoi bin thc hin c 3 c ch trn. - Mt s t khng nguyn c th b h min dch b qua, do vy khi lymph bo tip xc vi nhng khng nguyn ny th khng to c p ng nhng t bo vn cn sng v vn c chc nng bnh thng. C ch ca iu ny vn cha c r nn chng ta khong cp n trong chng ny. 2. Dung th t bo T Dung th trong t bo T CD4+ l mt c ch nhm ngn chn p ng min dch i vi cc khng nguyn protein bi v t bo T gip l t bo cn thit khi ng c p ng min dch t bo ln dch th i vi protein. Ngi ta mt kh nhiu cng sc nhn thc ra c iu ny v nhm n mc tiu l to ra chin lc iu tr mi: to ra dung th trong chng thi ghp v tiu dit chc nng dung th i vi t khng nguyn. i vi t bo T CD8+ th hiu bit v dung th trong t bo ny cn qu t. 2.1. Dung th trung ng i vi t bo T

Hnh 4. Dung th trung ng i vi t bo T (Ngun: Abul K. Abbas, 2003)

S nhn din khng nguyn bn thn bi t bo T trong tuyn c c th dn n git cht t bo ny (gi l la chn m tnh, loi t) hoc hnh thnh nhng t bo T iu ha i n cc m ngoi bin.

Trong sut thi gian pht trin trong tuyn c, t bo T non no nhn din khng nguyn vi i lc cao s b loi b (Hnh 4). Hai yu t quyt nh vic loi b t bo T ny bao gm nng cao ca t khng nguyn v i lc mnh ca t khng nguyn vi th th ca n trn t bo T . Khng nguyn bn thn cng c x l v trnh din cng vi MHC trn t bo trnh din khng nguyn (APC)trong tuyn c. T khng nguyn c mt trong tuyn c rt a dng v bao gm nhiu protein lu ng cng nh nm trong t bo. Trong s nhng t bo T non trong tuyn c c to ra t nhng t bo tin thn (precursor) tuyn c c mt s mang th th c hiu c th nhn din phc hp peptid-MHC vi i lc cao. Nu cc t bo tuyn c dng tnh mnh vi nhng th th i lc cao ni trn gp t khng nguyn tng ng trong tuyn c, th kt qu xy ra l t bo ny s b cht theo kiu lp trnh (apoptosis). Mt gii thch v tnh trng dung th ch xy ra t bo lymph cha trng thnh l do nhng tn hiu to ra trong qu trnh s nhn din khng nguyn t bo non khc vi tn hiu to ra khi t bo trng thnh. Tuy nhin chng ta cha bit c nhng tn hiu ny khc nhau th no v n hot ng khc nhau ra sao. Qu trnh ny xy ra cho c t bo T ph thuc MHC lp I v II v do cn thit cho c dung th t bo T CD8+ v CD4+. C gi thuyt cho rng tnh t min l hu qu ca s tht bi ca s chn la m tnh trong tuyn c. Tuy vy, cha c bng chng no nmang tnh thuyt phc v gi thuyt ny ngi hay ng vt th nghim. Trong thc t, khi dung th trung ng khng thc hin c th dung th ngoi bin c trch nhim duy tr tnh khng p ng vi khng nguyn bn thn. 2.2. Dung th t bo T ngoi bin

Dung th ngoi bin l c ch t bo T trng thnh chu trch nhim nhn din t khng nguyn m ngoi bin tr nn khng p ng i vi nhng khng nguyn ny. C ch ca dung th ngoi bin l chu trch nhim v dung th ca t bo T i vi nhng t khng nguyn c hiu m thng khng c nhiu trong tuyn c. C ch ny cng to ra tnh cht khng p ng i vi khng nguyn ngoi lai. Bng cc th nghim vi t bo T CD4+, ngi ta tm thy rng dung th ngoi bin l do tnh tr, do s loi b hay c ch ca t bo T i vi khng nguyn. 2.2.1. Tnh tr c to ra khi nhn din khng nguyn m khng c ng kch thch tng ng

Hnh 5. Tr t bo T (Ngun: Abul K. Abbas, 2003)

p ng t bo T c khi ng khi chng nhn din khng nguyn do APC c mang yu t ng kch thch trnh din v ng thi nhn din yu t ng kch thch (vd. B7) bng th th hot ha CD28. Nu t bo T nhn din khng nguyn m khng c yu t ng kch thch hoc c s hin din ca tng tc CTLA-4:B7 th t bo T khng to c p ng v tr nn mt kh nng p ng ngay c khi sau ny khng nguyn c trnh din cng vi yu t ng kch thch.

Nu t bo T CD4+ nhn din khng nguyn peptid c trnh din bi APC m khng c cc ng kch thch th t bo T vn cn sng st nhng tr nn khng c kh nng p ng vi khng

nguyn sau ny khi c APC trnh din (Hnh 5). Kiu mt kh nng p ng ny ln u tin c m t trong mt th nghim vi cc cln t bo T chut v c gi l tnh tr cln (clonal anergy). Trc y chng ta c cp rng c s hot ha y t bo T cn c s nhn din khng nguyn (tn hiu 1) v nhn din ng kch thch, m ch yu l B7-1 v B7-2 bi CD28 (tn hiu 2). Nu ch c tn hiu 1 (tc nhn din khng nguyn) th c th dn n tnh tr. Tnh tr c th to ra nu t bo T dng th th c ch i vi phn t B7, tc CTLA-4, nhn din ng kch thch trn APC lc t bo ang nhn din khng nguyn. Trong trng hp ny, tnh tr khng phi l hu qu ca nhn din khng nguyn thiu ng kch thch m do th th CTLA-4 to ra tn hiu c ch i vi t bo T khi th th ny tip xc vi cc ng kch thch B7 trn APC. Nhng pht hin ny chng t rng ng vt bnh thng CTLA-4 hot ng lin tc kim sot t bo T. Chng ta cn cha bit c yu t no quyt nh khi no th t bo T nhn din phn t B7 dng th th CD28 to ra p ng min dch v khi no th li nhn din B7 dng th th c ch CTLA-4 to ra dung th. C th rng khi t bo APC bc l mc B7 thp th phn ng u tin vi CTLA-4 v CTLA-4 gn vi B7 vi i lc cao hn CD28. ng thi, CD28 th li c biu hin trn t bo T trinh v do c dng to ra p ng min dch, trong khi CTLA-4 c bc l sau khi t bo T c hot ha v dng chm dt p ng. Nhiu th nghim trn ng vt a n gi thuyt rng bn cht ca APC m l yu t quyt nh xem s xy ra dung th hay tnh t min i vi mt t khng nguyn no . APC c mt trong m lymph hoc khng lymph ngoi bin thng trng thi ngh v ch biu hin rt t hoc khng c ng kch thch. Nhng APC ny c l chuyn dng trnh din t khng nguyn nn t bo T nhn din nhng t khng nguyn ny tr nn b tr. Cc nhim trng v vim ti ch c th hot ha APC v lm tng biu hin ng kch thch, lm mt kh nng dung th v xut hin phn ng t min i vi khng nguyn m. Tuy nhin, t khng nguyn no thng gy tnh tr cho t bo T tng ng, v s phn ca nhng t bo T th no in vivo th cha r. C ch ha sinh ca tnh tr cng cn c bit rt t. T bo T tr khng sn xut c yu t pht trin, IL-2, v khng tng sinh khi p ng vi khng nguyn. Trong cc cln t bo T c to tnh tr th lin kt cho vi TCR khng thc hin c nn khng th dn n hot ha cc enzym JNK v ERK tham gia to ra yu t sao chp AP-1. iu th v l khng phi tt c tn hiu qua trung gian TCR u b mt trong nhng t bo T bt hot ny, v c ch v sao ch b mt chn la chc nng ha sinh th vn cha c r. 2.2.2. Loi b t bo T bng to ra ci cht t bo do hot ha S kch thch lp i lp li t bo T bi nhng khng nguyn tn ti thng xuyn to ra ci cht cho t bo T hot ha ny theo cch cht lp trnh (Hnh 6). Dng cht ny c gi l cht t bo do hot ha (activation-induced cell death). iu ny xy ra khi mt lng ln t bo T mi hot ha c ti hot ha bi khng nguyn hoc mt yu t ging khng nguyn no .

Hnh 6. Ci cht do hot ha i vi t bo T, qua trung gian ca Fas (Ngun: Abul K. Abbas, 2003)
Khi khng nguyn c trnh din bi APC bnh thng t bo T p ng bng cch tit ra IL-2 v ng thi tng sinh, bit ha. Nu li ti kch thch t bo T mi c hot ha ny bng khng nguyn th s dn n biu hin ng thi c th th cht Fas ln ligand ca n (FasL), sau s xy ra lin kt gia Fas v FasL dn n ci cht lp trnh ca t bo T. Lu rng FasL trn t bo T c th lin kt vi Fas trn chnh bn thn n hoc trn mt t bo T khc.

Ci cht t bo do hot ha l mt dng cht lp trnh c to ra do tn hiu t th th cht ca mng. Trong t bo T CD4+, s hot ha lp i lp li dn n s ng biu hin ca hai phn t, mt phn t l th th to ra ci cht gi l Fas (CD95) v mt l ligand ca n tc FasL. Fas l thnh vin ca h th th yu t hoi t m, TNF, v FasL th ging vi cytokin TNF. Khi t bo T c hot ha lp i lp li, FasL c biu hin trn mng t bo v lin kt vi Fas b mt v lin kt vi Fas trn cng mt t bo T hay t bo T kt cn. iu ny hot ha mt dy chuyn phn ng ca cc protease cystein ni bo c tn l caspase, v dn n kt qu cui cng l ci cht lp trnh ca t bo. T bo cht lp trnh nhanh chng b tiu hy bi i thc bo v khng to ra phn ng vim. Ni dung ch yu ca hin tng ny l s loi b qun th lymph trng thnh b kch thch lin tc bi khng nguyn c hiu. Nng cao ca yu t pht trin IL-2 lm tng tnh nhy cm ca t bo T c khng nguyn kch thch i vi hin tng cht lp trnh qua trung gian Fas. Do c ch dung th bng cch loi b t bo thng gp khi mt lng ln t bo T c hot ha v sn xut IL-2. Mt con ng khc ca ci cht lp trnh l s loi b cc kch thch ko di trong c khng nguyn v cc yu t pht trin. Con ng ny hnh nh quan trng trong vic duy tr tnh hng nh ni mi hn l t dung th v chng ta s bn n vo cui chng ny. Ngi ta cho rng ci cht lp trnh ca t bo do s hot ha qua trung gian ca Fas chu trch nhim trong vic loi b t bo T c hiu vi nhng t khng nguyn hin din vi lng ln ngoi bin. Con ng cht lp trnh ny cng tham gia loi b t bo B phn ng t thn. Chut khng c biu hin Fas v tr em t bin Fas c biu hin ca bnh t min rt ging vi lupus ban h thng. iu ng ngc nhin l chut thc nghim b loi b IL-2 cng xut hin tnh t min.

C ch cho trng hp ny c th l chut khng c IL-2 cng khng to c cht lp trnh cho t bo T phn ng t thn c trung gian bi Fas. Thut ng ci cht do hot ha (activation-induced cell death) cng c dng m t ci cht lp trnh do t bo T b khng nguyn kch thch khi khng c min dch t nhin hoc ng kch thch. Ngi ta cho rng nhn din khng nguyn gy ra s chuyn ch trong ty th ca cc protein tin t ca ci cht lp trnh (pro-apoptotic protein). Nhng protein ny l thnh vin ca h Bcl. Trong tnh hung ny, ci cht ca t bo l do con ng ty th v khng ph thuc vo cc th th cht (death receptor). Cc siu khng nguyn v c l c t khng nguyn c th khi ng s loi b t bo T bng con ng ny. 2.2.3. Dung th do lymph bo T iu ha

Hnh 7. c ch min dch qua trung gian t bo T (Ngun: Abul K. Abbas, 2003)

Trong p ng min dch bnh thng, t bo T nhn din khng nguyn ri tng sinh v bit ha thnh t bo hiu qu. Mt s t bo T c th bit ha thnh t bo iu ha trong m ngoi bin hoc trong tuyn c, v nhng t bo ny c ch s pht trin hoc chc nng ca t bo hiu qu.

Mt s p ng min dch b c ch bi nhng t bo c kh nng phong b s hot ha v chc nng ca t bo lymph T hiu qu (Hnh 7). Nhng t bo c ch ny cng l t bo T v c gi l lymph bo T iu ha. Ngi ta thc hin c nhiu th nghim chng minh tm quan trng ca t bo T iu ha trong vic duy tr t dung th. Cc nghin cu chng minh rng ngi v chut t bo iu ha l CD4+ c biu hin mnh chui ca th th IL-2 (tc phn t CD25) nhng khng c bt c marker hot ha no khc. T bo T iu ha c th c hnh thnh d nhn din t khng nguyn trong tuyn c hoc trong c quan lymph ngoi bin; tuy nhin chng ta vn cn cha bit nhng iu kin c bit no khi tip xc khng nguyn to ra nhng t bo ny. IL-2 c th c vai tr trong s pht trin hoc chc nng ca t bo T iu ha, nn khi thiu IL-2 hoc IL-2R th c th dn n thiu t bo iu ha. S thiu ht ny c th ng gp vo vic to ra tnh t min chut thiu IL-2 hoc th th IL-2. C cho rng t bo T iu ha nhn dng c t khng nguyn, nhng tnh c hiu th khng xc nh c. C ch hot ng ca t bo iu ha vn cn cha c r. Mt s nghin cu th cho rng t bo T iu ha c ch p ng min dch bng cch tit cc cytokin c ch min dch v d nh IL-10 v yu t pht trin chuyn dng (transforming growth factor) - (TGF-) (Hnh 8). TGF- l mt cht c ch i vi s tng sinh t bo T v B. IL-10 do mt s t bo T gip to ra c th c ch hot ha i thc bo v i khng vi hot ng ca mt cytokin hot ha i thc bo l interferon- (IFN-). Nh vy, cc t bo T tit cc cytokin c ch ny c th c ch p ng ca cc t bo T khc. C mt s nghin cu khc cho rng t bo T iu ha tc ng nh tng tc trc tip vi APC hoc vi t bo T p ng, ch khng phi nh tit cytokin.

Hnh 8. C ch hot ng ca t bo T iu ha (Ngun: Abul K. Abbas, 2003)

y l gi thuyt v c ch ca t bo T iu ha c ch p ng T H1. APC trnh din khng nguyn cho t bo T trinh v tit IL-12 kch thch t bo trinh bit ha thnh TH1. TH1 sn xut IFN- hot ha i thc bo trong giai on hiu qu ca p ng. T bo T iu ha c th c ch s hot ha t bo T. Mt s t bo T iu ha c th tit cc cytokin c ch min dch, vd. IL-10, TGF-.

2.2.4. Dung th ngoi bin ca t bo T CD8+ Phn ln hiu bit ca chng ta cho n nay v dung th ngoi bin ch lin quan n t bo T CD4+, nhng cng c mt s thng tin cho rng c ch dung th cng c lin quan n t bo T CD8+. C th l nu t bo T CD8+ nhn din MHC lp I gn peptid m khng c ng kch thch hoc gip ca t bo T th t bo T CD8+ tr nn tr. Trong trng hp ny, t bo T CD8+ ch tip nhn tn hiu 1 (tc khng nguyn) m khng c tn hiu 2, v c ch tr chc chn l ging vi trng hp t bo gip . Vai tr ca CTLA-4 trong vic to ra tnh tr cho t bo T CD8+ vn cn cha r. T bo T CD8+ tip xc vi t khng nguyn c nng cao c th chu ci cht do hot

ha, nhng qu trnh ny hnh nh khng lin quan g n th th cht Fas. Ngi ta vn cha bit t bo T iu ha c c ch trc tip s hot ha t bo T CD8+ hay khng. 2.2.5. Cc yu t quyt nh tnh dung th ca t khng nguyn C nhiu tnh cht ca khng nguyn tham gia quyt nh xem khng nguyn ny c th c dung th hay to ra s hot ha t bo T (Bng 1). Ring t khng nguyn c nhng tnh cht c bit khin cho chng d dng c dung th. Mt s t khng nguyn hin din vi nng cao trong m lymph trung ng, iu ny c th dn n dung th trung ng hoc to ra cc t bo T iu ha. ngoi bin, t khng nguyn thng xut hin trc h thng min dch m khng gy vim hoc min dch t nhin. Trong nhng iu kin ny, APC bc l t hoc khng c ng kch thch, v nhn din khng nguyn c th b qua p ng hoc to ra tnh tr. Bi v t khng nguyn khng th b loi b nn nhng t khng nguyn no tip xc APC th c th hot ha t bo lymph T lp i lp li nhiu ln, v kch thch nhiu ln ny c th gy ra ci cht t bo do hot ha (activation-induced cell death). Quan im ny ch yu da trn nhng m hnh th nghim trn chut. Do , mt trong nhng kh khn hin nay l tm ra nhng tnh cht ca t khng nguyn ngi gip cho chng to ra dung th min dch.

Bng 1. Cc yu t tham gia quyt nh tnh dung th ca khng nguyn protein 3. Dung th lymph bo B Dung th i vi lymph bo B rt cn thit duy tr tnh khng p ng i vi cc t khng nguyn khng ph thuc tuyn c, v d cc polysaccharid v lipid. Dung th t bo B cng quan trng trong trong vic ngn nga p ng khng th i vi khng nguyn protein. Cc nghin cu trn ng vt truyn gen cho thy rng c nhiu trm kim sot i vi qu trnh trng thnh v hot ha t bo B, ti nhng im nhng t bo B tip xc vi t khng nguyn s b loi b. 3.1. Dung th trung ng i vi t bo B

Nhng lymph bo B non khi nhn din t khng nguyn vi i lc cao trong ty xng th s b loi b hoc thay i tnh c hiu. Cng nh i vi t bo T, cc yu t quyt nh xem t bo B non c b loi b hay khng chnh l bn cht v nng ca t khng nguyn trong ty xng v i lc ca th th t bo B vi khng nguyn. Dung th trung ng hu nh xy ra i vi cc cc t khng nguyn a gi, c th lin kt cho vi nhiu th th khng nguyn trn mt t bo B c hiu v to ra tn hiu qua trung gian Ig (Ig-mediated signal) cc mnh i vi t bo B. V d cho nhng khng nguyn a gi nh vy l cc phn t mng v phn t polymer chng hn nh DNA chui kp. C ch ch yu ca dung th trung ng ca t bo B non i vi t khng nguyn a gi, v d protein mng, l kiu cht lp trnh. iu ny cng ging c ch chn la m tnh ca t bo T non trong tuyn c. T bo B trong ty xng tip xc vi t khng nguyn cng c th p ng vi khng nguyn ny bng cch ti hot ha cc gen RAG1 v RAG2 v bc l mt chui nh Ig mi, tc l c tnh c hiu mi. Qu trnh ny c gi l chnh sa th th (receptor editing) v l mt c ch t bo B phn ng t thn nh mt tnh c hiu ny v tip tc tn ti. 3.2. Dung th ngoi bin t bo B Lymph bo B trng thnh nhn din t khng nguyn trong m lymph ngoi bin khi khng c t bo T gip c hiu c th tr nn mt tnh p ng hoc b loi b khi cc nang lymph. Nhiu c ch dung th t bo B ngoi bin c nghin cu trn chut truyn gen. Trong , t bo B c hiu c th tip xc vi t khng nguyn ha tan ngoi bin m khng c t bo T gip (Hnh 9). S phn ca cc t bo B ny l tr thnh tr trong thi gian di v do khng p ng vi khng nguyn. Nu t bo B tr tip xc vi t bo T gip c hiu khng nguyn th c th b git do FasL trn t bo T kt hp vi Fas trn t bo B. C ch lai b t bo B kiu ny khng xy i vi chut hoc ngi c t bin gen Fas hoc FasL v dn n sn xut t khng th. C ch ha sinh i vi tnh trng tr t bo B cn cha c r. T bo B tr khng c kh nng hot ha tyrosine kinase, v d Syk, duy tr s gia tng calci ni bo khi tip xc vi khng nguyn. Nhng t bo B tip xc vi t khng nguyn ngoi bin cng mt kh nng di chuyn vo nang lymph nn khng c hot ha v sn xut khng th chng li t khng nguyn . C ch c th gii thch i vi vic loi b ra khi nang ny l t bo B nhn mt phn tn hiu t khng nguyn khng hot ha dn n bc l mt cch yu t th th chemokin (CXCR5) l th th gip chuyn t

bo

trinh

vo

nang

lymph.

Hnh 9. Dung th ngoi bin i vi t bo B trong mt th nghim truyn gen (Ngun: Abul K.
Abbas, 2003) T bo B c hiu lysozym trng g (HEL) c truyn cho chut rtuyn gen co mang HEL lu ng trong mu nh l mt t khng nguyn. (T bo T c hiu HEL b loi b trong chut ny v HEL hin din trong tuyn c.) Khi t bo b tip xc vi t khng nguyn m khng c t bo t gip th t bo B b y ra khi nang lymph v chng khng cn kh nng p ng vi khng nguyn na.

Ngi ta nghi ng rng c nhiu bnh do t khng th gy ra c th l do vic dung th t bo B khng thc hin c, nhng nguyn nhn v sao khng thc hin c th cn cha r. Ngi

bnh thng khng sn xut t khng th chng li protein bn thn mnh, iu ny c th do s loi b cln hoc dung th i vi t bo lymph T gip , trong khi chc nng t bo B vn bnh thng. Trong nhng trng hp ny, thiu ht kh nng duy tr dung th t bo T chnh l nguyn nhn to ra sn xut t khng th. C ch dung th t bo T v B c nhiu ch ging nhau, nhng cng c nhiu khc nhau c bn (Bng 2). Tt c nhng hiu bit ny u hin ang do cc m hnh thc nghim mang li. p dng nhng hiu bit thc nghim suy ra cc c ch dung th i vi cc khng nguyn khc nhau trn ngi bnh thng, v tm xem khi no th dung th tht bi dn n bnh t min l vn hin ang c quan tm nghin cu.

Bng 2. T dung th t bo lymph T v B 4. Dung th vi khng nguyn protein l Khng nguyn l c th c a vo c th sao cho to ra dung th ch khng phi l p ng min dch. Nhn chung, khng nguyn protein a vo c th cng vi t cht c khuynh hng to ra p ng min dch, trong khi liu cao khng nguyn a vo ton thn m khng c t cht c xu hng to dung th. L do c th gii thch: t cht l cht kch thch s bc l ng kch thch trn APC, nn khi khng c ng kch thch th vic nhn din khng nguyn ca t bo T s lm cho n b tr i vi khng nguyn . Khng nguyn c dung th cng c th hot ha t bo T iu ha hoc thc y s bit ha t bo T thnh cc qun th sn xut cytokin, nh IL-4, khng to ra min dch t bo. Khng nguyn protein a vo theo ng ming thng dn n c ch mnh s hnh thnh p ng min dch t bo v th dch ton thn. Hin tng ny c gi l dung th ng ming. Ngi ta a ra gi thuyt rng vai tr sinh l ca dung th ng ming l c ch quan trng ngn chn p ng min dch i vi cc loi khng nguyn thc phm v i vi nhng vi khun k

sinh bnh thng ng tiu ha, cn thit cho vic tiu ha v hp thu. Liu lng khc nhau ca khng nguyn a vo theo ng ming c th to ra tnh tr cho mt s t bo T c hiu khng nguyn hoc c th sn xut cytokin, nh TGF-, c ch s tng sinh lymph bo, to ra c ch p ng min dch. Trong thc t, TGF- c th tham gia vo c hai p ng khc nhau i vi khng nguyn ng ming l sn xut IgA cho nim mc v dung th ton thn, bi v cytokin ny gy chuyn mch t bo B sn xut IgA v c ch tng sinh lymph bo. Ngi ta vn cn cha r ti sao khi a mt liu ln mt khng nguyn no vo theo ng ming th to ra dung th ton thn, nhng khi gy min dch vi mt s khng nguyn khc theo ng ung, v d vc xin polio th to ra p ng khng th bo v ph thuc t bo T v c min dch nh lu di. Dung th ng ming l mt liu php c tim nng iu tr bnh t min khi bit r t khng nguyn, hoc c th dng cho nhng bnh cnh lm sng khc khi cn c ch p ng min dch c hiu i vi mt khng nguyn no . Tuy nhin nhng th nghim lm sng v khng nguyn ng ming iu tr bnh t min vn cha thnh cng. 5. Cn bng ni mi i vi h min dch: Chm dt p ng min dch bnh thng Trn y chng ta cp n vic ti sao h min dch tr nn khng p ng vi khng nguyn bn thn. Ci cht v s bt hot ca lymph bo l rt quan trng trong vic duy tr s lng n nh ca t bo lymph trong sut i sng sinh vt mc d lun c hin tng tip tc sinh sn ca t bo v hin tng tng sinh khi c p ng min dch. S duy tr s lng c nh ca t bo c gi l s hng nh ni mi. p ng min dch i vi khng nguyn l c tnh t gii hn v tt dn khi khng nguyn b loi b, a h min dch tr li tnh trng ngh ngi c bn ban u. Trong phn trc, chng ta cp n s m rng cln t bo lymph B v T sau kch thch khng nguyn v cc tn hiu khc, s bit ha ca nhng t bo lymph ny thnh t bo hiu qu v t bo nh. Nhng lymph bo no khng nhn tn hiu hot ha s cht v s lng qun. Khng nguyn, ng kch thch, v cytokin c sn xut trong p ng min dch ngn khng cho lymph bo cht theo kiu cht lp trnh. S kch thch ang hin hu lm cho lymph bo hot ng v bc l nhng protein chng ci cht lp trnh (anti-apoptotic), m quan trng nht l h Bcl. T bo lymph tn ti c nh kch thch ca khng nguyn, ng kch thch v cytokin s khi u cho vic m rng cln v bit ha thnh t bo hiu qu. T bo hiu qu hnh thnh trong sut p ng min dch c chc nng loi b khng nguyn cng vi s phi hp ca p ng min dch t nhin. Kt qu l, nhng cln lymph c hot ha bi khng nguyn b mt i kch thch ang hin hu v b git bi hin tng cht lp trnh (Hnh 10). S gim dn p ng min dch to cn bng ni mi chnh l do t bo lymph b cht theo kiu lp trnh do thiu kch thch khng nguyn. Cc t bo hiu qu hnh thnh sau kch thch khng nguyn cng c thi gian na i sng ngn v thng khng t lm mi c. Do , sau khi khng nguyn b loi b, du hiu duy nht cn li l s tn ti ca lymph bo nh. Nhng t bo ny sng lu nhng trong trng thi khng hot ng.

Hnh 10. C ch gim dn p ng min dch bnh thng (Ngun: Abul K. Abbas, 2003)
Khi gp khng nguyn xm nhp c th t bo lymph T tng sinh v bit ha. Nhng n khi khng nguyn b loi b , th nhiu t bo T cng cht i do hin tng cht lp trnh. Mt s p ng c th c chm dt bng c ch iu ha ch ng, v d nhwj c ch qua trung gian CTLA-4 hoc s lin kt vi th th cht. Vo cui mt p ng min dch, ch cn t bo nh l t bo sng duy nht. C ch cht lp trnh l c ch chnh gy ra s tn li dn ca mt p ng min dch bnh thng.

Bn cnh s gim dn p ng min dch do nhiu t bo cht i, nhng lymph bo c khng nguyn kch thch c th to ra nhng c ch iu ha nhm tham gia vo vic kt thc p ng min dch. Hai trong nhng c ch ny c trnh by trn phn cc c ch dung th t bo T ngoi bin. T bo T hot ha bt u bc l CTLA-4 tng tc vi phn t B7 v c ch s tng sinh lymph bo.. CTLA-4 xut hin vo thi im 3-4 ngy sau khi hot ha t bo T in vitro, v iu ny bo trc cho s tt dn ca p ng t bo T. Nh vy, chng ta c th xem CTLA-4 nh mt yu t chm dt hot ha t bo T. T bo T hot ha cng c th biu hin nhng th th gy cht nh Fas v cc ligand cho cc th th ny, v s tng tc ca nhng phn t ny gy ra ci cht lp trnh. Tuy nhin, cha c bng chng r rng v vic CTLA-4 hoc th th gy cht c th chm dt p ng min dch bnh thng i vi khng nguyn ngoi lai. Tng t chng ta khng bit t bo T iu ha c tham gia vo vic hn ch p ng i vi khng nguyn ngoi lai hay khng. p ng ca t bo B cng c kim sot cht ch bi v IgG do t bo B sn xut c th ta phc hp vi khng nguyn v phc hp lin kt vi th th Fc trn t bo B c ch t bo ny. Qu trnh phn hi khng th (antibody feedback) ny c m t k trong chng Hot ha t bo B v p ng khng th.

Mt c ch khc iu ha p ng min dch thu c c Niels Jerne xut trong nhng nm 1970, l gi thuyt mng idiotyp. Gi thuyt ny da vo mt thc t l th th khng nguyn ca t bo lymph rt a dng v th th ca bt c tnh c hiu no u c trnh t acid amin khc vi th th ca tnh c hiu khc. Trnh t duy nht ny to ra mt cu to gi l idiotyp c nhn din bi ch cc lymph bo c tnh c hiu, hay anti-idiotyp tng ng. Nguyn l c bn ca gi thuyt mng idiotyp l: cc tng tc b sung gia idiotyp v anti-idiotyp s dn n mt trng thi n nh cn thit cho s cn bng ni mi ca h min dch. Khi mt khng nguyn l xm nhp h thng, mt hoc mt vi cln lymph bo s tham gia p ng, cc idiotyp ca chng s c m rng, v p ng anti-idiotyp c to ra nhm mc ch lm gim bt cc t bo lymph c hiu khng nguyn. Mc d gi thuyt ny vn cn l mt tng hp dn, nhng trn thc nghim ngi ta cha chng minh c rngmng idiotyp tht s c tham gia vo vic iu ha p ng min dch bnh thng.