NGHIÊN cứu độc TÍNH và tác DỤNG KÍCH THÍCH MIỄN DỊCH của VIÊN NANG KOVIR TRÊN ĐỘNG vật THỰC NGHIỆM

B GIO DC V O TO B Y T TRNG I HC Y H NI INH TH THU HNG NGHIÊN CứU ĐộC TíNH Và TáC DụNG KíCH THíCH MIễN DịCH CủA VIÊN NANG KOVIR TRÊN ĐộNG VậT THựC NGHIệM Chuyờn ngnh : Dc lý Mó s : NT 62725001 CNG LUN VN BC S NI TR NGI HNG DN KHOA HC: TS Phm Th Võn Anh H NI - 2016 DANH MC CH VIT TT IL : Interleukin CY : Cyclophosphamid DAS : Diallyl sulfid DADS : Diallyl disulfid SCID : Severe combined immunodeficiency disease (Bnh suy gim dch phi hp nng) HIV : Human immodeficiency virus AIDS : Acquired immune deficiency syndrome JAK : Janus kinase STAT : The signal transducers and activators of transcription (Cỏc yu t hot húa v dn truyn tớn hiu ca s phiờn mó) MHC : Major histocompatibility complex G-CSF : Granulocyte colony-stimulating factor (Yu t kớch thớch to cm bch cu ht) GM-CSF : Granulocyte-macrophage colony-stimulating factor (Yu t kớch thớch to cm bch cu ht v i thc bo) CD : Clutster of differentiation Fc : Crystalisable fragment IFN : Interferon TNF : Tumor necrosis factor Th1, Th2 : T helper cells type and type Tc : Cytotoxic T lymphocyte CR3 : Complement receptor TLR : Toll-like receptor IGF : Insulin growth factor (yu t tng trng ging insulin) FDA : Food and Drug Administration ELISA : Enzyme linked immunosorbent assay Ig : Immunoglobulin LD50 : Lethal dose 50 (liu cht 50%) TNF : Tumor Necrosis Factor WHO : World Health Organization (T chc Y t Th gii) FKBP : FK-binding protein NFAT : Nuclear factor of activated T lymphocytes (Yu t nhõn ca cỏc t bo lympho T hot húa) MC LC TI LIU THAM KHO PH LC DANH MC BNG DANH MC HèNH NH T VN Min dch hc ang l mt nhng lnh vc phỏt trin mnh m v cú nhiu trin vng ca ngnh cụng ngh y sinh hc Mt hng nghiờn cu quan trng v cp thit ca dch l cỏc liờn quan n phũng nga v iu tr ri lon chc nng ca h dch nh bnh lý viờm nhim, ung th, bnh t Cỏc ri lon ú cú th l tỡnh trng c ch hay biu hin quỏ mc h dch nhiu nguyờn nhõn gõy [1],[2] Vỡ vy, s iu bin nhm khụi phc li s cõn bng ca h dch ang l mc tiờu ca thuc, húa cht v cỏc bin phỏp iu tr khỏc hin Cỏc cht iu bin dch c gi l cht kớch thớch dch lm tng cng hot ng chc nng ca cỏc t bo dch v ngc li, nu lm suy gim h dch ca c th c gi l cht c ch dch [2],[3],[4],[5] Cỏc cht c ch dch cú vai trũ quan trng iu tr cỏc bnh lý ung th, bnh t v chng thi ghộp c quan Ngoi ra, chỳng cũn c s dng ph bin trờn thc nghim vic gõy mụ hỡnh suy gim dch, c bit l cỏc thuc, húa cht nh cyclophosphamid, corticoid, azathioprin [3],[6],[7] Trong ú, cyclophosphamid l mt nhng tỏc nhõn cú hiu qu nht gõy c ch dch trờn ng vt thc nghim c ỏp dng bi nhiu tỏc gi v ngoi nc [8],[9],[10],[11] Da vo ngun gc, cỏc cht kớch thớch dch c chia thnh nhiu loi nh cỏc cytokin tỏi t hp (interleukin-2, cỏc interferon, ), cỏc cht kớch thớch dch cú ngun gc húa cht (nh levamisol, imuthiol), ngun gc vi sinh vt (nh vaccin BCG) hay cỏc cht cú ngun gc t thc vt [1],[6] Nhỡn chung, vic s dng cỏc cht kớch thớch dch cú ngun gc húa hc, c tng hp hoc bỏn tng hp em li hiu qu cao lõm sng phũng v iu tr bnh cng nh cỏc nghiờn cu invitro, invivo Tuy nhiờn, ln nht ca chỳng l gõy cỏc tỏc dng khụng mong mun i vi ngi bnh v chi phớ iu tr cao Trong ú, vic s dng cỏc cht cú ngun gc t nhiờn em li nhiu u im hn v giỏ thnh cng nh an ton hn cho ngi s dng Mt s lng ln thc vt v cỏc cht phõn lp t chỳng ó cho thy hiu qu kớch thớch ỏp ng dch [8] Ti v sa non t lõu c s dng phũng v iu tr cỏc tỡnh trng nhim trựng, ung th v cỏc bnh lý ri lon dch khỏc [12],[13] Ti thuc ging Allium, c bit n vi thnh phn c trng l cỏc hp cht hu c cú cha lu hunh nh allicin, ajoene, diallyl sulfid (DAS), diallyl disulfid (DADS), Nhng cht ny cú vai trũ quan trng hot tớnh sinh hc ca ti, c bit l tớnh khỏng khun v khỏng ung th [14],[15],[16],[17] Sa non l sa m c tit t tuyn vỳ ca ng vt cú vỳ nhng ngy u tiờn sau sinh Thnh phn sa non ca loi bũ ngoi cỏc cht dinh dng nh carbohydrat, cht bộo, vitamin, amino acid v cht khoỏng cũn cha cỏc globulin dch bao gm IgG, IgM v IgA, cỏc cytokin nh IL-1, IL-6, TNF-, TNF- cú vai trũ quan trng hng ro dch bo v c th [18],[19],[20],[21] Cỏc tỏc dng tng cng dch ca ti v sa non s dng riờng r ó cho thy cú nhiu hiu qu trờn lõm sng cng nh cỏc nghiờn cu invivo v invitro Chỳng iu hũa s bi tit cytokin, thỳc y thc bo v hot húa i thc bo; sn xut cỏc globulin dch; tham gia phn ng d ng v s tng sinh cỏc t bo lympho [22] Tuy nhiờn, trờn th gii cng nh Vit Nam cho n cha cú cụng trỡnh nghiờn cu v tớnh an ton cng nh tỏc dng trờn dch dựng phi hp hai dc liu ny [18] Vỡ vy, ỏnh giỏ tớnh an ton v tỏc dng kớch thớch dch ca mt ch phm phi hp hai thnh phn chớnh l ti v sa non (viờn nang KOVIR), chỳng tụi tin hnh nghiờn cu ti Nghiờn cu c tớnh v tỏc dng kớch thớch dch ca viờn nang KOVIR trờn ng vt thc nghim vi mc tiờu nh sau: Nghiờn cu c tớnh cp v c tớnh bỏn trng din ca viờn nang KOVIR Nghiờn cu tỏc dng kớch thớch dch ca viờn nang KOVIR trờn mụ hỡnh gõy suy gim dch bng cyclophosphamid Chng TNG QUAN TI LIU 1.1 i cng v ỏp ng dch 1.1.1 nh ngha Min dch l kh nng ca c th nhn bit, ỏp ng v loi tr cỏc yu t gõy hi Do vy, dch l phng thc khỏng t v ht sc quan trng ca c th [23] 1.1.2 Phõn loi Khi cỏc yu t gõy bnh xõm nhp, trc tiờn c th hnh mt s t bo v phõn t sn cú kp thi ngn chn, x lý, sau ú to cỏc t bo v phõn t c hiu tng ng vi tng loi khỏng nguyờn khỏc loi tr chỳng T c ch ú, ngi ta chia ỏp ng dch thnh hai loi: ỏp ng dch t nhiờn (hay cũn gi l dch khụng c hiu) v ỏp ng dch thu c (cũn gi l dch c hiu) [1],[6],[23],[24] 1.1.2.1 ỏp ng dch t nhiờn Min dch t nhiờn c hỡnh thnh quỏ trỡnh tin húa ca ng vt chng li s xõm nhp gõy nhim ca cỏc vi sinh vt gõy bnh c im ca dch t nhiờn l dch sn cú ca c th t mi sinh ra, khụng li trớ nh; cú tớnh cht di truyn, khỏc gia cỏc loi v cỏc cỏ th cựng loi v cỏc yu t thuc dch t nhiờn l phng tin chung dựng chng li s xõm nhim ca cỏc vi sinh vt gõy bnh Cỏc yu t tham gia vo ỏp ng dch t nhiờn gm cú: da v niờm mc, cỏc t bo (cỏc tiu thc bo, cỏc i thc bo, bch cu ỏi toan, bch cu ỏi kim, t bo dit t nhiờn) v cỏc phõn t (gm cú h thng b th, protein phn ng C, interferon) Cỏc cht iu bin dch cú th tỏc ng vo mt hay nhiu khõu lm thay i hng ro dch khụng c hiu ny [7],[23] 1.1.2.2 ỏp ng dch thu c ỏp ng dch thu c l trng thỏi dch xut hin tng ng vi tng khỏng nguyờn, c to sau c th tip xỳc vi khỏng nguyờn Min dch thu c chia thnh loi: - Min dch dch th: cỏc t bo lympho B m nhim vi cỏc globulin - dch lu hnh cỏc dch: IgG, IgM, IgA, IgE v IgD Min dch qua trung gian t bo: cỏc t bo lympho T m nhim vi cỏc di nhúm ca chỳng nh Tc, Th, v cỏc cytokin chỳng tit Min dch dch th v dch qua trung gian t bo u phi tri qua ba giai on: nhn din khỏng nguyờn, hot húa cỏc t bo dch v quỏ trỡnh hiu ng loi b khỏng nguyờn [1],[23],[24] 1.2 Suy gim dch trờn lõm sng 1.2.1 Khỏi nim Suy gim dch hay cũn gi l thiu ht dch l tỡnh trng h dch ỏp ng di mc cn thit trc cỏc yu t gõy hi lm xut hin cỏc bnh lý im c trng ca s suy gim dch l c th d nhim nhiu loi virus, nm, ký sinh trựng, tng nguy c mc ung th v bnh t [1],[23],[25] Suy gim dch l mt tỡnh trng bnh lý khỏ ph bin khụng nhng cỏc nc cú nn kinh t thp, m cỏc tỡnh trng nhim khun, suy dinh dng, cũn ph bin c nhng nc ó phỏt trin [24] Cỏc bnh lý suy gim dch cú th nguyờn nhõn bm sinh hay th phỏt cỏc yu t bờn ngoi nh nhim vi khun, virus hay thuc v húa cht [1] 1.2.2 Phõn loi Da theo nguyờn nhõn, ngi ta chia suy gim dch lm hai loi: suy gim dch bm sinh v suy gim dch mc phi 10 1.2.2.1 Suy gim dch bm sinh Cỏc ri lon di truyn ca h dch gõy c ch bt k dũng t bo dch no, giai on no ca s bit húa u cú th gõy bnh cnh suy gim dch bm sinh tng ng [25] Da vo quỏ trỡnh phỏt trin ca cỏc t bo cú thm quyn dch cú th chia suy gim dch bm sinh thnh loi [23]: - Suy gim dch bm sinh dũng t bo lympho T (bnh lý in hỡnh l hi - chng Di George) Suy gim dch bm sinh dũng t bo lympho B (bnh lý in hỡnh l hi - chng Bruton) Suy gim dch phi hp nng (SCID): s phỏt trin khụng bỡnh - thng ca cỏc t bo gc lympho B v T t ty xng Suy gim dch bm sinh ca thc bo v b th 1.2.2.2 Suy gim dch mc phi Khỏc vi suy gim dch bm sinh, tỡnh trng suy gim dch mc phi (th phỏt) khụng phỏt sinh t cỏc ri lon di truyn m cỏc tỏc nhõn bờn ngoi gõy nờn [25] Da vo cỏc yu t gõy nờn suy gim dch mc phi cú th phõn thnh cỏc loi chớnh sau [23]: - Suy gim dch nhim vi sinh vt: nhim vi khun, virus, nm, ký sinh trựng c bit, HIV l loi virus gõy hi chng suy gim dch mc - phi (AIDS) ngi, to nờn mt i dch ln trờn ton th gii Suy gim dch suy dinh dng Suy gim dch ung th Suy gim dch cỏc thuc, húa cht Suy gim dch cỏc yu t vt lý (tia x, nhit , ) Suy gim dch cỏc nguyờn nhõn khỏc: luyn quỏ nng, sang chn, m x, tui tỏc cao, ằ Suy gim dch nhim HIV 52 Bng 3.17: nh hng ca thuc th lờn s lng bch cu Lụ n Lụ 1: Chng sinh hc Lụ 2: Mụ hỡnh CY 10 Lụ 4: KOVIR liu 5,62 g/kg 10 Lụ 5: KOVIR liu 11,24 g/kg ( X SD, G/l) 10 10 Lụ 3: Chng dng levamisol S lng bch cu 10 Nhn xột: Bng 3.18: nh hng ca thuc th lờn cụng thc bch cu mỏu ngoi vi Lụ S lng tuyt i cỏc loi BC ( X SD, G/l) BC lympho BCTT BC mono Lụ 1: Chng sinh hc Lụ 2: Mụ hỡnh CY Lụ 3: Chng dng levamisol Lụ 4: KOVIR liu 5,62 g/kg Lụ 5: KOVIR liu 11,24 g/kg Chỳ thớch: BC: Bch cu; BCTT: Bch cu trung tớnh Nhn xột: 3.2.2 nh hng ca viờn nang KOVIR lờn ỏp ng dch t bo v dch dch th ằ Phn ng bỡ vi khỏng nguyờn OA: Bng 3.19: nh hng ca thuc th n phn ng bỡ vi khỏng 53 nguyờn OA Phn ng bỡ: % tng chiu dy Lụ bn chõn chut n ( X SD, %) Lụ 1: Chng sinh hc Lụ 2: Mụ hỡnh CY 10 10 Lụ 3: Chng dng levamisol 10 Lụ 4: KOVIR liu 5,62 g/kg 10 Lụ 5: KOVIR liu 11,24 g/kg 10 Nhn xột: ằ nh lng cỏc cytokin mỏu Bng 3.20: nh hng ca viờn nang KOVIR lờn nng IL-2 mỏu ngoi vi Lụ n Lụ 1: Chng sinh hc Lụ 2: Mụ hỡnh CY 10 Lụ 4: KOVIR liu 5,62 g/kg 10 Lụ 5: KOVIR liu 11,24 g/kg ( X SD, pg/mL) 10 10 Lụ 3: Chng dng levamisol Nng IL-2 10 Nhn xột: Bng 3.21: nh hng ca viờn nang KOVIR lờn nng TNF- mỏu ngoi vi Lụ Lụ 1: Chng sinh hc n 10 Nng TNF- ( X SD, pg/mL) 54 Lụ 2: Mụ hỡnh CY 10 Lụ 3: Chng dng levamisol 10 Lụ 4: KOVIR liu 5,62 g/kg 10 Lụ 5: KOVIR liu 11,24 g/kg 10 Nhn xột: ằ nh lng nng IgG mỏu ngoi vi Bng 3.22: nh hng ca viờn nang KOVIR lờn nng IgG mỏu ngoi vi Lụ n Lụ 1: Chng sinh hc Lụ 2: Mụ hỡnh CY 10 Lụ 4: KOVIR liu 5,62 g/kg 10 Lụ 5: KOVIR liu 11,24 g/kg ( X SD, pg/mL) 10 10 Lụ 3: Chng dng levamisol Nng IgG 10 Nhn xột: 3.2.2 nh hng ca viờn nang KOVIR lờn cu trỳc vi th ca lỏch v tuyn c Bng 3.23 Kt qu gii phu vi th lỏch v tuyn c Lụ nghiờn cu Lụ 1: Chng sinh hc Lụ 2: Mụ hỡnh Lụ 3: Chng dng Lụ 4: KOVIR liu 5,62 g/kg Cu trỳc vi th lỏch Cu trỳc vi th tuyn c 55 Lụ 4: KOVIR liu 11,24 g/kg Hỡnh 3.7 Hỡnh thỏi vi th lỏch chut lụ chng sinh hc Hỡnh 3.8 Hỡnh thỏi vi th lỏch chut lụ mụ hỡnh Hỡnh 3.9 Hỡnh thỏi vi th lỏch chut lụ chng dng Hỡnh 3.10 Hỡnh thỏi vi th lỏch chut lụ KOVIR liu 5,62 g/kg Hỡnh 3.11 Hỡnh thỏi vi th lỏch chut lụ KOVIR liu 11,24 g/kg Hỡnh 3.12 Hỡnh thỏi vi th tuyn c chut lụ chng sinh hc Hỡnh 3.13 Hỡnh thỏi vi th tuyn c chut lụ mụ hỡnh Hỡnh 3.14 Hỡnh thỏi vi th tuyn c chut lụ chng dng Hỡnh 3.15 Hỡnh thỏi vi th tuyn c chut lụ KOVIR liu 5,62 g/kg Hỡnh 3.16 Hỡnh thỏi vi th tuyn c chut lụ KOVIR liu 11,24 g/kg 56 D KIN KT LUN Qua kt qu nghiờn cu v c tớnh ca viờn nang KOVIR v tỏc dng kớch thớch dch trờn mụ hỡnh gõy suy gim dch bng húa cht trờn ng vt thc nghim, chỳng tụi xin a kt lun: V c tớnh: - c tớnh 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