本文關(guān)鍵詞： CTLA4-Ig重組腺病毒 非清髓性 嵌合體 免疫耐受 后肢移植物　出處：《第四軍醫(yī)大學(xué)》2008年碩士論文　論文類(lèi)型：學(xué)位論文

【摘要】： 目的:探討基于CTLA4-Ig重組腺病毒(AdCTLA4-Ig)的非清髓性方案在造血干細(xì)胞嵌合體誘導(dǎo)復(fù)合組織異體移植免疫耐受中的作用。 方法:以近交系Brown Norway(RT1n)大鼠為供體,Lewis(RT11)大鼠為受體。實(shí)驗(yàn)分4組:A組:受體直接給予同種異體后肢移植,移植前不進(jìn)行非清髓性預(yù)處理,移植后僅給予低劑量CsA(8 mg/kg/d)腹腔注射。B組:受體先給予非清髓性預(yù)處理,首先每天給予免疫抑制劑三聯(lián)方案(腹腔注射RAPA+MMF+MP;days -33～100),然后分3次尾靜脈注射AdCTLA4 -Ig(5×109 PFU/d,days -30,0,30),而后接受3Gy(照射率0.5Gy/min)低強(qiáng)度全身照射,不給予骨髓移植,全身照射后30d進(jìn)行大鼠后肢移植(day 0)。C組:受體預(yù)處理方案同B組,在低強(qiáng)度全身照射后4h內(nèi)尾靜脈注射供體骨髓細(xì)胞(100×106,day -30),骨髓移植后30d進(jìn)行大鼠后肢移植(day 0)。D組:受體預(yù)處理方案及骨髓移植方法同C組,但大鼠后肢移植供體為第三方動(dòng)物WF大鼠(day 0)。在后肢移植后第100d各組均停止免疫抑制劑三聯(lián)方案,僅給予低劑量CsA(8 mg/kg/d,days 100～),直至大鼠后肢移植物發(fā)生排斥反應(yīng)而壞死。通過(guò)外周血嵌合率檢測(cè),GVHD檢測(cè),后肢移植物存活情況觀察,移植物組織病理學(xué)檢查與評(píng)價(jià)及混合淋巴細(xì)胞反應(yīng)對(duì)免疫耐受狀態(tài)進(jìn)行分析評(píng)價(jià)。 結(jié)果:C組外周血嵌合率為(38.8±10.6%,day 0)并長(zhǎng)期保持穩(wěn)定(29.3±11.9%,day 300),均未發(fā)生GVHD,停止免疫抑制劑三聯(lián)方案后移植物存活天數(shù)200天(A組,B組、D組均發(fā)生免疫排斥,存活天數(shù)分別為8±2天,18±3天及20±2天,與C組相比較,p0.01)。C組移植物病理學(xué)檢查顯示無(wú)毛囊炎及血管周?chē)椎嚷悦庖吲懦猬F(xiàn)象,混合淋巴反應(yīng)顯示為供體特異性免疫耐受狀態(tài)。 結(jié)論:基于CTLA4-Ig重組腺病毒(AdCTLA4-Ig)的非清髓性骨髓移植方案可以誘導(dǎo)長(zhǎng)期穩(wěn)定的造血干細(xì)胞嵌合體狀態(tài),并可以誘導(dǎo)受體對(duì)大鼠后肢移植物的供體特異性部分性免疫耐受。
[Abstract]:Aim: to investigate the role of nonmyeloablative regimen based on CTLA4-Ig recombinant adenovirus AdCTLA4-Igin in the induction of allograft tolerance by hematopoietic stem cell chimerism. Methods: the inbred Brown Norwayl RT1n rat was used as the recipient of Lewis tachycardia RT11. The rats were divided into 4 groups: group A: the recipients were given allograft hind limb transplantation directly, and no non-myeloablative preconditioning was performed before transplantation. After transplantation, only low dose CsA(8 mg / kg / d was injected intraperitoneally. Group B was given non-myeloablative preconditioning. Three doses of immunosuppressant regimen (intraperitoneal injection of RAPA MMF MPP days -33) were given daily, followed by three caudal intravenous injections of AdCTLA4 -IgA 5 脳 109PFU / dd days -30g / d, followed by low-intensity whole-body irradiation of 3 Gy (0.5 Gy / min) without bone marrow transplantation. 30 days after the whole body irradiation, the rat hind limbs were transplanted into group C: the receptor preconditioning regimen was the same as that in group B. Donor bone marrow cells were injected into the tail vein within 4 hours after low intensity whole body irradiation. Group D received rat hind limb transplantation on 30 days after bone marrow transplantation: the receptor preconditioning regimen and the bone marrow transplantation method were the same as those in C group. However, the donor of hindlimb transplantation was WF rats. On the 100th day after hind limb transplantation, all groups stopped the triple regimen of immunosuppressive drugs. Only a low dose of CsA(8 mg / kg / d days was given until the rat hind limb graft developed rejection and necrosis, and the survival of the hind limb graft was observed by the peripheral blood chimerism rate and the survival rate of the hind limb graft. Graft histopathology and mixed lymphocyte reaction were used to evaluate the immune tolerance state. Results the chimeric rate of peripheral blood was 38.8 鹵10.6 / day _ 0 in group C and kept stable for a long time (29.3 鹵11.9day). No GVHD was found in all of them. The graft survived 200 days after stopping the triple regimen of immunosuppressant. All the patients in group A and group B developed immune rejection. The survival days were 8 鹵2 days, 18 鹵3 days and 20 鹵2 days, respectively. Compared with group C, the grafts of group C showed no chronic immune rejection, such as folliculitis and perivascular inflammation, and mixed lymphoid reaction showed donor specific immune tolerance. Conclusion: Non-myeloablative bone marrow transplantation based on CTLA4-Ig recombinant adenovirus AdCTLA4-Igcan induce long-term stable hemopoietic stem cell chimeric status and donor specific partial tolerance to rat hind limb grafts.
【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2008
【分類(lèi)號(hào)】：R392

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 張慶殷,金永柱,張海濱,謝蜀生;CTLA-4 Ig腺病毒基因治療聯(lián)合供體細(xì)胞輸注誘導(dǎo)混合嵌合體和大鼠心臟移植耐受[J];中華微生物學(xué)和免疫學(xué)雜志;2003年04期

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本文編號(hào)：1521250