免疫抑制剂对Fractalkine及CX3CR1在慢性移植肾肾病中表达影响的研究
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摘要
目的了解不同免疫抑制剂对Fractalkine及其受体CX3CR1在慢性移植肾肾病(Chronic allograft nephropathy，CAN)中表达的影响及其临床意义。
方法1．建立SD→Wistar大鼠强化缺血再灌注损伤CAN加快模型。实验分为6组：假手术组、对照组(CsA 10mg·kg~(-1)·d~(-1)×10d)、CsA组(6mg·kg~(-1)·d~(-1))、FK506组(0.15mg·kg~(-1)·d~(-1))、MMF组(20mg·kg~(-1)·d~(-10)、RAPA组(0.8 mg·kg~(-1)·d~(-1))，每组各时间点动物均为8只。分别于术后4w、8w及12w时处死实验动物。除假手术组外，其它各组动物均于肾移植后当天即开始使用CsA10mg·kg~(-1)·d~(-1)×10d，以避免急性排异反应，10d后各实验组使用相应的免疫抑制剂进行干预处理。2．采用免疫组织化学和实时荧光定量PCR法检测Fractalkine及CX3CR1的蛋白和mRNA在移植肾中的定位及其表达情况。
结果 免疫组织化学结果显示，Fractalkine、CX3CR1主要表达于肾小管上皮细胞的胞膜和肾小管间质，部分见于间质血管，偶见于肾小球壁层细胞。术后4w、8w及12w的移植肾标本中，对照组Fractalkine、CX3CR1的mRNA和蛋白表达均高于假手术组，差异有显著性。CsA组和FK506
Objective Some recent studies have suggested that Fractalkine/CX3CR1 system may contribute to the pathogenesis of vascular and tissue injury in chronic allograft nephropathy (CAN). It is still unknown of the influence of different immunosuppresants on expression of Fractalkine/CX3CR1 in CAN. This study is to investigate what role Fractalkine/CX3CR1 play in CAN and whether there are different effects among different immunosuppresants on expression of Fractalkine/CX3CR1 in CAN.
Methods The SD→Wistar rat accelerated kidney sclerosis model was performed following the procedure of Kamada with our modification. Before the transplantation, the kidney was preserved one hour in 0-4℃ heparin sodium chloride solution for reinforcement of the injury of cold ischemia. The recipient rats were divided into 6 groups (each group n=8). Group A: pseudo-operation group; Group B (control group ): CsA 10mg·kg~(-1)·d~(-1)×10d, followed by vehicle; Group C: CsA emg·kg~(-1)·d~(-1); Group D:FK506 0.15 mg·kg~(-1)·d~(-1) Group E: MMF 20 mg·kg~(-1)·d~(-1) Group F: RAPA 0.8mh·kg~(-1)·d~(-1)
方法1．建立SD→Wistar大鼠强化缺血再灌注损伤CAN加快模型。实验分为6组：假手术组、对照组(CsA 10mg·kg~(-1)·d~(-1)×10d)、CsA组(6mg·kg~(-1)·d~(-1))、FK506组(0.15mg·kg~(-1)·d~(-1))、MMF组(20mg·kg~(-1)·d~(-10)、RAPA组(0.8 mg·kg~(-1)·d~(-1))，每组各时间点动物均为8只。分别于术后4w、8w及12w时处死实验动物。除假手术组外，其它各组动物均于肾移植后当天即开始使用CsA10mg·kg~(-1)·d~(-1)×10d，以避免急性排异反应，10d后各实验组使用相应的免疫抑制剂进行干预处理。2．采用免疫组织化学和实时荧光定量PCR法检测Fractalkine及CX3CR1的蛋白和mRNA在移植肾中的定位及其表达情况。
结果 免疫组织化学结果显示，Fractalkine、CX3CR1主要表达于肾小管上皮细胞的胞膜和肾小管间质，部分见于间质血管，偶见于肾小球壁层细胞。术后4w、8w及12w的移植肾标本中，对照组Fractalkine、CX3CR1的mRNA和蛋白表达均高于假手术组，差异有显著性。CsA组和FK506
Objective Some recent studies have suggested that Fractalkine/CX3CR1 system may contribute to the pathogenesis of vascular and tissue injury in chronic allograft nephropathy (CAN). It is still unknown of the influence of different immunosuppresants on expression of Fractalkine/CX3CR1 in CAN. This study is to investigate what role Fractalkine/CX3CR1 play in CAN and whether there are different effects among different immunosuppresants on expression of Fractalkine/CX3CR1 in CAN.
Methods The SD→Wistar rat accelerated kidney sclerosis model was performed following the procedure of Kamada with our modification. Before the transplantation, the kidney was preserved one hour in 0-4℃ heparin sodium chloride solution for reinforcement of the injury of cold ischemia. The recipient rats were divided into 6 groups (each group n=8). Group A: pseudo-operation group; Group B (control group ): CsA 10mg·kg~(-1)·d~(-1)×10d, followed by vehicle; Group C: CsA emg·kg~(-1)·d~(-1); Group D:FK506 0.15 mg·kg~(-1)·d~(-1) Group E: MMF 20 mg·kg~(-1)·d~(-1) Group F: RAPA 0.8mh·kg~(-1)·d~(-1)
引文
1. Solez K, Benediktsson H, Cavallo T, et al. Report of the Third Banff Conference on Allograft Pathology (July 20-24, 1995) on classification and lesion scoring in renal allograft pathology. Transplant Proc 1996 Feb; 28(1): 441-4.
2. Freese P, Svalander CT, Molne J, et al. Chronic allograft nephropathy: biopsy findings and outcome. Nephrol Dial Transplant 2001 Dec; 16(12): 2401-2406.
3. Paul LC. Chronic allograft nephropathy: an update. Kidney Int 1999; 56:783-793.
4. Bazan JF, Bacon KB, Hardiman G, et al. A new class of membrane-bound chemokine with a CX3C motif. Nature 1997; 385: 640-644.
5．辛宇鹏，卢一平，张秀辉等．大鼠原位异体肾移植硬化加快模型的建立．四川大学学报(医学版)2004；35(2)：267．
6. Kamada NA.Description of cuff techniques for renal transplantation in the rat. Transplantation 1985; 39(1): 93.
7．金冬雁，黎孟枫，译．分子克隆实验指南[M]．第二版，北京：科技出版社 1995：343．
8. Lorranine C, Racusen RT, Solezk P, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55:713-723.
9. Racusen LC, Solez K, Colvin R. Fibrosis and atrophy in the renal allograft: interim report and new directions. Am J Transp lant 2002;2(3):203-206.
10. Vazquez MA. Chronic rejection of renal transplants: new clinical insights. Am J Med Sci 2000;320:43-58.
11．贾瑞鹏，季曙明．移植肾纤维化的分子机制研究．肾脏病与透析肾移植 杂志 2003; 12 (5): 485-489.
12. Scherer A, Krause A, Walker JR , et al. Early prognosis of the development of renal chronic allograft rejection by gene expression profiling of human protocol biopsies. Transplantation 2003;75 :1323-1330.
13. Bazan JF, Bacon KB, Hanliman G, et al. A new class of membrane-bound chemokine with a CX3 2 motif. Narture 1997;385:64.
14. Foussat A, Coulomb-L'hermine A, Gosling J, et al. Fractalkine receptor expression by T lymphocyte subpopulations and in vivo production of fractalkine in human. Eur J Immunol 2000;30:87-97.
15. Chapman GA, Moores KE, Gohil J, et al. The role of fractalkine in the recruitment of monocytes to the endothelium. Eur J Pharmacol 2000; 392:189-95.
16. Fraticelli P, Sironi M, Bianchi G, et al. Fractalkine (CX3CL1) as an amplification circuit of polarized Th1 responses. J Clin Invest 2001;107:1173-1181.
17. Goda S, Imai T, Yoshie O, et al. CX3C-chemokine, fractalkine-enhanced adhesion of THP-1 cells to endothelial cells through integrin-dependent and - independent mechanisms. J Immunol 2000; 164:4313-4320.
18. Yoneda O, Imai T, Goda S, et al. Fractalkine-mediated endothelial cell injury by NK cells. J Immunol 2000; 164:4055-62.
19. Combadiere C, Salzwedel K, Smith ED, et al. Identification of CX3CR1. A chemotactic receptor for the human CX3C chemokine fractalkine and a fusion coreceptor for HIV-1. J Biol Chem 1998; 273:23799-23804.
20. Imai T, Hieshima K, Haskell C, et al. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 1997;91:521—530.
21. Umehara H, Bloom ET, Okazaki T, et al. Fractalkine in Vascular Biology: From Basic Research to Clinical Disease. J American Heart Association 2004;24(1): 34-40.
22. Nishimura M, Umehara H, Nakayama T, et al. Dual functions of fractalkine/CX3CR1 in trafficking of circulating cytotoxic effector lymphocytes that are defined by CX3CR1 expression. J Immunol 2002; 168:6173-6180.
23. Yoneda O, Imai T, Gouda S, et al. NK cell-mediated vascular injury. J Immunol 2000; 164: 4055-4062.
24. Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21: 1876-1890.
25. Moatti D, Faure S, Fumeron F, et al. Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease. Blood 2001; 97: 1925-1928.
26. MacDermott DH, Halcox JPJ, Schenke WH, et al. Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ Res 2001; 89: 401-407.
27. Kledal TN, Rosenkilde MM, Schwartz TW. Selective recognition of the membrane-bound CX3C chemokine, fractalkine, by the human cytomegalovirus-encoded broad-spectrum receptor US28. FEBS Lett 1998; 441:209-214.
28. Casarosa P, Bakker RA, Verzijl D, et al. Constitutive signaling of the human cytomegalovirus-encoded chemokine receptor US28. J Biol Chem 2001; 276:1133 - 1137.
29. Robinson LA, Nataraj C, Thomas DW, et al. A role for Fractalkine and its receptor (CX3CR1) in cardiac allograft rejection. J Immunol 2000; 165: 6067-6072.
30. Haskell C, Hancock WW, Salant DJ, et al. Targeted deletion of CX3CR1 reveals a role for Fractalkine in cardiac allograft rejection. J Clin Invest 2001;108: 679-688.
31. Chakravorty SJ, Cockwell P, Girdlestone J, et al. Fractalkine expression on human renal tubular epithelial cells: potential role in mononuclear cell adhesion. Clin Exp Immunol 2002; 129:150-159.
32. Cockwell P, Chakravorty SJ, Girdlestone J, et al. Fractalkine expression in human renal inflammation. J Pathol 2002;196:85.
33. Zhang JG, Wedmsley MN, Mon JV, et al. Differential effects of CsA and tacrolimus on the production of TGF- 3 implication for development of obliteractive bronchiolitis after lung transplantation. Transplant Int 1998;11:325—327.
34. Baboolal K, Jones GA, Janezic A, et al. Molecular and structural consequences of early renal allograft injury. Kidney Int 2002 Feb; 61(2): 686-696.
35. Weir MR, Ward MT, Blahut SA, et al. Long-term impact of discontinued or reduced calcineurin inhibitor in patients with chronic allograft nephropathy. Kidney Int 2001 Apr; 59(4): 1567-73.
36. Burdmann EA, Andoh TF, Nast CC, et al. Prevention of experimental cyclosporin-induced interstitial fibrosis by losartan and enalapril. Am J Physiol 1995 Oct; 269(4 Pt 2): F491-499.
37. Young BA, Burdmann EA, Johnson RJ, et al. Cellular proliferation and macrophage influx precede interstitial fibrosis in cyclosporine nephrotoxicity. Kidney Int 1995 Aug; 48(2): 439-48.
38．谷峰，郭广宏，田亚平等．肾移植患者服用药物FK506后血清细胞因子及生化指标的变化．解放军药学学报2005；21(3)：178-181．
39. Blaheta RA, Leckel K, Wittig B, et al. Mycophenolate mofetil impairs transendothelial migration of allogeneic CD4 and CD8 T-cells. Transplant Proc 1999; 31: 1250.
40. Laurent AF, Dumont S, Poindron P, et al. Mycophenolic acid suppresses protein N-linked glycosylation in human monocytes and their adhesion to endothelial cells and to some substrates. Exp Hematol 1996; 24: 59.
41. Glomsda BA, Blaheta RA, Hailer NP. Inhibition of monocyte/endothelial cell interactions and monocyte adhesion molecule expression by the immunosuppressant mycophenolate mofetil. Spinal Cord 2003; 41: 610.
42. Heemann U, Azuma H, Hamar P, et al. Mycophenolate mofetil inhibits lymphocyte binding and the upregulation of adhesion molecules in acute rejection of rat kidney allografts. Transpl Immunol 1996; 4: 64.
43. Zohlnhofer D, Nuhrenberg TG, Neumann FJ, et al. Rapamycin effects transcriptional programs in smooth muscle cells controlling proliferative and inflammatory properties. Mol Pharmacol 2004; 65(4):880-889.
44. Ruiz JC, Campistol JM, Mota A, et al. Early elimination of cyclosporine in kidney transplant recipients receiving sirolimus prevents progression of chronic pathologic allograft lesions. Transplant Proc 2003;35(5): 1669-1670.
45. Dominguez J, Mahalati K, Kiberd B, et al. Conversion to rapamycin immunosuppression in renal transplant recipients: report of aninitial experience. Transplantation 2000;70 (8): 1244-1247.
46. Feng L, Chen S, Garcia GE,et al.Prevention of crescent glomerulonephritis by immunoneutralization of the Fractalkine receptor CX3CR1. Kidney Int 1999; 56: 612-620.
1. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity 2000; 12: 121-127.
2. Nomiyama H, Imai T, Kusuda J, et al. Human chemokines fractalkine (SCYD1), MDC(SCYA22) and TARC(SCYA17) are clustered on chuomosome 16q13. Cytogenet Cell Genet 1998;81(1): 10-11.
3. Bazan JF, Bacon KB, Hardiman G, et al. A new class of membrane-bound chemokine with a CX3C motif. Nature 1997; 385: 640-644.
4. Raport CJ, Schweickart VL, Eddy RL Jr. et al. The orphan G-protein- coupled receptor-encoding gene V28 is closely related to genes for chemokine receptors and is expressed in lymphoid and neural tissues. Gene 1995;163(2):295-299.
5. Combadiere C, Salzwedel K, Smith ED. et al Identification of CX3CR1.A chemotactic receptor for the human CX3C Chemokine fractalkine and a fusion coreceptor for HIV-1.J Biol Chem 1998;273(37):23799-23804.
6. MacDermott DH, Halcox JPJ, Schenke WH, et al. Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ Res 2001; 89: 401-407.
7. Imai T, Hieshima K, Haskell C, et al. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. J Cell 1997;91(4):521-530.
8. Umehara H, Bloom ET, Okazaki T, et al. Fractalkine in Vascular Biology: From Basic Research to Clinical Disease. J American Heart Association 2004;24(1): 34-40.
9. Kourilsky P, Truffa-Bachi P. Cytokine fields and the polarization of the immune response. Trends Immunol 2001; 22: 502-509.
10. Fraticelli P, Sironi M, Bianchi G et al. Fractalkine (CX3CL1) as an amplification circuit of polarized Th1 responses. J Clin Invest 2001; 107: 1173-1181.
11. Cambien B, Pomeranz M, Schmid Antomarchi H, et al, Signal transduction pathways involved in soluble fractalkine induced monocytic cell adhesion. Blood 2001; 97(7):2031-2037.
12. Al-Aoukaty A, Rolstad B, Giaid A, et al. MIP-alpha, MIP-3beta and fractalkine induce the locomotion and the mobilization of intracellular calcium, and activate the heterotrimeric G proteins in human natural killer cells. Immunology 1998;95(4):618-624.
13. Yoneda O, Imai T, Gouda S, et al. NK cell-mediated vascular injury. J Immunol 2000; 164: 4055-4062.
14. Yoneda O, Imai T, Inoue H, et al. Membrane bound form of fractalkine induces IFN-[gamma] production by NK cells: a role for Thl response. Eur J Immunol 2003; 33: 53-58.
15．顾晓，唐孝达，顾沈阳等。急性排斥反应时Fractalkine及其受体在移植心脏中的表达。中华外科杂志2003；41(2)：139-142．
16. Cockwell P, Chakravorty SJ, Girdlestone J, et al. Fractalkine expression in human renal inflammation. Pathology 2002; 196(1):85-90.
17. Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21: 1876-1890.
18. Combadiere C, Potteaux S, Gao J-L, et al. Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice. Circulation 2003; 107: 1009-1016.
19. Moatti D, Faure S, Fumeron F, et al. Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease. Blood 2001; 97: 1925-1928.
20. MacDermott DH, Halcox JPJ, Schenke WH, et al. Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ Res 2001; 89: 401-407.
21. Kledal TN, Rosenkilde MM, Schwartz TW. Selective recognition of the membrane-bound CX3C chemokine, fractalkine, by the human cytomegalovirus-encoded broad-spectrum receptor US28. FEBS Lett 1998; 441:209-214.
22. Casarosa P, Bakker RA, Verzijl D, et al. Constitutive signaling of the human cytomegalovirus-encoded chemokine receptor US28. J Biol Chem 2001; 276:1133-1137.
23. Foxman EF, Campbell JJ, Butcher EC. Multistep navigation and the combinatorial control of leukocyte chemotaxis. J Cell Boil 1997; 139(5): 1349-1360.
24. Robinson LA, Nataraj C, Thomas DW, et al. A role for fractalkine and its receptor (CX3CR1) in cardiac allograft rejection. J Immunol 2000; 165: 6067-6072.
25. Haskell C, Hancock WW, Salant DJ, et al. Targeted deletion of CX3CR1 reveals a role for fractalkine in cardiac allograft rejection. J Clin Invest 2001; 108: 679-688.
2. Freese P, Svalander CT, Molne J, et al. Chronic allograft nephropathy: biopsy findings and outcome. Nephrol Dial Transplant 2001 Dec; 16(12): 2401-2406.
3. Paul LC. Chronic allograft nephropathy: an update. Kidney Int 1999; 56:783-793.
4. Bazan JF, Bacon KB, Hardiman G, et al. A new class of membrane-bound chemokine with a CX3C motif. Nature 1997; 385: 640-644.
5．辛宇鹏，卢一平，张秀辉等．大鼠原位异体肾移植硬化加快模型的建立．四川大学学报(医学版)2004；35(2)：267．
6. Kamada NA.Description of cuff techniques for renal transplantation in the rat. Transplantation 1985; 39(1): 93.
7．金冬雁，黎孟枫，译．分子克隆实验指南[M]．第二版，北京：科技出版社 1995：343．
8. Lorranine C, Racusen RT, Solezk P, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55:713-723.
9. Racusen LC, Solez K, Colvin R. Fibrosis and atrophy in the renal allograft: interim report and new directions. Am J Transp lant 2002;2(3):203-206.
10. Vazquez MA. Chronic rejection of renal transplants: new clinical insights. Am J Med Sci 2000;320:43-58.
11．贾瑞鹏，季曙明．移植肾纤维化的分子机制研究．肾脏病与透析肾移植 杂志 2003; 12 (5): 485-489.
12. Scherer A, Krause A, Walker JR , et al. Early prognosis of the development of renal chronic allograft rejection by gene expression profiling of human protocol biopsies. Transplantation 2003;75 :1323-1330.
13. Bazan JF, Bacon KB, Hanliman G, et al. A new class of membrane-bound chemokine with a CX3 2 motif. Narture 1997;385:64.
14. Foussat A, Coulomb-L'hermine A, Gosling J, et al. Fractalkine receptor expression by T lymphocyte subpopulations and in vivo production of fractalkine in human. Eur J Immunol 2000;30:87-97.
15. Chapman GA, Moores KE, Gohil J, et al. The role of fractalkine in the recruitment of monocytes to the endothelium. Eur J Pharmacol 2000; 392:189-95.
16. Fraticelli P, Sironi M, Bianchi G, et al. Fractalkine (CX3CL1) as an amplification circuit of polarized Th1 responses. J Clin Invest 2001;107:1173-1181.
17. Goda S, Imai T, Yoshie O, et al. CX3C-chemokine, fractalkine-enhanced adhesion of THP-1 cells to endothelial cells through integrin-dependent and - independent mechanisms. J Immunol 2000; 164:4313-4320.
18. Yoneda O, Imai T, Goda S, et al. Fractalkine-mediated endothelial cell injury by NK cells. J Immunol 2000; 164:4055-62.
19. Combadiere C, Salzwedel K, Smith ED, et al. Identification of CX3CR1. A chemotactic receptor for the human CX3C chemokine fractalkine and a fusion coreceptor for HIV-1. J Biol Chem 1998; 273:23799-23804.
20. Imai T, Hieshima K, Haskell C, et al. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 1997;91:521—530.
21. Umehara H, Bloom ET, Okazaki T, et al. Fractalkine in Vascular Biology: From Basic Research to Clinical Disease. J American Heart Association 2004;24(1): 34-40.
22. Nishimura M, Umehara H, Nakayama T, et al. Dual functions of fractalkine/CX3CR1 in trafficking of circulating cytotoxic effector lymphocytes that are defined by CX3CR1 expression. J Immunol 2002; 168:6173-6180.
23. Yoneda O, Imai T, Gouda S, et al. NK cell-mediated vascular injury. J Immunol 2000; 164: 4055-4062.
24. Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21: 1876-1890.
25. Moatti D, Faure S, Fumeron F, et al. Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease. Blood 2001; 97: 1925-1928.
26. MacDermott DH, Halcox JPJ, Schenke WH, et al. Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ Res 2001; 89: 401-407.
27. Kledal TN, Rosenkilde MM, Schwartz TW. Selective recognition of the membrane-bound CX3C chemokine, fractalkine, by the human cytomegalovirus-encoded broad-spectrum receptor US28. FEBS Lett 1998; 441:209-214.
28. Casarosa P, Bakker RA, Verzijl D, et al. Constitutive signaling of the human cytomegalovirus-encoded chemokine receptor US28. J Biol Chem 2001; 276:1133 - 1137.
29. Robinson LA, Nataraj C, Thomas DW, et al. A role for Fractalkine and its receptor (CX3CR1) in cardiac allograft rejection. J Immunol 2000; 165: 6067-6072.
30. Haskell C, Hancock WW, Salant DJ, et al. Targeted deletion of CX3CR1 reveals a role for Fractalkine in cardiac allograft rejection. J Clin Invest 2001;108: 679-688.
31. Chakravorty SJ, Cockwell P, Girdlestone J, et al. Fractalkine expression on human renal tubular epithelial cells: potential role in mononuclear cell adhesion. Clin Exp Immunol 2002; 129:150-159.
32. Cockwell P, Chakravorty SJ, Girdlestone J, et al. Fractalkine expression in human renal inflammation. J Pathol 2002;196:85.
33. Zhang JG, Wedmsley MN, Mon JV, et al. Differential effects of CsA and tacrolimus on the production of TGF- 3 implication for development of obliteractive bronchiolitis after lung transplantation. Transplant Int 1998;11:325—327.
34. Baboolal K, Jones GA, Janezic A, et al. Molecular and structural consequences of early renal allograft injury. Kidney Int 2002 Feb; 61(2): 686-696.
35. Weir MR, Ward MT, Blahut SA, et al. Long-term impact of discontinued or reduced calcineurin inhibitor in patients with chronic allograft nephropathy. Kidney Int 2001 Apr; 59(4): 1567-73.
36. Burdmann EA, Andoh TF, Nast CC, et al. Prevention of experimental cyclosporin-induced interstitial fibrosis by losartan and enalapril. Am J Physiol 1995 Oct; 269(4 Pt 2): F491-499.
37. Young BA, Burdmann EA, Johnson RJ, et al. Cellular proliferation and macrophage influx precede interstitial fibrosis in cyclosporine nephrotoxicity. Kidney Int 1995 Aug; 48(2): 439-48.
38．谷峰，郭广宏，田亚平等．肾移植患者服用药物FK506后血清细胞因子及生化指标的变化．解放军药学学报2005；21(3)：178-181．
39. Blaheta RA, Leckel K, Wittig B, et al. Mycophenolate mofetil impairs transendothelial migration of allogeneic CD4 and CD8 T-cells. Transplant Proc 1999; 31: 1250.
40. Laurent AF, Dumont S, Poindron P, et al. Mycophenolic acid suppresses protein N-linked glycosylation in human monocytes and their adhesion to endothelial cells and to some substrates. Exp Hematol 1996; 24: 59.
41. Glomsda BA, Blaheta RA, Hailer NP. Inhibition of monocyte/endothelial cell interactions and monocyte adhesion molecule expression by the immunosuppressant mycophenolate mofetil. Spinal Cord 2003; 41: 610.
42. Heemann U, Azuma H, Hamar P, et al. Mycophenolate mofetil inhibits lymphocyte binding and the upregulation of adhesion molecules in acute rejection of rat kidney allografts. Transpl Immunol 1996; 4: 64.
43. Zohlnhofer D, Nuhrenberg TG, Neumann FJ, et al. Rapamycin effects transcriptional programs in smooth muscle cells controlling proliferative and inflammatory properties. Mol Pharmacol 2004; 65(4):880-889.
44. Ruiz JC, Campistol JM, Mota A, et al. Early elimination of cyclosporine in kidney transplant recipients receiving sirolimus prevents progression of chronic pathologic allograft lesions. Transplant Proc 2003;35(5): 1669-1670.
45. Dominguez J, Mahalati K, Kiberd B, et al. Conversion to rapamycin immunosuppression in renal transplant recipients: report of aninitial experience. Transplantation 2000;70 (8): 1244-1247.
46. Feng L, Chen S, Garcia GE,et al.Prevention of crescent glomerulonephritis by immunoneutralization of the Fractalkine receptor CX3CR1. Kidney Int 1999; 56: 612-620.
1. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity 2000; 12: 121-127.
2. Nomiyama H, Imai T, Kusuda J, et al. Human chemokines fractalkine (SCYD1), MDC(SCYA22) and TARC(SCYA17) are clustered on chuomosome 16q13. Cytogenet Cell Genet 1998;81(1): 10-11.
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