供体脾细胞联合抗CD154单抗对非清髓骨髓移植建立异基因嵌合体的影响
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摘要
目的探讨供体脾细胞及其输注途径以及联合抗CD154单克隆抗体(antiCD154 mAb,克隆号AH.F5)对非清髓性骨髓移植预处理方案建立异基因嵌合体的影响及诱导供体特异性免疫耐受的可能机制.方法Lewis(Rtl~l)大鼠为供体,Wistar(Rtl~u)大鼠为受体,SD大鼠为无关第三品系。按不同预处理方案将Lewis供鼠脾细胞(Sc)、骨髓细胞(BMc)悬液输注给Wistar大鼠。受鼠随机分为4组,每组20只:(1)Sc_外组:第0天(d_0)经受体外周阴茎背静脉输注2×10~8供鼠Sc;(2)Sc_门组:d_0经受体门静脉输注2×10~8供鼠Sc;(3)Sc_门+BMc_外组:d_0经受体门静脉输注2×10~8供鼠Sc,第3天(d_3)再经阴茎背静脉输注1×10~8供鼠BMc;(4)Se_门+anti CD154mAbq-BMc_外组:d_0经受体门静脉输注2×10~8供鼠Sc,2h后腹腔注射anti CD154mAb 3mg,d3再经阴茎背静脉输注1×10~8供鼠BMc。通过酶联免疫吸附法(ELISA)分别检测脾细胞输注术后第20(d_(20))、40天(d_(40))Wistar大鼠血清IL-10和IFN-γ水平;通过d_(20)、d_(40)单向混合淋巴细胞反应(MLR),大鼠重组白细胞介素2(IL-2)逆转实验和d_(50)迟发性超敏反应(DTH)对受鼠耐受程度进行评估;通过流式细胞术对d_(20)、d_(40)受鼠脾、胸腺细胞中Rt1~(1+)嵌合比例进行测定,d_(100)对Sc_门+anti CD154 mAb+BMc_外组加做此项检查。结果Sc_外组血清细胞因子水平在两时间点均无变化,与正常对照组比较无显著性差异(P＞0.05);Sc_门+anti CD154 mAb+BMc_外组血清IL-10、IFN-γ水平在d_(20)分别为(42.01±4.87)pg/mL和(28.97±3.83)pg/mL,d_(40)分别为(40.19±a:5.30)g/mL和(25.89±4.30)pg/mL,其中IL-10浓度明显高于其它各组,差异有统计学意义(P＜0.01),IFN-γ浓度均处于较低水平,Th1/Th2平衡向Th2偏移;而Scn和Sc_门+BMc_外组细胞因子水平向Th1偏移。单向MLR中Sc_门+anti CD154mAbq-BMc_外组对Lewis供鼠脾细胞的刺激指数(SI)在d_(20)、d_(40)分别为(4.43±0.19)和(4.97±0.25),均显著低于其余各组(P＜0.01),加入外源性IL-2后可部分逆转其低反应性,但对第三方SD大鼠来源的脾细胞仍保持强烈增殖活性,SI值与阳性对照体系无显著性差异(P＞0.05)。DTH实验中只有Sc_门+anti CD154 mAb+BMc_外组表现为显著低反应性,其余各组脚掌厚度差值(FI)与正常对照组比较,差异无统计学意义(P＞0.05)。嵌合体检测结果表明Sc_外组在脾和胸腺中均不能形成嵌合体;Sc_门和Sc_门+BMc_外组在d_(20)能建立较低水平嵌合体,于d_(40)很快下降甚至消失;而sc_门+anti CD154 mAb+BMc_外组在d_(20)、d_(40)的脾和胸腺中均可形成稳定的高水平嵌合,并持续超过100天。结论单纯经外周静脉输注2×10~8供体sc不能诱导嵌合体和免疫耐受的形成;将其输注途径改为门静脉后,可诱导出受鼠轻度的免疫耐受状态,建立短暂(＜20天)、低水平(＜20%)的外周性嵌合体;在此基础上联合输注1×10~8供体BMc可部分增强耐受状态,延长嵌合体水平至40天,但仍不稳定;而只有加入anti CD154 mAb后才可显著增强BMc植入率,三者具有协同作用。外周嵌合体＞30%、中枢嵌合体＞20%是保证骨髓细胞发挥强大致耐受作用的基础。Sc_门+anti CD154 mAb+BMc_外预处理方案可能与Th1/Th2细胞因子偏移、T细胞克隆无能和克隆清除等多种机制有关,在无大剂量骨髓细胞、骨髓抑制剂和放射线参与下,可获得稳定的高水平异基因混合性嵌合体,成功诱导受体针对供体抗原的特异性免疫耐受。
目的为研究胰腺移植术后排斥反应提供实验手段,建立异基因大鼠全胰十二指肠移植(WPDT)模型,并探讨手术过程操作要点。方法在双套管+腹主动脉三通管外接法建模的经验基础之上改进动脉吻合方式,将供受体腹主动脉端侧吻合,供体门静脉与受体左肾静脉袖套吻合,供体十二指肠与受体小肠端侧吻合,成功建立Lewis→Wistar糖尿病大鼠异基因WPDT模型。记录STZ诱导糖尿病大鼠的情况,对移植成功的受鼠3次/周监测随机血糖,并记录存活时间(ST),术后第7天取材3只大鼠移植物行病理学检查。结果STZ诱导糖尿病大鼠成模率为85.7%,酮症酸中毒(DKA)发生率为5.6%,病死率7.4%。50只糖尿病大鼠行WPDT术式,44例移植成功,术后24h血糖由术前(22.83±4.37)mmol/L降至(6.36±2.18)mmol/L。其中有8例于术后3d内死亡,其余36例受鼠存活时间为6～16d,平均为(10.45±3.3)d,术后4d、7d、10d、13d血糖水平呈进行性升高,术后7～10d为死亡高峰,移植物病理改变呈典型的急性排斥反应.结论熟练显微技术,重视操作细节,是成功建立WPDT模型的关键因素。本法建立的WPDT模型可见到移植胰发挥内分泌功能以及典型的急性排斥反应病理改变,该模型稳定、可靠,适用于排斥反应的研究。
Objective To explore the role and possible mechanisms of donor-derived spleen cells(Scs) and it's transfusion pathway combined with anti CD154 monoclonal antibody(mAb) on bone marrow transplantation in non-myeloablative preconditioning regimen for induction of allogeneic mixed chimerism and donor-specific immune tolerance.Methods We adopt Lewis(Rtl~1) as donor,Wistar-Furth(Wistar,Rtl~u) as recipient and Sprague-Dawley(SD) as the third party donor.Scs and bone marrow cells(BMCs) were harvested from donor Lewis rats.Recipient Wistar rats were randomly divided into 4 groups,20 rats in each group. Group Scs_(i.v.),penis dorsal vein(i.v.) injection of Lewis rats 2×10~8 Scs on day 0 alone. Group Scs_(P.V.),portal vein(P.V.) injection of Lewis rats 2×10~8 Scs on day 0 alone. Group Scs_(P.V.)+BMCs_(i.v.),P.V.injection of Lewis rats 2×10~8 Scs on day 0,in combination with i.v.injection of Lewis rats 1×10~8 BMCs on day 3. Group Scs_(P.V.)+ AH.F5(hamster anti-rat CD154 mAb)+BMCs_(i.v.),P.V.injection of Lewis rats 2×10~8 Scs on day 0,intraperitoneal injection 3 mg AH.F5 2 hours later,in combination with i.v.injection of Lewis rats 1×10~8 BMCs on day 3.On day 20 and 40, enzyme linked immunosorbent assay(ELISA) to determine the levels of the serum interleukin(IL)-10 and interferon(IFN)-γ,were performed.Tolerance was assessed by stimulation index(SI) of one-way mixed lymphocyte reaction(MLR),rat recombined IL-2 reverse assay of one-way MLR on day 20,40 and foodpad increment(FI) of delayed type hypersensitivity(DTH) on day 50.Rtl~1 positive chimersim in recipients spleen and thymus were followed by fluorescenceactivited cell sortor(FACS) on day 20,40.Group SCS_(P.V.)+AH.F5+BMCs_(i.v) was additionally carried on chimerism detection on day 100.Moreover,tolerance mechanism was investigated.Results The levels of cytokine were invariable in group Scs_(i.v.) on day 20,40.While,the levels of IL-10 and IFN-γin group Scs_(P.V.)+AH.F5+BMCs_(i.v.) were individual(42.01±4.87) pg/mL and(28.97±3.83) pg/mL on day 20,(40.19±5.30) pg/mL and(25.89±4.30) pg/mL on day 40.UP-regulation of IL-10 was significant higher than other groups, down-regulation of IFN-γwas significant difference from groups Scs_(P.V.) and Scs_(P.V.)+BMCs_(i.v.) The balance of Th1/Th2 alter to Th2 in group SCS_(P.V.)+AH.F5+BMCs_(i.v.),to Th1 in groups Scs_(P.V.) and Scs_(P.V.)+BMCs_(i.v.) SI values were(4.43±0.19) and(4.97±0.25) in group Scs_(P.V.)+AH.F5+BMCs_(i.v.) on day 20,40. There were significant lower than other groups(P<0.01).IL-2 added to one-way MLR can partly reverse immue hyporesponsiveness to allogeneic antibody. Meanwhile,Scs derived from this group had strong activity of proliferation to Scs from the third party SD rats.In DTH test,only group Scs_(P.V.)+AH.F5+BMCs_(i.v.) had suppressive activity.FI values of other groups had no significant difference from normal control group(P>0.05).The results of Rtl~(1+) assay reveal that there was no chimersim in group Scs_(i.v.).While chimersim was transient and low in groups Scs_(P.V.) and Scs_(P.V.)+BMCs_(i.v.) on day 20,and rapidly descend,even disappeared on day 40. Only group SCS_(P.V.)+AH.F5+BMCs_(i.v.) had stable and higher level chimerism in spleen and thymus on day 20,40.Furthermore,long-term chimerism(>100 days) was observed in the group.Conclusion I.V.injection of 2×10~8 Scs alone can't induce chimerism and tolerance.Transfusion pathway of Scs via P.V.can only induce gentle tolerance and establish short-course(< 20 days) and low level(< 20%) peripheral chimerism.Combined with 1×10~8 BMCs can partly enhance tolerance and prolong the existence of chimerism to 40 days,but not stable.However,only combined with anti CD 154 mAb can significantly promote BMCs engraftment.High level of chimerism (>30%in peripheral spleen and >20%in central thymus) provide the foundation to BMCs to play a critical role in the induction or maintenance of tolerance.Our studies demonstrate that P.V.injection of Scs and anti CD154 mAb,plus i.v.injection of BMCs have synergistic effect to induce donor-specific tolerance and establish stable allogeneic mixed chimersim,without participation of megadose BMCs, myleosuppressive drugs and irradiation.Multiple mechanisms,including altering the balance in Th1/Th2,T cells clonal anergy and clonal deletion are involved in the tolerance.
Objective To provide a tool for research grafts rejection and to explore the key technique of this operation,we establish the model of allogeneic whole pancreaticoduodenal transplantation(WPDT) in rats.Methods Wistar-Furth rats with type 1 diabetes mellitus(DM) were induced by intraperitoneal administration of streptozotocin(STZ) at a single dose of 60mg/Kg.On the basis of our primal model established by dual cuff combined with abdominal aorta connected with Y-tube,we improved the way of arterial anastomosis.End to side anastomosis was performed for abdominal aorta of donors and recipients.The portal vein of the graft was anastomosed with the recipients left renal vein by cuff technique.And side to side anastomosis was made between the graft duodenum and the host jejunum.According to the technique mentioned above,we successfully established WPDT model between Lewis rats as donors and Wistar rats as recipients.To monitor the levels of blood glucose 3 times weekly and record the survival time(ST) of each rats.And grafts of 3 rats were collected to observe pathohistologieal changes on day 7 posttransplantation. Results The successful rate of diabetes rats induced by STZ was 85.7%.The incidence rate of diabetic ketoacidosis was 5.6%and the mortality was 7.4%.44 rats were successfully performed WPDT of 50 rats.The mean levels of blood glucose were decreased from(22.83±4.37) mmol/L preoperative to(6.36±2.18) mmol/L postoperative in 44 rats.Among of them,8 rats died in 3 days postoperative,the ST of residual 36 rats was 6-16 days,the mean of ST was(10.45±3.3) d.Three was a progressive increase of blood glucose on day 4,7,10 and 13.The peak of death appeared on day 7-10.The typical acute rejection in pathological changes was observed on day 7.Conclusion Skilled microsurgical techniques and emphasis on details are important to establish WPDT model.The endocrine function of grafts and typical acute rejection can be observed in this model.It is a stable and reliable model, which might be used in research of the theoretical problems involved in clinical pancreas transplantation rejection.
目的为研究胰腺移植术后排斥反应提供实验手段,建立异基因大鼠全胰十二指肠移植(WPDT)模型,并探讨手术过程操作要点。方法在双套管+腹主动脉三通管外接法建模的经验基础之上改进动脉吻合方式,将供受体腹主动脉端侧吻合,供体门静脉与受体左肾静脉袖套吻合,供体十二指肠与受体小肠端侧吻合,成功建立Lewis→Wistar糖尿病大鼠异基因WPDT模型。记录STZ诱导糖尿病大鼠的情况,对移植成功的受鼠3次/周监测随机血糖,并记录存活时间(ST),术后第7天取材3只大鼠移植物行病理学检查。结果STZ诱导糖尿病大鼠成模率为85.7%,酮症酸中毒(DKA)发生率为5.6%,病死率7.4%。50只糖尿病大鼠行WPDT术式,44例移植成功,术后24h血糖由术前(22.83±4.37)mmol/L降至(6.36±2.18)mmol/L。其中有8例于术后3d内死亡,其余36例受鼠存活时间为6～16d,平均为(10.45±3.3)d,术后4d、7d、10d、13d血糖水平呈进行性升高,术后7～10d为死亡高峰,移植物病理改变呈典型的急性排斥反应.结论熟练显微技术,重视操作细节,是成功建立WPDT模型的关键因素。本法建立的WPDT模型可见到移植胰发挥内分泌功能以及典型的急性排斥反应病理改变,该模型稳定、可靠,适用于排斥反应的研究。
Objective To explore the role and possible mechanisms of donor-derived spleen cells(Scs) and it's transfusion pathway combined with anti CD154 monoclonal antibody(mAb) on bone marrow transplantation in non-myeloablative preconditioning regimen for induction of allogeneic mixed chimerism and donor-specific immune tolerance.Methods We adopt Lewis(Rtl~1) as donor,Wistar-Furth(Wistar,Rtl~u) as recipient and Sprague-Dawley(SD) as the third party donor.Scs and bone marrow cells(BMCs) were harvested from donor Lewis rats.Recipient Wistar rats were randomly divided into 4 groups,20 rats in each group. Group Scs_(i.v.),penis dorsal vein(i.v.) injection of Lewis rats 2×10~8 Scs on day 0 alone. Group Scs_(P.V.),portal vein(P.V.) injection of Lewis rats 2×10~8 Scs on day 0 alone. Group Scs_(P.V.)+BMCs_(i.v.),P.V.injection of Lewis rats 2×10~8 Scs on day 0,in combination with i.v.injection of Lewis rats 1×10~8 BMCs on day 3. Group Scs_(P.V.)+ AH.F5(hamster anti-rat CD154 mAb)+BMCs_(i.v.),P.V.injection of Lewis rats 2×10~8 Scs on day 0,intraperitoneal injection 3 mg AH.F5 2 hours later,in combination with i.v.injection of Lewis rats 1×10~8 BMCs on day 3.On day 20 and 40, enzyme linked immunosorbent assay(ELISA) to determine the levels of the serum interleukin(IL)-10 and interferon(IFN)-γ,were performed.Tolerance was assessed by stimulation index(SI) of one-way mixed lymphocyte reaction(MLR),rat recombined IL-2 reverse assay of one-way MLR on day 20,40 and foodpad increment(FI) of delayed type hypersensitivity(DTH) on day 50.Rtl~1 positive chimersim in recipients spleen and thymus were followed by fluorescenceactivited cell sortor(FACS) on day 20,40.Group SCS_(P.V.)+AH.F5+BMCs_(i.v) was additionally carried on chimerism detection on day 100.Moreover,tolerance mechanism was investigated.Results The levels of cytokine were invariable in group Scs_(i.v.) on day 20,40.While,the levels of IL-10 and IFN-γin group Scs_(P.V.)+AH.F5+BMCs_(i.v.) were individual(42.01±4.87) pg/mL and(28.97±3.83) pg/mL on day 20,(40.19±5.30) pg/mL and(25.89±4.30) pg/mL on day 40.UP-regulation of IL-10 was significant higher than other groups, down-regulation of IFN-γwas significant difference from groups Scs_(P.V.) and Scs_(P.V.)+BMCs_(i.v.) The balance of Th1/Th2 alter to Th2 in group SCS_(P.V.)+AH.F5+BMCs_(i.v.),to Th1 in groups Scs_(P.V.) and Scs_(P.V.)+BMCs_(i.v.) SI values were(4.43±0.19) and(4.97±0.25) in group Scs_(P.V.)+AH.F5+BMCs_(i.v.) on day 20,40. There were significant lower than other groups(P<0.01).IL-2 added to one-way MLR can partly reverse immue hyporesponsiveness to allogeneic antibody. Meanwhile,Scs derived from this group had strong activity of proliferation to Scs from the third party SD rats.In DTH test,only group Scs_(P.V.)+AH.F5+BMCs_(i.v.) had suppressive activity.FI values of other groups had no significant difference from normal control group(P>0.05).The results of Rtl~(1+) assay reveal that there was no chimersim in group Scs_(i.v.).While chimersim was transient and low in groups Scs_(P.V.) and Scs_(P.V.)+BMCs_(i.v.) on day 20,and rapidly descend,even disappeared on day 40. Only group SCS_(P.V.)+AH.F5+BMCs_(i.v.) had stable and higher level chimerism in spleen and thymus on day 20,40.Furthermore,long-term chimerism(>100 days) was observed in the group.Conclusion I.V.injection of 2×10~8 Scs alone can't induce chimerism and tolerance.Transfusion pathway of Scs via P.V.can only induce gentle tolerance and establish short-course(< 20 days) and low level(< 20%) peripheral chimerism.Combined with 1×10~8 BMCs can partly enhance tolerance and prolong the existence of chimerism to 40 days,but not stable.However,only combined with anti CD 154 mAb can significantly promote BMCs engraftment.High level of chimerism (>30%in peripheral spleen and >20%in central thymus) provide the foundation to BMCs to play a critical role in the induction or maintenance of tolerance.Our studies demonstrate that P.V.injection of Scs and anti CD154 mAb,plus i.v.injection of BMCs have synergistic effect to induce donor-specific tolerance and establish stable allogeneic mixed chimersim,without participation of megadose BMCs, myleosuppressive drugs and irradiation.Multiple mechanisms,including altering the balance in Th1/Th2,T cells clonal anergy and clonal deletion are involved in the tolerance.
Objective To provide a tool for research grafts rejection and to explore the key technique of this operation,we establish the model of allogeneic whole pancreaticoduodenal transplantation(WPDT) in rats.Methods Wistar-Furth rats with type 1 diabetes mellitus(DM) were induced by intraperitoneal administration of streptozotocin(STZ) at a single dose of 60mg/Kg.On the basis of our primal model established by dual cuff combined with abdominal aorta connected with Y-tube,we improved the way of arterial anastomosis.End to side anastomosis was performed for abdominal aorta of donors and recipients.The portal vein of the graft was anastomosed with the recipients left renal vein by cuff technique.And side to side anastomosis was made between the graft duodenum and the host jejunum.According to the technique mentioned above,we successfully established WPDT model between Lewis rats as donors and Wistar rats as recipients.To monitor the levels of blood glucose 3 times weekly and record the survival time(ST) of each rats.And grafts of 3 rats were collected to observe pathohistologieal changes on day 7 posttransplantation. Results The successful rate of diabetes rats induced by STZ was 85.7%.The incidence rate of diabetic ketoacidosis was 5.6%and the mortality was 7.4%.44 rats were successfully performed WPDT of 50 rats.The mean levels of blood glucose were decreased from(22.83±4.37) mmol/L preoperative to(6.36±2.18) mmol/L postoperative in 44 rats.Among of them,8 rats died in 3 days postoperative,the ST of residual 36 rats was 6-16 days,the mean of ST was(10.45±3.3) d.Three was a progressive increase of blood glucose on day 4,7,10 and 13.The peak of death appeared on day 7-10.The typical acute rejection in pathological changes was observed on day 7.Conclusion Skilled microsurgical techniques and emphasis on details are important to establish WPDT model.The endocrine function of grafts and typical acute rejection can be observed in this model.It is a stable and reliable model, which might be used in research of the theoretical problems involved in clinical pancreas transplantation rejection.
引文
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21.Jin T,Toki J,Inaba M,et al.A novel strategy for organ allografts using sublethal(7Gy)irradiation followed by injection of donor bone marrow cells via portal vein.Transplantation,2001,71(12):1725-1731.
22.Clarkson MR,Sayegh MH.T-cell costimulatory pathways in allograft rejection and tolerance.Transplantation,2005,80:555-563.
23.Kurtz J,Shaffer J,Lie A,et al.Mechanisms of early peripheral CD4 T-cell tolerance induction by anti-CD154 monoelonal antibody and allogeneic bone marrow transplantation:evidence for anergy and deletion but not regulatory cells.Blood,2004,103:4336-4343.
24.Yuan X,Dong VM,Coito AJ,et al.A novel CD154 monoelonal antibody in acute and chronic rat vascularized cardiac allograft rejection.Transplantation,2002,73(11):1736-1742.
25.Gray JD,Liu T,Huynh N,et al.Transforming growth factor beta enhances the expression of CD154(CD40L) and production of tumor necrosis factor alpha by human T lymphocytes.Immunol Lett,2001,78(2):83-88.
26.于平,熊思东,何球藻等.应用未成熟树突状细胞诱导形成异基因嵌合体的方法学研究.中国医学检验杂志,2002,3(5):310-312.
27.Koyama I,Kawai T,Andrews D,et al.Thrombophilia associated with anti-CD154monoclonal antibody treatment and its prophylaxis in nonhuman primates.Transplantation,2004,77:460.
28.Callery MP,Mangino MJ,Fly MW,et al.A biologic basis for limited kupffer cell reactivity to portal derived endotoxin.Surgery,1991,10:221-227.
29.Qian JH,Hashimoto T,Fujinars H,et al.Studies on the induction of tolerance to alloantigens I:abrogation of delayed-type hypersensitivity response to alloantigens by portal veneus inoculation with allogenic cells.J Immunol,1985,134:3656-3658.
30.叶明,吴乃石,夏求明.门静脉预输注供者凋亡骨髓细胞延长大鼠移植心脏的存活时间.中华器官移植杂志,2006,27(5):301-304.
31.王翔,赵鸿,张元芳等.未成熟树突状细胞诱导大鼠免疫低反应性.中华器官移植杂志,2005,26(4):203-206.
32.Tsui TY,Deiwick A,Ko S,et al.Specific immunosuppression by postoperative infusion of allogeneic spleen cells:requirement of donor major histocompatibility complex expression and graft-versus-host reactivity.Transplantation,2000,69(1):25-30.
33.Sugiura K,Kato K,Hashimoto F,et al.Induction of donor-specific T cell anergy by portal venous injection of allogeneic cells.Immunobiology,1997,197:460.
34.Hirano A,Luke PP,Specht SM,et al.Graft hyporeactivity induced by immature donor-derived dendritic cells.Transplant Immunol,2000,8(3):161-168.
35.Reich-Zeliger S,Baehar-Lustig E,Bar-Ilan A,et al.Tolerance induction in presensitized bone marrow recipients by veto CTLs:effective deletion of host anti-donor memory effector cells.J Immunol,2007,179(10):6389-6394.
36.Hashimoto F,Sugiura K,Inoue K,Ikehara S.Major histocompatibility complex restriction between hematopoietic stem cells and stromal cells in vivo.Blood,1997,89:49.
37.Seung E,Mordes JP,Rossini AA et al.Hematopoietie chimerism and central tolerance created by peripheral tolerance induction without myeloablative conditioning.J Clin Invest,2003,112:795.
38.Mai G,Bucher P,Morel P,et al.Anti-CD154 mAb treatment but notrecipient CD154deficiency leads to long-term survival of xenogeneic islet grafts.Am J Transplant,2005,5:1021-1031.
39.Ito H,Kurtz J,Shaffer J,et al.CD4 T cell-mediated alloresistance to fully MHC-mismatched allogeneic bone marrow engraftment is dependent on CD40-CD40 ligand interactions,and lasting T cell tolerance is induced by bone marrow transplantation with initial blockade of this pathway.J Immunol,2001,166(5):2970-2981.
40.Pree I,Bigenzahn S,Fuchs D,et al.CTLA4Ig promotes the induction of hematopoietic chimerism and tolerance independently of indoleamine-2,3-Dioxygenase.Transplantation,2007,83(5):663-667.
1.Gruessner AC,Sutherland DE.Pancreas transplant outcomes for United States(US) and non-US cases as reported to the United Network for Organ Sharing(UNOS) and the International Pancreas Transplant Registry(IPTR) as of June 2004.Clin Transplant,2005,19(4):433-455.
2.刁畅,魏晓平,李立等.双套管+腹主动脉三通管外接法建立大鼠胰十二指肠移植模型.中国普外基础与临床杂志,2008,4(15):254-257.
3.朱兴国,田清水,陈彦等.大鼠胰十二指肠移植动物模型的制作.中华实验外科杂志,2005,22(4):496-497.
4.张召辉,李玺,路逵阳等.大鼠胰十二指肠移植模型的建立.徐州医学院学报,2003,23(3):205-206.
5.虞俊波,徐泽宽.肠造瘘式大鼠胰十二指肠移植模型的建立.中华实验外科杂志,2006,23(1):109.
6.Jiga LP,Nit(?) G,Dornean V,et al.Experimental model of pancreas transplantation with portal or systemic drainage in the laboratory rat.Chirurgia(Bucur),2007,102(5):563-570.
7.陈彦,朱兴国,李德春等.RANTES在同种异体胰腺十二指肠移植大鼠中的表达.苏州大学学报(医学版,2006,26(1):422-430.
8.Miao G,Ito T,Uchikoshi F,et al.Development of donor-specific immunoregulatory T-cells after local CTLA4Ig gene transfer to pancreatic allograft.Transplantation,2004,78(1):59-64.
9.Yuan CH,Liu YF,Cheng Y,et al.Protective effects of L-arginine on reperfusion injury after pancreaticoduodenal transplantation in rats.Hepatobiliary Pancreat Dis Int,2004,3(3):349-354.
10.Ma Y,Guo ZY.Use of surgical techniques in the rat pancreas transplantation model.Hepatobiliary Pancreat Dis Int,2008,7(2):156-160.
11.Dong GH,Zhang ZD,Hu WM,et al.Establishment of whole pancreaticoduodenal allotransplantation model with portal venous drainage and enteric drainage in pigs.Nan Fang Yi Ke Da Xue Xue Bao,2006,26(5):626-628.
12.Gu Y,Li J,Li N.Insulin sensitivity after pancreaticoduodenal transplantation with systemic and portal venous drainage in inbred rats.Chin Med J(Engl),2002,115(4):549-551.
13.刘忠,关风林,沈忠义等.异基因大鼠全胰十二指肠移植急性排斥反应的病理变化.中国普通外科杂志,2002,11(3):165-167.
14.Mark,W,Hechenleitner P,Dietze O,et al.Duodenal histology for monitoring treatment of acute rejection in pancreaticoduodenal allografts in rats.Transplantation,2002,73(2):198-203.
1.Gruessner AC,Suthedand DE.Pancreas transplant outcomes for United States(US) and non-US cases as reported to the United Network for Organ Sharing(UNOS) and the International Pancreas Transplant Registry(IPTR) as of June 2004.Clin Transplant,2005,19(4):433-455.
2.Jin T,Toki J,Inaba M,et al.A novel strategy for organ allografts using sublethal(7Gy)irradiation followed by injection of donor bone marrow cells via portal vein.Transplantation,2001,71(12):1725-1731.
3.Masaki H,C.Appel M,Leahy L,et al.Anti-mouse CD154 antibody treatment facilitates generation of mixed xenogeneic rat hematopoietic chimerism,prevents wasting disease and prolongs xenograft survival in mice.Xenotransplantation,2006,13:224-232.
4.Soulillou JP,Giral M.Controlling the incidence of infection and malignancy by modifying immunosuppression.Transplantation 2001;72:S89.
5.Ito T,Uchikoshi F,Tori M,et al.Immunological characteristics of pancreas transplantation:review and our experimental experience.Pancreas,2003(1):31-37.
6.Salomon B,Bluestone JA.Complexities of CD28 / B7:CTLA4 costimulatory pathways in autoimmunity and transplantation.Annu Rev Immunol,2001,19:225-252.
7.Quezada SA,Jarvinen L,Lind EF,et al.CD40/CD154 interactions at the interface of tolerance and immunity.Annu Rev Immunol,2004,22:307-328.
8.Delis S,Ciancio G,Burke GW 3rd,et al.Donor bone marrow transplantation:chimerism and tolerance.Transpl Immunol,2004,13(2):105-115.
9.Schwartz RH.A cell culture model for T lymphocyte clonal anergy.Science,1990,248:1349-1356.
10.Coulombe M,RG Gill.T lymphocyte indifference to extrathymic islet allografts.J Immunol,1996,156:1998.
11.Nikolic B,Cooke DT,Zhao G,et al.Both gamma delta T cells and NK cells inhibit the engraftment of xenogeneic rat bone marrow cells and the induction of xenograft tolerance in mice.J Immunol,2001,166:1398.
12.Lederman S,Yellin MJ,Krichevsky A,et al.Identification of a novel surface protein on activated CD4 T cell that induces contact-dependent B cell differentiation.J Exp Med,1992,175:1091.
13.Bumgardner GI,Li J,Heininger M,el al.Efficacy of anti intercellular adhesion molecule-1immunotherapy on immune responses to allogeneic hepatocytes in mice.Hepatology,1998,28(4):1005-1012.
14.Chowdhury SA,Nagata M,Yamada K,et al.Tolerance mechanisms in murine autoimmune diabetes induced by anti-ICAM-1/LFA-1 mAb and anti-CD8 mAb.Kobe J Med Sci,2002,48(5-6):167-175.
15.Yusuf-Makagiansar H,Anderson ME,Yakovleva TV,et al.Inhibition of LFA-1/ICAM-1 and VLA-4/VCAM-1 as a therapeutic approach to inflammation and autoimmune diseases.Med Res Rev,2002,22(2):146-167.
16.Filby A,Seddon B,Kleczkowska J,et al.Fyn regulates the duration of TCR engagement needed for commitment to effector function.J Immunol,2007,179(7):4635-4644.
17.Foell J,Hewes B,Mittler RS.T cell costimulatory and inhibitory receptors as therapeutic targets for inducing anti-tumor immunity.Curr Cancer Drag Targets,2007,7(1):55-70.
18.Scharpf J,Strome M,Siemionow M.Immunomodulation with anti-alphabeta T-cell receptor monoclonal antibodies in combination with cyclosporine A improves regeneration in nerve allografts.Mierosurgery,2006,26(8):599-607.
19.Brook MO,Jones ND,Wood KJ.Inhibition of chronic rejection and development of tolerogenic T cells after ICOS-ICOSL and CD40-CD40L co-stimulation blockade.Transplantation,2005,80(2):255-263.
20.Li ZL,Xue WJ,Tian PX,et al.Prolongation of islet allograft survival by coexpression of CTLA4Ig and CD40LIg in mice.Transplant Proc,2007,39(10):3436-3437.
21.Lee JH,Ha J,Kim SH,et al.IL-2 pathway blocking in combination with anti-CD154synergistically establishes mixed macrochirnerism with limited dose of bone marrow cells and prolongs skin graft survival in mice.J Korean Med Sci,2006,21(6):1005-1011.
22.Emmanouilidis N,Guo Z,Dong Y,et al.Immunosuppressive and trafficking properties of donor splenic and bone marrow dendritic cells.Transplantation,2006,81(3):455-462.
23.Chavez H,Beaudreuil S,Abbed K,et al.Absence of CD4CD25 regulatory T cell expansion in Neumimmunology,2005,162(1):28-42.
36.Ito H,Kurtz J,Shaffer J,Sykes M.CD4 T cell-mediated alloresistance to fully MHC-mismatched allogeneic bone marrow engraftment is dependent on CD40-CD40 ligand interactions,and lasting T cell tolerance is induced by bone marrow transplantation with initial blockade of this pathway.J Immuno12001;166:2970.
37.Kurtz J,Shaffer J,Lie A,et al.Mechanisms of early peripheral CD4 T-cell tolerance induction by anti-CD154 monoclonal antibody and allogeneic bone marrow transplantation:evidence for anergy and deletion but not regulatory cells.Blood.2004,103:4336-4343.
38.Ito T,Stepkowski SM,Kahan BD.Soluble antigen and cyclosporine-induced specific unresponsiveness in rats.Frequency of alloantigen-specific T cytotoxic cells in normal,sensitized and unresponsive rats.Transplantation,1990,49(2):422-428.
39.Ito T,Uchikoshi F,Tori M,et al.Immunological characteristics of pancreas transplantation:review and our experimental experience.Pancreas,2003(1):31-37.
40.冷希圣,黄萃庭.供体脾细胞在大鼠胰十二指肠移植中抗免疫排斥作用的初步观察.中华实验外科杂志,1989,6(3):106-107.
41.周峰,万赤丹,熊炯忻等.供体特异性输血对大鼠胰十二指肠移植的保护作用.中华实验外科杂志,2004,21(12):1477-1478.
42.韩曙光,徐泽宽,张轩等.可诱导性共刺激分子单抗联合细胞毒T淋巴细胞4Ig在大鼠胰腺移植中的作用.中华实验外科杂志,2007,24(4):420-422.
43.孟令祥,胡伟明,张肇达等.Ad-CTLA-4Ig基因导入对胰十二指肠移植大鼠免疫耐受的实验研究.四川大学学报,2007,38(3):374-377.
44.Schulak JA,Engelstad KM.Immunologic consequences of combined pancreas-spleen transplantation in the rat.J Surg Res,1989,47(1):52-58.
45.Sakuma Y,Sato Y,Inoue S,et al.Lympho-myeloid chimerism achieved by spleen graft of green fluorescent protein transgenic rat in a combined pancreas transplantation model.Transplant Immunol,2004,12(2):115-122.
46.Masaki Y,Suzuki K,Yan H,et al.Quantitative aspects of microchimerism after rat small bowel and pancreaticoduodenal transplantation.Transplant Proc,2000,32(7):2483-2484.
47.Drevillon C,Elian N,Zinzindohoue F,et al.Prolonged improvement of total pancreatic allograft function by previous intrathymic bone marrow cell injection in rats.Eur Surg Res, 2003,35(1):1-5.
48.Burke GW,Ciancio G,Garcia-Morales R,et al.Evidence for microchimerism in peripheral blood,bone marrow,and skin following donor bone marrow/kidney-pancreas transplantation at 3 years.Transplant Proc,1998,30(4):1555.
49.Corry R J,Chakrabarti PK,Shapiro R,et al.Simultaneous administration of adjuvant donor bone marrow in pancreas transplant recipients.Ann Surg,1999,230(3):372-381.
50.Kuhr CS,Nelson K,Gaur L,et al.Induced microchimerism by spleen reperfusion affords no immunological advantage in pancreas transplantation.Transplant Proc,2003,35(2):878-879.
2.Millan MT,Shizuru JA,Hoffmann P,et al.Mixed chimerism and immunosuppressive drug withdrawal after HLA-mismatched kidney and hematopoietic progenitor transplantation.Transplantation,2002,73(9):1386 -1391.
3.Bachar-Lustig E,Rachamim N,Li HW,et al.Megadose of T cell-depleted bone marrow overcomes MHC barriers in sublethally irradiated mice.Nat Med,1995,1:1268-1273.
4.Schwartz RH.A cell culture model for T lymphocyte clonal anergy.Science,1990,248:1349-1356.
5.Starzl TE,Demetris A J,Trucco M,et al.Chimerism and donor-specific nonreactivity 27 to 29years after kidney allotransplantation.Transplantation,1993,55(6):1272-1277.
6.Shirwan H,Wu GD,Barwart L,et al.Induction of allograft nonresponsiveness after intrathymic inoculation with donor class Ⅰ allopeptides Ⅱ.Evidence for persistent chemic rejection despite high levels of donor micmchimefism.Transplantation,1997,64(12):1671-1676.
7.Kuhr CS,Nelson K,Gaur L,et al.Induced Microchimerism by Spleen Reperfusion Affords No Immunological Advantage in Pancreas Transplantation.Transplant Proc,2003,35:878-879.
8.Nikolic B,Khan A,Sykes M.Induction of tolerance by mixed chimerism with nonmyeloblative host conditioning:the importance of overcoming intrathymic alloresistance.Biol Blood Marrow Transplant,2001,7(3):144-153.
9.Nikolic B,Cooke DT,Zhao G,et al.Both gamma delta T cells and NK cells inhibit the engraftment of xenogeneic rat bone marrow cells and the induction of xenograft tolerance in mice.J Immunol,2001,166(2):1398-1404.
10.Jin YZ,Xie SS.Bicistronic adenovirus-mediated gene transfer of the CTLA4Ig and CD40Ig genes results in indefinite survival of islet xenograft.Transplant Proc,2003,35:3165-3166.
11.Masaki H,C.Appel M,Leahy L,et al.Anti-mouse CD154 antibody treatment facilitates generation of mixed xenogeneic mt hematopoietic chimerism,prevents wasting disease and prolongs xenograft survival in mice.Xenotransplantation,2006,13:224-232.
12.Jochum C,Beste M,Zellmer E,et al.CD154 blockade and donor-specific transfusions m DLA-identical marrow transplantation in dogs conditioned with 1-Gy total body irradiation.Biology of Blood and Marrow Transplantation.2007,13:164-171.
13.Graca L,Daley S,Fairchild PJ,el al.Co-receptor and co-stimulation blockade for mixed chimerism and tolerance without myelosuppressive conditioning.BMC Immunology,2006,7:9-17.
14.Hale DA,Gottschalk R,Umemura A,et al.Establishment of stable muhilineage hematopo ietie chimerism and donor-specific tolerance without irradiation.Transplantation,2000,69(7):1242.
15.Drevillon C,Elian N,Zinzindohoue F,et al.Prolonged improvement of total pancreatic allograft function by previous intrathymic bone marrow cell injection in rots.Eur Surg Res,2003,35(1):1-5.
16.SakumaY,SatoY,Inoue S,el al.Lympho-myeloid chimerism achieved by spleen graft of green fluorescent protein transgenic rat in a combined pancreas transplantation model.Transplant Immunology,2004,12:115-122.
17.Kuwatani M,Ikarashi Y,Mineishi S,et al.An irradiation-free nonmyeloablative bone marrow transplantation model:importance of the balance between donor T-cell number and the intensity of conditioning.Transplantation,2005,80(9):1145-1152.
18.张庆殷,郝洁,蒋激扬,等.供体骨髓细胞促进大鼠心脏移植耐受及机制的研究.上海免疫学杂志,2002,22(4):225-229.
19.Ikehara S.A novel strategy for allogeneic stem cell transplantation:perfusion method plus intra-bone marow injection of stem cells.ExpHemalol,2003,31:1142-1146.
20,Askenasy N.Localized bone marrow transplantation leads to skin allograft acceptance in nonmyeloablated recipients:comparison of intra-bone marrow and isolated limb perfusion.Stem Cells,2002,20(1):86-93.
21.Jin T,Toki J,Inaba M,et al.A novel strategy for organ allografts using sublethal(7Gy)irradiation followed by injection of donor bone marrow cells via portal vein.Transplantation,2001,71(12):1725-1731.
22.Clarkson MR,Sayegh MH.T-cell costimulatory pathways in allograft rejection and tolerance.Transplantation,2005,80:555-563.
23.Kurtz J,Shaffer J,Lie A,et al.Mechanisms of early peripheral CD4 T-cell tolerance induction by anti-CD154 monoelonal antibody and allogeneic bone marrow transplantation:evidence for anergy and deletion but not regulatory cells.Blood,2004,103:4336-4343.
24.Yuan X,Dong VM,Coito AJ,et al.A novel CD154 monoelonal antibody in acute and chronic rat vascularized cardiac allograft rejection.Transplantation,2002,73(11):1736-1742.
25.Gray JD,Liu T,Huynh N,et al.Transforming growth factor beta enhances the expression of CD154(CD40L) and production of tumor necrosis factor alpha by human T lymphocytes.Immunol Lett,2001,78(2):83-88.
26.于平,熊思东,何球藻等.应用未成熟树突状细胞诱导形成异基因嵌合体的方法学研究.中国医学检验杂志,2002,3(5):310-312.
27.Koyama I,Kawai T,Andrews D,et al.Thrombophilia associated with anti-CD154monoclonal antibody treatment and its prophylaxis in nonhuman primates.Transplantation,2004,77:460.
28.Callery MP,Mangino MJ,Fly MW,et al.A biologic basis for limited kupffer cell reactivity to portal derived endotoxin.Surgery,1991,10:221-227.
29.Qian JH,Hashimoto T,Fujinars H,et al.Studies on the induction of tolerance to alloantigens I:abrogation of delayed-type hypersensitivity response to alloantigens by portal veneus inoculation with allogenic cells.J Immunol,1985,134:3656-3658.
30.叶明,吴乃石,夏求明.门静脉预输注供者凋亡骨髓细胞延长大鼠移植心脏的存活时间.中华器官移植杂志,2006,27(5):301-304.
31.王翔,赵鸿,张元芳等.未成熟树突状细胞诱导大鼠免疫低反应性.中华器官移植杂志,2005,26(4):203-206.
32.Tsui TY,Deiwick A,Ko S,et al.Specific immunosuppression by postoperative infusion of allogeneic spleen cells:requirement of donor major histocompatibility complex expression and graft-versus-host reactivity.Transplantation,2000,69(1):25-30.
33.Sugiura K,Kato K,Hashimoto F,et al.Induction of donor-specific T cell anergy by portal venous injection of allogeneic cells.Immunobiology,1997,197:460.
34.Hirano A,Luke PP,Specht SM,et al.Graft hyporeactivity induced by immature donor-derived dendritic cells.Transplant Immunol,2000,8(3):161-168.
35.Reich-Zeliger S,Baehar-Lustig E,Bar-Ilan A,et al.Tolerance induction in presensitized bone marrow recipients by veto CTLs:effective deletion of host anti-donor memory effector cells.J Immunol,2007,179(10):6389-6394.
36.Hashimoto F,Sugiura K,Inoue K,Ikehara S.Major histocompatibility complex restriction between hematopoietic stem cells and stromal cells in vivo.Blood,1997,89:49.
37.Seung E,Mordes JP,Rossini AA et al.Hematopoietie chimerism and central tolerance created by peripheral tolerance induction without myeloablative conditioning.J Clin Invest,2003,112:795.
38.Mai G,Bucher P,Morel P,et al.Anti-CD154 mAb treatment but notrecipient CD154deficiency leads to long-term survival of xenogeneic islet grafts.Am J Transplant,2005,5:1021-1031.
39.Ito H,Kurtz J,Shaffer J,et al.CD4 T cell-mediated alloresistance to fully MHC-mismatched allogeneic bone marrow engraftment is dependent on CD40-CD40 ligand interactions,and lasting T cell tolerance is induced by bone marrow transplantation with initial blockade of this pathway.J Immunol,2001,166(5):2970-2981.
40.Pree I,Bigenzahn S,Fuchs D,et al.CTLA4Ig promotes the induction of hematopoietic chimerism and tolerance independently of indoleamine-2,3-Dioxygenase.Transplantation,2007,83(5):663-667.
1.Gruessner AC,Sutherland DE.Pancreas transplant outcomes for United States(US) and non-US cases as reported to the United Network for Organ Sharing(UNOS) and the International Pancreas Transplant Registry(IPTR) as of June 2004.Clin Transplant,2005,19(4):433-455.
2.刁畅,魏晓平,李立等.双套管+腹主动脉三通管外接法建立大鼠胰十二指肠移植模型.中国普外基础与临床杂志,2008,4(15):254-257.
3.朱兴国,田清水,陈彦等.大鼠胰十二指肠移植动物模型的制作.中华实验外科杂志,2005,22(4):496-497.
4.张召辉,李玺,路逵阳等.大鼠胰十二指肠移植模型的建立.徐州医学院学报,2003,23(3):205-206.
5.虞俊波,徐泽宽.肠造瘘式大鼠胰十二指肠移植模型的建立.中华实验外科杂志,2006,23(1):109.
6.Jiga LP,Nit(?) G,Dornean V,et al.Experimental model of pancreas transplantation with portal or systemic drainage in the laboratory rat.Chirurgia(Bucur),2007,102(5):563-570.
7.陈彦,朱兴国,李德春等.RANTES在同种异体胰腺十二指肠移植大鼠中的表达.苏州大学学报(医学版,2006,26(1):422-430.
8.Miao G,Ito T,Uchikoshi F,et al.Development of donor-specific immunoregulatory T-cells after local CTLA4Ig gene transfer to pancreatic allograft.Transplantation,2004,78(1):59-64.
9.Yuan CH,Liu YF,Cheng Y,et al.Protective effects of L-arginine on reperfusion injury after pancreaticoduodenal transplantation in rats.Hepatobiliary Pancreat Dis Int,2004,3(3):349-354.
10.Ma Y,Guo ZY.Use of surgical techniques in the rat pancreas transplantation model.Hepatobiliary Pancreat Dis Int,2008,7(2):156-160.
11.Dong GH,Zhang ZD,Hu WM,et al.Establishment of whole pancreaticoduodenal allotransplantation model with portal venous drainage and enteric drainage in pigs.Nan Fang Yi Ke Da Xue Xue Bao,2006,26(5):626-628.
12.Gu Y,Li J,Li N.Insulin sensitivity after pancreaticoduodenal transplantation with systemic and portal venous drainage in inbred rats.Chin Med J(Engl),2002,115(4):549-551.
13.刘忠,关风林,沈忠义等.异基因大鼠全胰十二指肠移植急性排斥反应的病理变化.中国普通外科杂志,2002,11(3):165-167.
14.Mark,W,Hechenleitner P,Dietze O,et al.Duodenal histology for monitoring treatment of acute rejection in pancreaticoduodenal allografts in rats.Transplantation,2002,73(2):198-203.
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