受者来源的PIR-B转染的树突状细胞对小鼠异基因骨髓移植GVHD的保护作用
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摘要
目的：建立一个稳定可靠的异基因骨髓移植(allogeneic bone marrow transplantation, allo-BMT)小鼠急性移植物抗宿主病(acut graft-versus-host disease, aGVHD)动物模型,为后期实研究验allo-BMT后aGVHD和移植耐受提供理想的实验平台。
方法：将供者C57BL/6J (H-2b)雄性小鼠骨髓细胞和脾细胞按不同比例(1:1和1：2)混合,输入接受致死性全身照射(8.5Gy)的受鼠雌性BALB/C (H-2d)小鼠以引起不同程度的aGVHD,检测嵌合体情况,根据受鼠的一般情况、临床表现、生存期和组织病理学等判断aGVHD程度。
结果：混合不同比例的供鼠骨髓细胞和脾细胞allo-BMT的小鼠均发生了aGVHD,但出现aGVHD的时间和程度均有差异。其中骨髓与脾细胞1：2组小鼠可在相对集中的时间内观察到典型的aGVHDI临床和病理改变,所有小鼠均在14-24d死亡。骨髓与脾细胞1:1组aGVHD程度较轻,移植后4周小鼠均全部存活。
结论：骨髓细胞和脾细胞比例为1:2组比1:1组出现更典型的aGVHD,其发病和死亡时间较集中。选定TBI8.5Gy及细胞移植的混合比例(1:2)构建小鼠aGVHD模型,为后续实验提供理想模型。
目的：探讨不同方法诱导的受者来源树突状细胞(dendritic cells, DCs)输注对异基因骨髓移植(allogeneic bone marrow transplantation, allo-BMT)小鼠急性移植物抗宿主病(acut graft-versus-host disease,aGVHD)和造血重建的影响。
方法：受鼠为雌性BALB/C (H-2d)小鼠,供鼠为雄性C57BL/6J (H-2b)小鼠。无菌分离受鼠骨髓细胞(bone marrow cell, BMC),与GM-CSF共培养得到未成熟树突状细胞(immature dendritic cells, imDCs);受鼠BMC与GM-CSF、IL-10共培养得到IL-10-DCs;用配对性免疫球蛋白样受体B (Paired immunoglobin-like receptor B, PIR-B)慢病毒载体转染imDCs得到PIR-B-DCs。受鼠随机分为四组,在移植骨髓后分别予尾静脉注射imDCs、IL-10-DCs、PIR-B-DCs和RPMI1640培养液。以移植后aGVHD临床表现,肝脏、小肠、皮肤病理组织改变,生存期为观察指标并进行组间比较。
结果：PIR-B-DCs移植组、IL-10-DCs移植组、imDCs移植组和单纯移植组受鼠平均生存时间为(46.0±13.6)天、(36.4±13.0)天、(21.6±2.8)天和(17.4±3.6)天,p＜0.01；4组小鼠在移植后15天GVHD临床评分为(5.28±0.27)、(5.26±0.31)、(2.46±0.18)和(0.86±0.21),p<0.05。单纯移植组病理显示肝脏汇管区大量淋巴细胞浸润,小胆管塌陷破坏,皮肤基底层连续性中断,有大量淋巴细胞,肠粘膜下层淋巴细胞浸润,肠绒毛萎缩变性,PIR-B-DCs移植组病理组织检查仅有轻微GVHD表现。
结论：受者来源PIR-B-DCs联合骨髓移植能够明显延长受鼠生存时间,减轻移植后aGVHD反应,促进造血重建。
Object:To establish a murine model of acute graft-versus-host disease (aGVHD) induced by allogeneic bone marrow transplantation (allo-BMT) for providing experimental studies of aGVHD and transplantation tolerance.
Methods:All recipients female BALB/C (H-2d) mice were received total body irradiation 8.5Gy at 4 hours prior to transplantation. Bone marrow cells mixed with spleen cells of donors male C57BL/6J (H-2b) mice based upon different proportions (1:1 and 1:2) were injected into tail vein. The chimeras were evaluated as well as the recipients'survival time, clinical and pathologic manifestations of aGVHD.
Result:All mice received allo-BMT with different ratios of bone marrow cells and spleen cells showed aGVHD evidence. However, there were significant differences in the incidence and severity of aGVHD. The group with co-transplantation of bone marrow cells and spleen cells in ratio of 1:2 showed typical clinical and pathological manifestations of aGVHD at a relatively concentrated time, and died within 14-24d. Mice in group infused with bone marrow cells and spleen cells in ratio of 1:1 showed insignificant aGVHD, and were all alived (4 weeks after allo-BMT).
Conclusion:The group with co-transplantation of bone marrow cells and spleen cells in ratio of 1:2 showed more significant manifestations and more concentrated time of incident and death than the group that of 1:1. Thus, infusion of bone marrow cells and spleen cells in ration of 1:2 is perfect as to establish aGVHD murine model induced by allogeneic bone marrow transplantation for successoral experimental studies.
Object:To explore the influence of recipient-derived dendritic cells induced by different methods infused after allogeneic bone marrow transplantation (allo-BMT) on acute graft-versus-host disease (aGVHD) and hematopoietic reconstitution of mice.
Methods:Recipients were female BALB/c (H-2kd) mice, donors were male C57BL/6 (H-2kb) mice. Recipients'bone marrow cells were isolated sterilely. ImDCs were prepared by culturing BM cells with GM-CSF. IL-10-DCs were generated from BM cells cultured with GM-CSF and recombinant murine interleukin 10. PIR-B-DCs were obtained by Paired immunoglobin-like receptor B lentivirus transfected imDCs. The recipient mice were randomly divided into four groups, and received intravenous injections of various additional DCs from BALB/C mice (imDCs、IL-10-DCs、PIR-B-DCs) or PRMI 1640 at the time of BMS transplantation respectively. Incidence of GVHD, pathological lesion of liver、small intestine、skin, survival time and hematopoietic reconstitution in the recipients were observed after allo-BMT.
Result:The mean survival time of the four groups (PIR-B-DCs group, IL-10-DCs group, imDCs group and BMT group) was (46.0±13.6) days、(36.4±13.0) days、(21.6±2.8) days and (17.4±3.6) days, p<0.01. The GVHD clinical score at 15 days after transplantation in the four groups was (5.28±0.27)、(5.26±0.31)、(2.46± 0.18) and (0.86±0.21),P<0.05. Histopathologic analyses of BMT group showed extensive lymphocytic infiltration of the liver, small intestine and skin, bile duct damaged, intestinal villus atrophy or denaturation. Samples from the liver and skin of a mouse did not show clinical or histological signs of GVHD following the injection of PIR-B-DCs.
Conclusion:Recipient-derived paired immunoglobin-like receptor B lentivirus transfected dendritic cells infusion can mitigate the aGVHD so as to prolong survival time after allo-BMT in murine.
方法：将供者C57BL/6J (H-2b)雄性小鼠骨髓细胞和脾细胞按不同比例(1:1和1：2)混合,输入接受致死性全身照射(8.5Gy)的受鼠雌性BALB/C (H-2d)小鼠以引起不同程度的aGVHD,检测嵌合体情况,根据受鼠的一般情况、临床表现、生存期和组织病理学等判断aGVHD程度。
结果：混合不同比例的供鼠骨髓细胞和脾细胞allo-BMT的小鼠均发生了aGVHD,但出现aGVHD的时间和程度均有差异。其中骨髓与脾细胞1：2组小鼠可在相对集中的时间内观察到典型的aGVHDI临床和病理改变,所有小鼠均在14-24d死亡。骨髓与脾细胞1:1组aGVHD程度较轻,移植后4周小鼠均全部存活。
结论：骨髓细胞和脾细胞比例为1:2组比1:1组出现更典型的aGVHD,其发病和死亡时间较集中。选定TBI8.5Gy及细胞移植的混合比例(1:2)构建小鼠aGVHD模型,为后续实验提供理想模型。
目的：探讨不同方法诱导的受者来源树突状细胞(dendritic cells, DCs)输注对异基因骨髓移植(allogeneic bone marrow transplantation, allo-BMT)小鼠急性移植物抗宿主病(acut graft-versus-host disease,aGVHD)和造血重建的影响。
方法：受鼠为雌性BALB/C (H-2d)小鼠,供鼠为雄性C57BL/6J (H-2b)小鼠。无菌分离受鼠骨髓细胞(bone marrow cell, BMC),与GM-CSF共培养得到未成熟树突状细胞(immature dendritic cells, imDCs);受鼠BMC与GM-CSF、IL-10共培养得到IL-10-DCs;用配对性免疫球蛋白样受体B (Paired immunoglobin-like receptor B, PIR-B)慢病毒载体转染imDCs得到PIR-B-DCs。受鼠随机分为四组,在移植骨髓后分别予尾静脉注射imDCs、IL-10-DCs、PIR-B-DCs和RPMI1640培养液。以移植后aGVHD临床表现,肝脏、小肠、皮肤病理组织改变,生存期为观察指标并进行组间比较。
结果：PIR-B-DCs移植组、IL-10-DCs移植组、imDCs移植组和单纯移植组受鼠平均生存时间为(46.0±13.6)天、(36.4±13.0)天、(21.6±2.8)天和(17.4±3.6)天,p＜0.01；4组小鼠在移植后15天GVHD临床评分为(5.28±0.27)、(5.26±0.31)、(2.46±0.18)和(0.86±0.21),p<0.05。单纯移植组病理显示肝脏汇管区大量淋巴细胞浸润,小胆管塌陷破坏,皮肤基底层连续性中断,有大量淋巴细胞,肠粘膜下层淋巴细胞浸润,肠绒毛萎缩变性,PIR-B-DCs移植组病理组织检查仅有轻微GVHD表现。
结论：受者来源PIR-B-DCs联合骨髓移植能够明显延长受鼠生存时间,减轻移植后aGVHD反应,促进造血重建。
Object:To establish a murine model of acute graft-versus-host disease (aGVHD) induced by allogeneic bone marrow transplantation (allo-BMT) for providing experimental studies of aGVHD and transplantation tolerance.
Methods:All recipients female BALB/C (H-2d) mice were received total body irradiation 8.5Gy at 4 hours prior to transplantation. Bone marrow cells mixed with spleen cells of donors male C57BL/6J (H-2b) mice based upon different proportions (1:1 and 1:2) were injected into tail vein. The chimeras were evaluated as well as the recipients'survival time, clinical and pathologic manifestations of aGVHD.
Result:All mice received allo-BMT with different ratios of bone marrow cells and spleen cells showed aGVHD evidence. However, there were significant differences in the incidence and severity of aGVHD. The group with co-transplantation of bone marrow cells and spleen cells in ratio of 1:2 showed typical clinical and pathological manifestations of aGVHD at a relatively concentrated time, and died within 14-24d. Mice in group infused with bone marrow cells and spleen cells in ratio of 1:1 showed insignificant aGVHD, and were all alived (4 weeks after allo-BMT).
Conclusion:The group with co-transplantation of bone marrow cells and spleen cells in ratio of 1:2 showed more significant manifestations and more concentrated time of incident and death than the group that of 1:1. Thus, infusion of bone marrow cells and spleen cells in ration of 1:2 is perfect as to establish aGVHD murine model induced by allogeneic bone marrow transplantation for successoral experimental studies.
Object:To explore the influence of recipient-derived dendritic cells induced by different methods infused after allogeneic bone marrow transplantation (allo-BMT) on acute graft-versus-host disease (aGVHD) and hematopoietic reconstitution of mice.
Methods:Recipients were female BALB/c (H-2kd) mice, donors were male C57BL/6 (H-2kb) mice. Recipients'bone marrow cells were isolated sterilely. ImDCs were prepared by culturing BM cells with GM-CSF. IL-10-DCs were generated from BM cells cultured with GM-CSF and recombinant murine interleukin 10. PIR-B-DCs were obtained by Paired immunoglobin-like receptor B lentivirus transfected imDCs. The recipient mice were randomly divided into four groups, and received intravenous injections of various additional DCs from BALB/C mice (imDCs、IL-10-DCs、PIR-B-DCs) or PRMI 1640 at the time of BMS transplantation respectively. Incidence of GVHD, pathological lesion of liver、small intestine、skin, survival time and hematopoietic reconstitution in the recipients were observed after allo-BMT.
Result:The mean survival time of the four groups (PIR-B-DCs group, IL-10-DCs group, imDCs group and BMT group) was (46.0±13.6) days、(36.4±13.0) days、(21.6±2.8) days and (17.4±3.6) days, p<0.01. The GVHD clinical score at 15 days after transplantation in the four groups was (5.28±0.27)、(5.26±0.31)、(2.46± 0.18) and (0.86±0.21),P<0.05. Histopathologic analyses of BMT group showed extensive lymphocytic infiltration of the liver, small intestine and skin, bile duct damaged, intestinal villus atrophy or denaturation. Samples from the liver and skin of a mouse did not show clinical or histological signs of GVHD following the injection of PIR-B-DCs.
Conclusion:Recipient-derived paired immunoglobin-like receptor B lentivirus transfected dendritic cells infusion can mitigate the aGVHD so as to prolong survival time after allo-BMT in murine.
引文
1. Ferrara JL, Levy R, Chao NJ. Pathophysiologic mechanisms of acute graft-versus-host disease. Bio Blood Marrow Transplant,1999,5(6):347-356.
2. Antin JH, Ferrara JL. Cytokine dysregulation and acute graft-versus-host disease. Blood,1992,8:2964-2968.
3. Narita M, Takahashi M, Liu A, et al. Generation of dendritic cells from leukaemia cells of a patient with acute promyelocytic leukaemia by culture with GM-CSF, IL-4 and TNF-alpha. Acta Haematol,2001,106:89-94.
4. Tiurbe G, Matuschek A, Kammerer U, et al. Inhibitory effects of rat bone marrow-derived dendritic cells on naive and alloantigen-specific CD4+T cells:a com parison between dendritic cells generated with GM-CSF plus IL-4 and dendritic cells generated with GM-CSF plus IL-10. BMC Res Notes,2009,23,2:12.
5. Chang CC, Ciubotariu R, Manavalan JS, et al. Tolerization of dendritic cells by T(S) cells:the crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol,2002,3: 237-243.
6. Manavalan JS, Rossi PC, Vlad G, et al. High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells. Transpl Immunol,2003,11:245-258.
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11. Liu J, Liu Z, Witkowski P, et al. Rat CD8+ FOXP3+T suppressor cells mediate tolerance to allogeneic heart transplants, inducing PIR-B in APC and rendering the graft invulnerable to rejection. Transpl Immunol,2004,13:239-247.
12. Samaridis J, M Colonna. Cloning of novel immunoglobulin superfamily expressed on human myeloid and lymphoid cells:structural evidence for new stimulatory and inhibitory pathways. Eur J Immunol,1997,27:660-665.
13. Blery M, H Kubugawa, C Chen, et al. The paired lg-like receptor PIR-B is an inhibitory receptor that recruits the protein-tyrosine phosphatase SHP-1. Proc Natl Acad Sd USA, 1998,95:2446-2451.
14. Masuda A, N A, M Tsut, et al. Cis binding between inhibitory receptors and MHC class can regulate mast cell activation. JEM,2007,4:907-920.
15. Liu Z, Li W, Zhang M, et al. Paired Immunoglobin-like Peceptors A and B Are New Targets for Inducing Dendritic Cells Tolerance in Mice. J Huazhong Univ Sci Technolog Med Sci,2007,27(3):252-256.
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17. Frankel AD, Young JA. HIV-1:fifteen proteins and an RNA. Annu Rev Bio chem,1998, 67:1-25.
18.刘峥嵘,张敏,黎纬明等。IL-10诱导小鼠树突状细胞耐受的分子机制。中国病理生理杂志,2008,24(2)：373-378。
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1. Ferrara JL, Levy R, Chao NJ. Pathophysiologic mechanisms of acute graft-versus-host disease. Bio Blood Marrow Transplant,1999,5(6):347-356.
2. Antin JH, Ferrara JL. Cytokine dysregulation and acute graft-versus-host disease. Blood,1992,8:2964-2968.
3. Narita M, Takahashi M, Liu A, et al. Generation of dendritic cells from leukaemia cells of a patient with acute promyelocytic leukaemia by culture with GM-CSF, IL-4 and TNF-alpha. Acta Haematol,2001,106:89-94.
4. Tiurbe G, Matuschek A, Kammerer U, et al. Inhibitory effects of rat bone marrow-derived dendritic cells on naive and alloantigen-specific CD4+T cells:a com parison between dendritic cells generated with GM-CSF plus IL-4 and dendritic cells generated with GM-CSF plus IL-10. BMC Res Notes,2009,23,2:12.
5. Chang CC, Ciubotariu R, Manavalan JS, et al. Tolerization of dendritic cells by T(S) cells:the crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol,2002,3: 237-243.
6. Manavalan JS, Rossi PC, Vlad G, et al. High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells. Transpl Immunol,2003,11:245-258.
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14. Samaridis J, M Colonna. Cloning of novel immunoglobulin superfamily expressed on human myeloid and lymphoid cells:structural evidence for new stimulatory and inhibitory pathways. Eur J Immunol,1997,27:660-665.
15. Blery M, H Kubugawa, C Chen, et al. The paired lg-like receptor PIR-B is an inhibitory receptor that recruits the protein-tyrosine phosphatase SHP-1. Proc Natl Acad Sd USA, 1998,95:2446-2451.
16. Masuda A, N A, M Tsut, et al. Cis binding between inhibitory receptors and MHC class can regulate mast cell activation. JEM,2007,4:907-920.
17. Liu Z, Li W, Zhang M, et al. Paired Immunoglobin-like Peceptors A and B Are New Targets for Inducing Dendritic Cells Tolerance in Mice. J Huazhong Univ Sci Technolog Med Sci,2007,27(3):252-256.
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20.刘峥嵘,张敏,黎纬明等。IL-10诱导小鼠树突状细胞耐受的分子机制。中国病理生理杂志,2008,24(2)：373-378。
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