造血干细胞诱导大鼠肾脏移植免疫耐受的研究
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摘要
目的:
如何诱导供体特异性移植耐受成为解决器官移植排斥反应的最佳手段,也成为临床器官移植免疫学研究的热点领域及主要目标之一。本研究通过大鼠肾脏移植受体在接受低剂量放射线全身照射预处理后,输注供体造血干细胞(HSC)对肾脏移植受体及移植肾的影响,探讨造血干细胞能否诱导出针对供者特异性的免疫耐受。
方法:
1、建立支架管置入并固定于肾静脉代替静脉吻合大鼠肾脏移植模型:将供肾动脉开口端与受体左肾动脉作端端吻合,取1cm长度输尿管导管作为支架管,置入并固定供受体肾静脉,输尿管膀胱瓣与受体膀胱壁吻合。
2、造血干细胞诱导大鼠肾脏移植免疫耐受:(1)实验分组:32只受体Wistar大鼠随机分为4组,各组8只。A:对照组;B:造血干细胞(HSC)+肾移植;C:全身照射(TBI)+肾移植;D:HSC+TBI+肾移植。(2)受体Wistar大鼠术前接受低剂量放射线全身照射,提取供者造血干细胞,手术当日经尾静脉推注SD大鼠的造血干细胞,并当天完成肾移植,受体实验前1天,实验当天,及实验后1、3、4、5天按10mg/kg口服环孢素A。(3)观察各组大鼠的存活时间,监测血清肌酐浓度,并进行移植肾彩色多普勒超声。移植物病理学检查。采用体外混合淋巴细胞反应(MLR)法检测长期存活大鼠的免疫耐受状态。
结果:
1、建立模型:共施行大鼠。肾移植30例,5例动脉吻合处有少量出血,棉球压迫5min后2例出血停止,3例因吻合处出血于术后1-3h死亡(尸体解剖证实),2例因术中动脉吻合口狭窄死亡,2例因麻醉过量呼吸抑制于术中死亡,成功率为76.7%。
2、存活时间:D组平均存活时间为58.9d,与A组比较,差异有统计学意义(P＜0.01)。D组与B组及C组比较,差异有统计学意义(P＜0.05)。
3、移植肾功能测定:A组术后3d切除自体肾脏后,血清肌酐浓度迅速上升;B组及C组血清肌酐浓度呈现缓慢上升趋势,D组的移植肾功能基本保持稳定。
4、病理学结果:对照组移植肾肾间质水肿,并有淋巴细胞浸润,多见于间质小血管周围,肾小管上皮细胞变性坏死、脱落,血管内皮细胞肿胀,有纤维素样坏死并可见微血栓形成。B组和C组未见急性排斥反应,肾间质水肿不明显,见少量淋巴细胞浸润。肾小管上皮细胞变性坏死、脱落,血管内皮细胞肿胀不明显。同期D组未见淋巴细胞浸润,肾小管上皮细胞未见变性坏死、脱落。无微血栓形成。
5、移植肾超声检测:A组移植肾血供差,阻力指数0.7。D组移植肾血供丰富,阻力指数介于0.3～0.6之间,A组与B组差别不明显(P=0.06),A组与C组差别明显(P＜0.05),A组与D组差别明显(P＜0.05)。
6、混合淋巴细胞反应(MLR):A、B组大鼠脾细胞对供体SD大鼠或无关品系Lewis大鼠脾细胞的CPM值与空白对照组相比无显著性差异(P＞0.05)。而对SD大鼠脾细胞,D组的CPM值较空白对照组明显降低(P＜0.01),对Lewis大鼠脾细胞,上述三组的CPM与对照组比较未见显著性差异(P＞0.05)。
结论:
1、建立大鼠肾脏移植模型:供肾动脉端端吻合,输尿管导管作为支架,将其置入供受体肾静脉断端,行供受体肾静脉端端吻合,行输尿管膀胱瓣和受体膀胱壁吻合。此方法简便、易操作,手术成功率高。一般实验室均可开展,对肾移植实验研究有应用价值。
2、通过大鼠肾脏移植受体在接受全身照射预处理后,输注供体HSC可延长受者存活时间,移植肾功能基本保持稳定,短期内未见排斥反应,HSC可诱导针对供者特异性的免疫耐受。
Objectives:
Achieving immunological tolerance,a state of donor-specific unresponsiveness,remains a paramount goal in organ transplantation. Successful application would allow for allogeneic transplantation without the toxic effects of nonspecific immunosuppression and curb the high rates of graft loss due to acute and chronic rejection.We designed an animal study to induce immune tolerance in recipient rats of allogenic kidney transplantation with hematopoietic stem cells and to study the mechanism of the tolerance.
Methods:
1.A model of renal transplantation was established.Intravenous stent was inserted from the distal end to the donor's left renal vein and further into the lumen of the recipient's left renal vein.End-to-side anatomosis of both renal aortas was performed.Urinary tract reconstruction was accomplished by suturing the donor ureter with a bladder patch to the recipient bladder.
2.Study on the induction of immune tolerance in renal transplantation by hematopoietic stem cell:(1) Kidney transplantations were performed in 32rats. (2) Wistar rats were treated TLI before surgery,then HBC were injected to receptors.Renal transplantation was performed within the same day.(3) The survival days of receptor rats were observed.Serum creatinine was measured and color Doppler flow imaging was checked.The immunologic tolerance status was detected by MLR of 30th day receptor rat spleen cells cultured with the donor spleen cells and the third party.
Results:
1.Kidney transplantations were performed in 30rats.The pathological examinations showed that There model was failure due to hemorrhage of anatomosis of both renal aortas.Two models was failure due to thrombus of anatomosis of both renal aortas.Two models was failure due to overdose of anesthesia,achievement ratio of this model is 76.7%.
2.The mean survival time of case group(D group) was 58.9d,The difference was significant between case group and other three control groups.
3.Serum creatinine of control group(A group) went up quickly after resection of self-kidney,serum creatinine of B and C group went up smoothly after resection of self-kidney,but serum creatinine of case group was stable after resection of self-kidney.
4.There was no acute rejection in B and C group,interstitial edema necrosis and ablate of renal tubular epithelial cell were not obviously. Lymphocyte soakage,interstitial edema necrosis and ablate of renal tubular epithelial cell were not found in case group.
5.Blood supply of control group(A group) was badly,resistent index(RI) was＞0.7.Blood supply of case group(A group) was abundant,resistent index(RI) was between 0.3～0.6.The difference was significant between case group and A groups.
6.Recipients of this group show a low response to donor specific spleen cells when MLR are observed,but a hypore-sponsiveness to donor occurred while the normal reaction to the third parity was retained.
Conclusion:
1.This modified rat model of renal transplantation is simple,economical, reliable,stable with higher success rate and can be applied in the experiment of renal transplantation research.
2.The hematopoietic stem cells can induce donor-specific tolerance from allograft.
如何诱导供体特异性移植耐受成为解决器官移植排斥反应的最佳手段,也成为临床器官移植免疫学研究的热点领域及主要目标之一。本研究通过大鼠肾脏移植受体在接受低剂量放射线全身照射预处理后,输注供体造血干细胞(HSC)对肾脏移植受体及移植肾的影响,探讨造血干细胞能否诱导出针对供者特异性的免疫耐受。
方法:
1、建立支架管置入并固定于肾静脉代替静脉吻合大鼠肾脏移植模型:将供肾动脉开口端与受体左肾动脉作端端吻合,取1cm长度输尿管导管作为支架管,置入并固定供受体肾静脉,输尿管膀胱瓣与受体膀胱壁吻合。
2、造血干细胞诱导大鼠肾脏移植免疫耐受:(1)实验分组:32只受体Wistar大鼠随机分为4组,各组8只。A:对照组;B:造血干细胞(HSC)+肾移植;C:全身照射(TBI)+肾移植;D:HSC+TBI+肾移植。(2)受体Wistar大鼠术前接受低剂量放射线全身照射,提取供者造血干细胞,手术当日经尾静脉推注SD大鼠的造血干细胞,并当天完成肾移植,受体实验前1天,实验当天,及实验后1、3、4、5天按10mg/kg口服环孢素A。(3)观察各组大鼠的存活时间,监测血清肌酐浓度,并进行移植肾彩色多普勒超声。移植物病理学检查。采用体外混合淋巴细胞反应(MLR)法检测长期存活大鼠的免疫耐受状态。
结果:
1、建立模型:共施行大鼠。肾移植30例,5例动脉吻合处有少量出血,棉球压迫5min后2例出血停止,3例因吻合处出血于术后1-3h死亡(尸体解剖证实),2例因术中动脉吻合口狭窄死亡,2例因麻醉过量呼吸抑制于术中死亡,成功率为76.7%。
2、存活时间:D组平均存活时间为58.9d,与A组比较,差异有统计学意义(P＜0.01)。D组与B组及C组比较,差异有统计学意义(P＜0.05)。
3、移植肾功能测定:A组术后3d切除自体肾脏后,血清肌酐浓度迅速上升;B组及C组血清肌酐浓度呈现缓慢上升趋势,D组的移植肾功能基本保持稳定。
4、病理学结果:对照组移植肾肾间质水肿,并有淋巴细胞浸润,多见于间质小血管周围,肾小管上皮细胞变性坏死、脱落,血管内皮细胞肿胀,有纤维素样坏死并可见微血栓形成。B组和C组未见急性排斥反应,肾间质水肿不明显,见少量淋巴细胞浸润。肾小管上皮细胞变性坏死、脱落,血管内皮细胞肿胀不明显。同期D组未见淋巴细胞浸润,肾小管上皮细胞未见变性坏死、脱落。无微血栓形成。
5、移植肾超声检测:A组移植肾血供差,阻力指数0.7。D组移植肾血供丰富,阻力指数介于0.3～0.6之间,A组与B组差别不明显(P=0.06),A组与C组差别明显(P＜0.05),A组与D组差别明显(P＜0.05)。
6、混合淋巴细胞反应(MLR):A、B组大鼠脾细胞对供体SD大鼠或无关品系Lewis大鼠脾细胞的CPM值与空白对照组相比无显著性差异(P＞0.05)。而对SD大鼠脾细胞,D组的CPM值较空白对照组明显降低(P＜0.01),对Lewis大鼠脾细胞,上述三组的CPM与对照组比较未见显著性差异(P＞0.05)。
结论:
1、建立大鼠肾脏移植模型:供肾动脉端端吻合,输尿管导管作为支架,将其置入供受体肾静脉断端,行供受体肾静脉端端吻合,行输尿管膀胱瓣和受体膀胱壁吻合。此方法简便、易操作,手术成功率高。一般实验室均可开展,对肾移植实验研究有应用价值。
2、通过大鼠肾脏移植受体在接受全身照射预处理后,输注供体HSC可延长受者存活时间,移植肾功能基本保持稳定,短期内未见排斥反应,HSC可诱导针对供者特异性的免疫耐受。
Objectives:
Achieving immunological tolerance,a state of donor-specific unresponsiveness,remains a paramount goal in organ transplantation. Successful application would allow for allogeneic transplantation without the toxic effects of nonspecific immunosuppression and curb the high rates of graft loss due to acute and chronic rejection.We designed an animal study to induce immune tolerance in recipient rats of allogenic kidney transplantation with hematopoietic stem cells and to study the mechanism of the tolerance.
Methods:
1.A model of renal transplantation was established.Intravenous stent was inserted from the distal end to the donor's left renal vein and further into the lumen of the recipient's left renal vein.End-to-side anatomosis of both renal aortas was performed.Urinary tract reconstruction was accomplished by suturing the donor ureter with a bladder patch to the recipient bladder.
2.Study on the induction of immune tolerance in renal transplantation by hematopoietic stem cell:(1) Kidney transplantations were performed in 32rats. (2) Wistar rats were treated TLI before surgery,then HBC were injected to receptors.Renal transplantation was performed within the same day.(3) The survival days of receptor rats were observed.Serum creatinine was measured and color Doppler flow imaging was checked.The immunologic tolerance status was detected by MLR of 30th day receptor rat spleen cells cultured with the donor spleen cells and the third party.
Results:
1.Kidney transplantations were performed in 30rats.The pathological examinations showed that There model was failure due to hemorrhage of anatomosis of both renal aortas.Two models was failure due to thrombus of anatomosis of both renal aortas.Two models was failure due to overdose of anesthesia,achievement ratio of this model is 76.7%.
2.The mean survival time of case group(D group) was 58.9d,The difference was significant between case group and other three control groups.
3.Serum creatinine of control group(A group) went up quickly after resection of self-kidney,serum creatinine of B and C group went up smoothly after resection of self-kidney,but serum creatinine of case group was stable after resection of self-kidney.
4.There was no acute rejection in B and C group,interstitial edema necrosis and ablate of renal tubular epithelial cell were not obviously. Lymphocyte soakage,interstitial edema necrosis and ablate of renal tubular epithelial cell were not found in case group.
5.Blood supply of control group(A group) was badly,resistent index(RI) was＞0.7.Blood supply of case group(A group) was abundant,resistent index(RI) was between 0.3～0.6.The difference was significant between case group and A groups.
6.Recipients of this group show a low response to donor specific spleen cells when MLR are observed,but a hypore-sponsiveness to donor occurred while the normal reaction to the third parity was retained.
Conclusion:
1.This modified rat model of renal transplantation is simple,economical, reliable,stable with higher success rate and can be applied in the experiment of renal transplantation research.
2.The hematopoietic stem cells can induce donor-specific tolerance from allograft.
引文
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[1]Nagano H,Libby P,Taylor MK,et al.Coronary arteriosclerosis after T-cell-mediated injury in transplanted mouse hearts:role of interferon-gamma.Am J Pathol[J].1998,152(5):1187-1197.
[2]Mannon RB,Grriffiths R,Ruiz P,et al.Absence of donor MHC antigen expression ameliorates chronic kidney allograft rejection.Kidney Int[J].2002,62(1):290-300.
[3]Lazarovits AL,Popperma S,Zhang Z,et al.Prevention and reversal of renal allograft rejection by antibody against CD45RB,Nature[J].1996,380(6576):717-720.
[4]Wagner E.The rat experimental for organ t ransplanta2tion:technique of rat Kidney t ransplantation[J].Cont Nephrol,1980,19:167
[5]Fisher B,Lee S.Microvascular surgical technique in research,with special reference to renal t ransplantation inthe rat[J].Surgery,1965,58(5):904
[6]Lee S.An improved technique of renal t ransplantation inthe rat[J].Surgery,1967,61(5):771
[7]Kamada N.A description of cuff techniques for renalt ransplantation in the rat.Use in studies of tolerance in2duction during combined liver graf ting [J].Transplantation,1985,39(1):93
[8]Fabre J,Lim SH,Morris PJ.Renal t ransplantation in the rat:details of a technique[J].Aust NZ J Surg,1971,41(1):69
[9]Silber SJ,Crudop J.Kidney t ransplantation in inbredrats[J].Am J Surg,1973,125(5):551
[10]陈金芝,夏穗生.大白鼠异体肾移植术[J].中华器官移植杂志,1981,2(2):72
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[15]尚攀峰,赵彦宗,岳中瑾,等.大鼠肾移植动脉套叠吻合技术的改良.中国修复重建外科杂志.2005,19(5):386-388.
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[17]刘小友,于立新,孙煦勇,等.腹主动脉搭桥、硬膜外导管内撑法建立大鼠肾移植模型.中华实验外科杂志,2004,21(6):744-746.
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[24]王康,戴勇,李德萍,等.大鼠原位肾移植模型肾静脉吻合方法的改良.中华器官移植杂志,2006,27(1):54-56.
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[27]Gu YL,Dahmen U,Dirsch O,et al.Imp roved renal transplantationin the rat with a nonsp linted ureteroureterostomy.Microsurgery,2002,22:204-210.
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[31]黄赤兵,吴军,方玉华,等.一种用于大鼠肾移植模型的。肾血管体外结扎方法.上海实验动物科学,2001,21(2):82-84.
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[34]Wen JG,Ringgaard S,Frokiaer J,et al.Contralateral compensatory kidney growth in rats with partial unilateral ureteral obstruction monitored by magnetic resonance imaging.J Urol,1999,162:1084-1089.
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[1]Reisner Y,Bachar-Lustig E,Li HW,et al.The role of megadose CD34 progenitor ceils in the treatment of leukemia patients without a matched donor and in tolerance induction for organ transplantation.Ann N Y Acad Sci[J],1999,872:336-48.
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[1]Nagano H,Libby P,Taylor MK,et al.Coronary arteriosclerosis after T-cell-mediated injury in transplanted mouse hearts:role of interferon-gamma.Am J Pathol[J].1998,152(5):1187-1197.
[2]Mannon RB,Grriffiths R,Ruiz P,et al.Absence of donor MHC antigen expression ameliorates chronic kidney allograft rejection.Kidney Int[J].2002,62(1):290-300.
[3]Lazarovits AL,Popperma S,Zhang Z,et al.Prevention and reversal of renal allograft rejection by antibody against CD45RB,Nature[J].1996,380(6576):717-720.
[4]Wagner E.The rat experimental for organ t ransplanta2tion:technique of rat Kidney t ransplantation[J].Cont Nephrol,1980,19:167
[5]Fisher B,Lee S.Microvascular surgical technique in research,with special reference to renal t ransplantation inthe rat[J].Surgery,1965,58(5):904
[6]Lee S.An improved technique of renal t ransplantation inthe rat[J].Surgery,1967,61(5):771
[7]Kamada N.A description of cuff techniques for renalt ransplantation in the rat.Use in studies of tolerance in2duction during combined liver graf ting [J].Transplantation,1985,39(1):93
[8]Fabre J,Lim SH,Morris PJ.Renal t ransplantation in the rat:details of a technique[J].Aust NZ J Surg,1971,41(1):69
[9]Silber SJ,Crudop J.Kidney t ransplantation in inbredrats[J].Am J Surg,1973,125(5):551
[10]陈金芝,夏穗生.大白鼠异体肾移植术[J].中华器官移植杂志,1981,2(2):72
[11]Daniller A,Buchholz R,Chase RA.Renal transplantation in rats with the use of microsurgical techniques:A new method.Surgery[J].1968,63:956-961.
[12]张治国,张茂才,殷晓玲.改良式大鼠肾移植术.河南医学研究, 1994,3(1):24.
[13]康俊升,王霞,徐涛,等.改良袖套法大鼠原位肾移植术.肾脏病与透析肾移植杂志,1997,6(4):395.
[14]Blom D,O rloffM S.A mo re versatile and reliable method for renal transplantation in the rat.M icro surgery[J].1998,18(4):267-269.
[15]尚攀峰,赵彦宗,岳中瑾,等.大鼠肾移植动脉套叠吻合技术的改良.中国修复重建外科杂志.2005,19(5):386-388.
[16]赵彦宗,杜维成,郭喜桃,等.一种新的大鼠原位肾移植模型的建立.实验动物与比较医学,2007,27(1):37-40.
[17]刘小友,于立新,孙煦勇,等.腹主动脉搭桥、硬膜外导管内撑法建立大鼠肾移植模型.中华实验外科杂志,2004,21(6):744-746.
[18]朱晓明.大鼠异体肾移植操作体会[J].上海实验动物科学,1996,16:90.
[19]Chin J,Zhong R,Duff J,et al.Microsurgical renal transplant models in rats:a comparison of four anastomotic techniques.Transplant Proc,1989,21:3351.
[20]Schumacher M,Van Vliet BN,Ferrari P.Kidney transplantation in rats:an appraisal of surgical techniques and outcome.Microsurgery,2003,23:387-394.
[21]Pahlavan PS,MehrabiA,KashfiA,et al.Guidelines for p revention and management of comp lications following kidney transp lantation in rats.Transplant Proc,2005,37(5):2333-2337.
[22]胡建庭,赵高贤,李登宝,等.大鼠肾移植模型建立方法与比较.河南大学学报(医学科学版),2003,22(2):19-20.
[23]黄赤兵,吴军,罗高兴,等.一种改良的静脉吻合技术用于大鼠肾移植模型的建立.重庆医学,2002,31(8):666-667.
[24]王康,戴勇,李德萍,等.大鼠原位肾移植模型肾静脉吻合方法的改良.中华器官移植杂志,2006,27(1):54-56.
[25]Gonzal EE,Miller BF,Nathan p.A method for transplantation of the kidney.Ann N Y Acad Sei,1964,99:795
[26]Pietsch AP,Nett PC,Klar E,et al.A new modified technique of ureteroureterostomy in rat kidney transplantation.Transplant Proc,2005,37(1):189-191.
[27]Gu YL,Dahmen U,Dirsch O,et al.Imp roved renal transplantationin the rat with a nonsp linted ureteroureterostomy.Microsurgery,2002,22:204-210.
[28]王雪圃,朱洪荫.器官移植实验研究基础.北京:北京医学院出版社,1980:90.
[29]Harada H,Ishikura H,Nakagawa I,et al.Abortive alloantigen presentation by donor dendritic cells leads to donor-specific tolerance:a study with a preoperative CTLA4lg inoculation.Urol Res,2000,28:69-74
[30]Carr RI,Zhou J,Kearsey JA,et allProlongation of survival of primary renal allografts by feeding of donor spleen cells.Transplantation,1998,66:976-982
[31]黄赤兵,吴军,方玉华,等.一种用于大鼠肾移植模型的。肾血管体外结扎方法.上海实验动物科学,2001,21(2):82-84.
[32]冯嘉瑜,张艮甫,黄赤兵,等.改良的大鼠原位肾移植模型的建立.第三军医大学学报,2004,26(24):2264-2265.
[33]朱佳庚,张炜,钱立新,等.一种大鼠肾移植模型的建立.中华实验外科杂志,2004,21(1):103-104.
[34]Wen JG,Ringgaard S,Frokiaer J,et al.Contralateral compensatory kidney growth in rats with partial unilateral ureteral obstruction monitored by magnetic resonance imaging.J Urol,1999,162:1084-1089.
[35]庄建平,郭震华,侯建全.大鼠原位异体肾移植的模型研究.苏州医学院学报,1999,19(8):865.
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